TRANSCRIPT

The disclosures for guests on this podcast can be found in the show notes.

Dr. Peter Li: Welcome to this episode of JCO Article Insights. I am Dr. Peter Li, JCO's Editorial Fellow, and today, I am joined by Dr. Jahanzaib Khwaja on a new validated staging system on AL amyloidosis with stage lllC defining ultra-poor risk, AL International Staging System. This is a simultaneous publication that will be presented at this year's ASH Conference. 

At the time of this recording, our guest has disclosures that will be linked in the transcript. 

So, Dr. Khwaja, let's start off first: What would you say is the significance of your study?

Dr. Jahanzaib Khwaja: Thank you very much. This is an important study in that, in the current treatment era, we have really improved outcomes of patients with systemic AL amyloidosis. Traditionally, the staging systems that have been employed, which are the Mayo 2012 and the European modification 2016, have been founded in eras where there were historic treatment protocols.

So the significance of this new staging system is looking at outcomes of patients in the modern treatment era. That is patients who are treated with daratumumab-based treatments in the first line. And this is kind of the largest study which is externally validating a new prognostic model in the current treatment era with modern outcomes.

Dr. Peter Li: Can you tell our listeners what is different about your new staging system?

Dr. Jahanzaib Khwaja: The traditional staging systems, the Mayo 2012 and the European modification of 2016, looked at outcomes of patients with systemic AL amyloidosis with historic treatment protocols. And we know that they looked at outcomes according to an NT-proBNP and troponin, and in the Mayo 2012, they looked at it with the addition of the dFLC, which is the difference in the involved and uninvolved free light chain.

Over the years, we have seen that outcomes have improved, and over decades, actually, outcomes are much better when we compare them to the previous decade. If we look at current treatment approaches, those traditional staging systems inadequately determine the poorest prognostic risk. So they are unable to tell us those who are going to perform poorly.

Our current new validated staging system looks at the traditional NT-proBNP and troponin but uses the addition of the longitudinal strain. This is an echocardiographic parameter, and it is used widely in treatment centers who treat amyloidosis. This really identifies those ultra-high risk patients, and these are the patients who will perform poorly in current treatment protocols.

And why is that important? Well, we need a robust staging system in the current treatment era which can stratify patients who will do well but also stratify those patients who do not do well. Because that is important for counseling patients, for risk stratification, for treatment approaches, and in the future, for designing clinical trials.

Dr. Peter Li: And that is referring to the longitudinal strain greater than  -9% and NT-proBNP greater than 8,500 and then the high-sensitivity troponins greater than 50, which will define the new staging system. Can you talk more about how you picked these cutoffs and also what that alludes to in terms of the outcomes that you have discovered in this age of daratumumab-based therapy?

Dr. Jahanzaib Khwaja: Yeah, that is a really excellent question because we have aimed to build upon traditional staging systems. So clinicians have used these traditional models for many, many years, and they have robustly underpinned our stratification of patients and how we counsel patients. So we didn't want to change some of these well-established thresholds, but we wanted to test them in the current treatment era. So the NT-proBNP of 8,500 and the high-sensitivity troponin of 50 were the traditionally used thresholds. And they actually stand the test of time.

But we found that longitudinal strain additionally and independently predicts outcome independent of these other biomarkers. It is independent actually as a continuous variable, so you can cut this at a number of different stratification points and find independence. But we wanted to determine and discriminate those with the poorest outcomes. So we validated a longitudinal strain threshold of greater than  -9% by deriving this from a dataset of patients with the traditionally highest risk. Those are with European stage lllB. And looked at the optimal threshold with time-dependent ROC analysis.

So we did this in our derivation cohort and then validated this externally in our external validation cohort amongst a number of centers in Europe, in the US, and in the UK. And it is important to note because longitudinal strain is an echocardiographic parameter, and traditionally the limitations are considered to be inter-vendor and inter-operator variability and intra-operator variability, and there are challenges with reproducibility of some of these measurements. So that is often cited as a limitation. But we found, when we have externally validated this across different centers using different platforms, actually the threshold of -9% is independently predictive of poorer outcomes independent of the traditional NT-proBNP and troponin thresholds, and it is robustly predictive of poorest outcomes.

We know that those with stage lllC have a median overall survival of 4 to 7 months in the modern treatment era. And if we sub-stratify these by patients treated with daratumumab, outcomes have improved, but still, even if we look at daratumumab-treated patients, one-year overall survival is still only around 50 percent. So these are a poor risk group in the modern treatment era.

Dr. Peter Li: Which kind of makes sense in a way because this kind of predicts whether they have amyloid-related cardiomyopathy. So I think this all tracks with our listeners. But given the poor outcomes even with daratumumab-based therapies, do you think this new staging system would change practice, if at all?

Dr. Jahanzaib Khwaja: Yeah, I think that is a really good point because I think it comes to the question of why we use a staging system. What are its applications? I think one of the key things we think about in the clinic is how do we counsel patients when we first talk to them about their diagnosis. So there is a lot of information, but predominantly people want to know, what is my outlook going to look like?

And as I say, in the bortezomib treatment era, 2010 to 2020, we used to say you have stage lllB, you have very poor outcomes, median survival maybe around six months. We have shown here that actually those with lllB have much better outcomes definitely over 12 months, up to 24 months in those with daratumumab-based therapies. So we need to counsel them in a different way.

We then also need to say, "Well, who are the ultra-high risk?" So we said those with the longitudinal strain of greater than -9% with the traditional NT-proBNP and troponin cutoffs. And those patients will have poor outcomes. We need to talk about palliation. We need to talk about alternate treatment approaches.

And then importantly for the community is about treatment and clinical trial design. So again, traditionally the traditional high-risk group lllB used to be considered an exclusion for all major trials. So these were excluded in the ANDROMEDA study, which led to the approval of daratumumab-based therapy, and multiple other trials. And we show here that actually patients with lllB should not be excluded from these studies because they do have good outcomes.

And I think we make the important point that those with lllC, who do have poor outcomes, they need a different treatment approach, and we need to think about stratifying these patients differently. So perhaps the next modality of treatment will be the anti-fibril antibodies or a mode of treatment which can clear antibodies or clear the amyloid fibrils from the organs and reduce the organ toxicity early on.

We know that those with lllC have poor outcomes particularly within the first year, and organ dysfunction really predominates here. So a different treatment approach is required, and we need to design trials specifically for these patients which look beyond anti-plasma cell clone therapy but also look at clearing the amyloid fibrils and improving organ function as this is predominantly the cause of death in these patients.

Dr. Peter Li: That's an excellent point right there. 

Do you foresee any limitations to this new staging system, or can you comment on is there potentially a better way to refine this staging criteria in the future?

Dr. Jahanzaib Khwaja: Yeah, I think that is a really excellent point to consider, that staging systems always need refining across treatment eras. So we have looked at the bortezomib era, and then we have validated this in the daratumumab-based era. We know that amongst different countries access to treatment varies. We know that there are a number of factors which determine your health-related outcomes. That's access to healthcare, speed of diagnosis, access to tertiary diagnostics, ability to biopsy, and then supportive care.

And I think our staging system highlights the importance of organ dysfunction predominantly causing death early on. And I think that as treatments improve this should be refined. So the expectation I think is, as we have better anti-plasma cell directed therapies, and as we hopefully develop anti-fibril antibodies and anti-fibril clearance drugs, that we will need to revalidate new models to effectively prognosticate in this treatment era.

And I also think that as we become a bit more sophisticated with our approaches, we know that this can be refined in the future looking at other prognostic factors with regards to healthcare outcomes. I would say one of the strengths, however, of this model is that it builds on the traditional model, and it's quite simple to use. You just have the NT-proBNP and the troponin, and then longitudinal strain, which is used quite frequently in amyloid centers, and an echocardiogram is used in essentially all patients for diagnosis. So I think it will certainly be quite practical.

But certainly I think, as you say, as treatment approaches change over time, and as we have further options in the future, we will need to refine prognostication.

Dr. Peter Li: For the listeners out there, let's say someone comes in our clinic and we diagnose them with stage lllC amyloidosis. Can you comment on what clinical trials are out there that potentially they can refer their patients to? You mentioned anti-fibril therapy, which I think would be the way of the future. Can you kind of comment what you know at this current stage and point listeners in the right direction?

Dr. Jahanzaib Khwaja: This is the challenge in amyloidosis. We don't have specific trials that are looking at those with the highest risk. And at present, even the ISA International Guidelines talk about risk according to the old treatment approaches and discuss attenuating our current chemotherapy approaches. And I think that for clinicians out there who identify those at the highest risk, it is really important to have a multidisciplinary approach, to consider palliation and palliative services early, and really work with your fellow cardiologists and renal physicians and neurologists to enable the best supportive care you have in order to deliver this anti-plasma cell directed therapy.

We know that actually you only need for most patients small amounts of doses of chemotherapy to get good clonal responses, and we have seen that even in the bortezomib era that actually they have good CR rates and more impressive CR rates with daratumumab. But because of the organ dysfunction, it can be really challenging to deliver these doses. And supportive care is going to be really important particularly for these challenging patients.

The future will be designing clinical trials that are appropriate for these patients. At present, we currently don't have available options, but I think the more we gather this data, the more we work collaboratively as a community, we will be able to mobilize our resources and get the best outcomes for these patients. 

Dr. Peter Li: First build the field of dreams and then hopefully more therapies will arrive in the future.

Thank you so much, Dr. Khwaja, for speaking about the JCO article, "A New Validated Staging System for AL Amyloidosis With Stage lllC Defining Ultra-Poor Risk: AL International Staging System," and for all your valuable input today.

Dr. Jahanzaib Khwaja: Thank you very much.

Dr. Peter Li: Make sure to check out the presentation at this year's ASH Conference taking place from December 6 to December 9. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcast.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

Dr. Ece Cali: Welcome to this episode of JCO Article Insights. This is Dr. Ece Cali, JCO Editorial Fellow. Today I'm joined by Dr. Jeffrey Bradley, Professor of Radiation Oncology at the University of Pennsylvania, to discuss the manuscript, "Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non-Small-Cell Lung Cancer: The Phase III PACIFIC-2 Study."

The PACIFIC-2 study was a phase III, double-blind, randomized trial comparing the efficacy and safety of simultaneous durvalumab with concurrent chemoradiation followed by consolidation durvalumab to the concurrent chemoradiation followed by placebo in patients with unresectable stage III non-small cell lung cancer. The primary endpoint was progression-free survival by blinded independent central review. The secondary endpoints were overall response rate, overall survival, and safety.

Three hundred twenty-eight patients were randomized 2:1 to durvalumab and placebo, respectively. Unfortunately, this trial did not meet its primary endpoint. There were no statistically significant differences in PFS or OS. The frequency of adverse events was similar between the two arms. Grade 3 or higher adverse events were observed in 53% of the patients in the durvalumab arm compared to 59% of the patients in the placebo arm. Of note, the frequency of pneumonitis was similar in the two arms. Approximately 28% of patients in each arm developed pneumonitis, and about 5% of the pneumonitis observed in each arm was grade 3 or higher in severity. Treatment discontinuation rates secondary to the adverse events were higher in the durvalumab arm, 25% compared to 12%. Adverse events leading to treatment discontinuation and death were more frequently seen in the durvalumab arm during the first four months of the treatment, which corresponds to the simultaneous administration of chemoradiation and durvalumab.

Dr. Bradley, before we delve into the results, can you please explain the rationale for this study design and how this concept fits into the current treatment landscape?

Dr. Jeffrey Bradley: Yeah, this trial came on the heels of PACIFIC after there was a progression-free survival benefit showed in PACIFIC that in the locally advanced unresectable population that consolidation immunotherapy, in this case durvalumab, had a progression-free survival benefit. A number of us in the clinical trial space thought to add concurrent immunotherapy in addition to consolidation immunotherapy that that would also improve outcomes for patients. So a number of trials were launched to follow up of PACIFIC.

In this case, this is a phase III trial where the control arm was placebo. There was no overall survival results yet from PACIFIC, just a PFS benefit, and a number of countries across the world had not approved maintenance durvalumab in this space. So this trial looked at the experimental arm, which was concurrent immunotherapy, durvalumab, and chemoradiation followed by consolidation durvalumab versus placebo.

Dr. Ece Cali: And if we were to focus on the safety profile first, an increased pneumonitis risk was a theoretical concern when immunotherapy is given concurrently with radiation. Do we see any major differences in the safety profile between the two arms in this trial?

Dr. Jeffrey Bradley: No, and we were concerned about the addition of concurrent immunotherapy and chemoradiation, like you said, towards concern about increased pneumonitis rate, but we did not see increased pneumonitis in the experimental arm over placebo. And the grade 3 or higher, as you said, it was roughly 5%, more or less, in both arms, so we didn't see increase in pneumonitis toxicity with concurrent IO and chemoradiation.

Dr. Ece Cali: But interestingly though, despite the lack of significantly increased toxicity with durvalumab, unfortunately, administering immunotherapy simultaneously with chemoradiation therapy did not improve survival. Lack of superiority of this treatment regimen, as you mentioned, is further confirmed across multiple similar negative trial readouts such as ECOG-ACRIN 5181 and CheckMate 73L. Dr. Bradley, in your view, what are some potential explanations for why this strategy did not pan out in clinical trials?

Dr. Jeffrey Bradley: Regarding toxicity, let me go back and point out that we did see an increased number of immune-mediated adverse events. It was 34.7% in the concurrent immunotherapy arm versus 15.7% in the placebo arm. So that led to a higher number of discontinuations of immunotherapy which I think probably had an effect. So we didn't... there was an increased pneumonitis toxicity, but there were expected immune-mediated toxicities that caused people to stop giving immunotherapy. You can see that in the PFS curves. They were, you know, they crossed over after like a month, but initially there was lower PFS for the experimental arm, and then the experimental arm got better after we divided into four months, before four months and after four months.

Dr. Ece Cali: For one reason or another, it looks like the simultaneous administration did not really improve outcomes. We now know that simultaneously giving them another concurrent radiation should really no longer be pursued in clinical trials for this patient population. Can you share with our audience what strategies are being studied in this setting and what trials to watch out for in the future?

Dr. Jeffrey Bradley: Sure, I think when you add concurrent radiation to immunotherapy, there were more central tumors in this trial, I think you're killing lymphocytes and negating the effect of immunotherapy. So I think that's the smoking gun for this trial, for the ECOG trial, for the small cell trial that NRG reported, LU005, and other trials. So correct, I don't think there's any need to continue to pursue concurrent immunotherapy in this space of lung cancer.

But that's not to say there aren't many other trials that are either ongoing, have accrued and awaiting results, or being planned for the next phase of clinical trials. We have a trial within NRG Oncology called NRG-LU008. It's a randomized phase III trial that is using an SBRT boost to a peripheral primary and chemoradiation to the nodes, because the primary tumor is the one that fails more often than the lymph nodes, and that's compared to PACIFIC in the control arm.

PACIFIC-9 is another trial in the same line as the other PACIFIC trials. That one is using dual checkpoint inhibition versus the control arm being PACIFIC. So there are three arms in that trial, durva and oleclumab, durva and monalizumab versus the PACIFIC arm. And that trial is completed accrual, but we have no results from that study yet.

Johnson & Johnson has a trial open looking at a nanoparticle. That's a radiosensitizer where bronchoscopy is used to inject the primary tumor and the lymph nodes with a radiosensitizer. That's a randomized phase ll trial that's ongoing. It's got three arms, two different doses of this radiosensitizing drug and then a control arm without injection at all. The control arm is again the PACIFIC arm.

And then those of us within the NCI-based clinical trials evaluation program, CTEP, are proposing an intergroup trial that would compare induction chemo-immunotherapy followed by chemoradiation followed by maintenance immunotherapy versus PACIFIC in a phase III study. So I think there's other trials that are either completed, ongoing completed, or on the horizon to assess in this patient population.

Dr. Ece Cali: Yeah, we definitely have an unmet need to improve survival outcomes for stage III patients, and it's great to hear that there are so many efforts looking at different strategies to improve outcomes for these patients. 

Thank you so much, Dr. Bradley, for this informative discussion and for sharing your insights. Any last thoughts?

Dr. Jeffrey Bradley: Yeah, we need something, you know. PACIFIC was first reported in 2017, and we really haven't made progress in terms of changing that standard of care control for the last eight years. So we need progress in this area.

Dr. Ece Cali: Yep, definitely. Thank you so much for joining, Dr. Bradley. 

And thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

DISCLOSURES

Dr. Bradley
Honoria: Mevion Medical Systems, Inc.
Consulting or Advisory Role: Varian, Inc, Genentech, Inc.
Research Funding: Varian Medical Systems

Dr. Cali
Research Funding Company: BeiGene, Nuvalent, Inc., Astra Zeneca 

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Davide Soldato: Hello, and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale Policlinico San Martino in Genoa, Italy.

Today, we are joined by JCO author, Dr. Rusha Bhandari, a Pediatric Hematologist-Oncologist and Assistant Professor in the Department of Pediatrics and Population Science at City of Hope, California. Today, we will be discussing the article titled "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study."

So, thank you for speaking with us, Dr. Bhandari.

Dr. Rusha Bhandari: Thanks so much for having me.

Dr. Davide Soldato: So, I just want to go straight ahead in the paper and start from the title. So, we heard that you included in this study childhood survivors of pediatric cancer that were aged 50 years or higher. So, this is a very critical life stage when we know that there are a lot of aging-related comorbidities that can happen, also in the general population but potentially specifically in childhood cancer survivors. So, first of all, I wanted to ask you, why this specific study in this very specific population? Because I think that we had already some data in younger survivors, but now we are focusing specifically on patients aged 50 or more.

Dr. Rusha Bhandari: Absolutely. So, to answer that question, I'll take a little bit of a step back in terms of where we are now and where we came from in terms of treatment for childhood cancers. So, thankfully, we now have great curative therapies and survival rates for many childhood cancers, including the most common ones. But this was not necessarily the case 50 or more years ago. So, we essentially are now seeing the first generation of older survivors who are 30, 40, or more years from completion of their cancer treatment.

As you pointed out, we know from younger survivors that they have a markedly higher risk of malignancies and health conditions than the general population. You don't typically expect to see things like heart disease or diabetes, for example, in a young adult. But the question that remained was what the health status and risk of these conditions are in survivors who are entering this critical age, as you mentioned, 50 or older, when you do start to see these aging-related changes in the general population. And the question is whether we're still observing increased risks related to cancer treatment that was delivered 30 or more years ago in these survivors who are now entering ages 50 and beyond.

Dr. Davide Soldato: Thanks so much. You used the data from a study that is called the Childhood Cancer Survivor Study. So, just a little bit of explanation for our listeners. How is the study conducted? What type of data are you collecting? And specifically for the interest of the study that was reported in this manuscript, which outcomes were really important for you and were so evaluated in the manuscript?

Dr. Rusha Bhandari: Yes. So, the Childhood Cancer Survivor Study is a really excellent resource that combines information from children who were treated across North America at various different centers and sites. So it gives us a really good understanding of how different survivors are doing as they do progress through their survivorship journey.

The Childhood Cancer Survivor Study includes a baseline questionnaire when participants are first eligible or first enter the study, and then includes a series of follow-up questionnaires to really understand how they're doing, like I mentioned, as they progress throughout their survivorship journey. And so for this study, we really wanted to take a global look at how these patients were doing as they entered that older age range. And so we wanted to look at outcomes ranging from mortality through the health conditions that we've seen from other survivorship studies, including subsequent malignant neoplasms, other health conditions, I mentioned earlier heart disease and other comorbidities we know survivors can be at increased risk for, and also things like frailty, which we know is, you know, the most widely recognized phenotype of aging. And we see that earlier on in our younger survivors. We want to see how this translated to these older survivors and then also other health outcomes like their health status. What is their self-report of their physical health, their mental health? Things like that. So we wanted a very comprehensive understanding of their health.

Dr. Davide Soldato: This is a very comprehensive study. Right now it includes more than 30,000 patients that have been treated for childhood cancer, but specifically looking at the question of survivors aged 50 years or higher, you included more than 7,000 patients inside of this study. So, looking at the first outcome that you mentioned, which I think it's also one of the most important, you look specifically at mortality, and in this specific population, you saw a striking three-fold increase in mortality when comparing these survivors with the general population. I just wanted to dive in this result and ask you: What do you see as the main driver for this excess mortality in this population of survivors? And as you were mentioning, the study also collects information about the treatment received. So, was there any association with a specific kind of treatment that was received for curing these childhood cancers?

Dr. Rusha Bhandari: I agree. I would say it's striking to see that mortality risk among the survivors relative to the general population. And we do know, again from prior studies, that survivors of childhood cancer do have an increased risk of mortality compared to the general population, but I think looking at those curves of the cumulative mortality risk was really quite striking as they diverge, and that's, you know, just so long past their initial diagnosis and treatment.

We know that subsequent malignant neoplasms or secondary cancers are a really an important contributor to mortality among survivors. And I think it was important to note that even in these older survivors, it's still such an important contributor to mortality, and I think this really highlights the need for us to better understand what is driving specific secondary cancers and what are the differences in the biology and treatment approaches for some of these cancers? And how might that then be contributing to the mortality risk?

Dr. Davide Soldato: Related to the treatment mortalities - because I think that one of the main forces of the study, as it is conducted, is that it contains a lot of information regarding radiotherapy, allogeneic transplant, surgery, type of chemotherapy received by these survivors - so, are we able right now with the data that we have to pinpoint which of these treatments can potentially lead to such increased risk of mortality?

Dr. Rusha Bhandari: So, we weren't able to look at the comprehensive treatment exposures and mortality risk for this paper. So that might be one of the questions I would put on the side. We were able to look at that in relation to subsequent malignant neoplasms and health conditions though, as you mentioned.

Dr. Davide Soldato: Another thing that I think is very important is that you were able to look at specific causes for mortality. So for example, you mentioned the increased rate of neoplasm in this population and specifically, more or less 7.6% of the patients that were included in the study developed another neoplasm after the ones they were cured for in the childhood period. So, you saw a wide range of cancer, for example, bone and soft tissue sarcomas, breast cancer, genitourinary cancer. And as you were mentioning, there were some associations for treatment modalities that were associated with a higher risk of developing this type of cancer. Can you expand a little bit on this?

Dr. Rusha Bhandari: Absolutely. And so the key part here was that we really looked at any of these outcomes that occurred beyond age 50. What we found was there is still an increased risk of secondary cancers beyond that initial childhood cancer diagnosis, but when we really looked at that data, it was specifically among survivors who had a history of receiving radiation. And we did not necessarily see an association between different chemotherapy exposures and secondary cancers. And I think this speaks to what we're now learning in terms of the very long-term effects of radiation and how that impacts ongoing health risk even in patients who are 30 or more years out from their treatment. And I think it really highlights the importance of these- the efforts that have been made in the more recent decades to really try and reduce or eliminate radiation where possible, you know, as we've come to understand more about these long-term effects from it.

Dr. Davide Soldato: A clear association with radiation therapy but no association when we look at specific types of chemotherapy that were used for curing this childhood cancer.

Another thing that I think it's very interesting and you briefly mentioned before is that potentially when we look at these secondary malignant neoplasm that develop in this situation, we might also see some outcomes that are not comparable to the one of the general population, meaning that we managed to cure less this type of cancer when they develop in these childhood survivors. So, I just wanted to understand if you could provide us with a little bit of perspective also from a clinical standpoint being a pediatric hematologist-oncologist as to why this might be happening and how can we potentially increase the cure rate also in this population of childhood cancer survivors?

Dr. Rusha Bhandari: Absolutely. While that was not the focus of this study, it was something that we were certainly interested in is understanding how even once a childhood cancer survivor, for example, develops a health condition or a secondary cancer further into survivorship, how does that outcome then differ from someone in the general population? And there's a lot of interest in ongoing studies actually evaluating that and understanding what are the differences from the initial presentation, biology, the characteristics of that cancer, through how they're treated. So I don't know if we have all of the answers for that quite yet, but you can imagine if someone hypothetically had a history of receiving a lot of anthracycline chemotherapy or already having received a lot of radiation, that might impact what treatment they might receive for that secondary cancer or if they already have other existing comorbidities that need to be taken into consideration.

Dr. Davide Soldato: Speaking about comorbidities, you were mentioning in the beginning that one of the focuses of this scientific work was really to try and see whether also this type of adverse health outcomes that can be potentially related to treatments were more frequent among these childhood cancer survivors. So I think that it's very interesting that for this comparison, you were able to use the data from the siblings of the patients who were included inside of the study. So, just a little bit of a comment on why you decided to use this specific methodology, which I think has a very nice touch to it when we look at these outcomes like, for example, diabetes or cardiovascular disease, and in general, do we see an increased number of chronic health conditions among survivors who were treated for childhood cancers?

Dr. Rusha Bhandari: Yes, so this is a really excellent strength of the Childhood Cancer Survivor Study is that they have information, longitudinal information, on survivors as well as their siblings. So, you know, when we were discussing the design of the study, I mentioned that we have initial baseline questionnaires as well as multiple follow-up questionnaires, and that is for both the survivors and the siblings. And so we're able to really understand their health course over time. We chose to evaluate sibling data because then you're really able to look at people who have similar characteristics, right? Similar environmental exposures in theory, potentially similar genetic predispositions and makeups and things like that. And so you can really try and have as good of a comparison as possible.

Dr. Davide Soldato: Did we see any increase in chronic health condition when looking at survivors compared to the siblings?

Dr. Rusha Bhandari: We did. And while that's been reported before, again, I think it's important to demonstrate that in this older population when you would expect that these siblings would now also be starting to develop different health conditions.

Dr. Davide Soldato: One thing that was very interesting is that when we look at the coexistence of multiple comorbid conditions and chronic condition in this population, we also see that for some of these survivors, they basically have the same rates of comorbidities as compared to siblings who are potentially 20 years older than them. So I think that there is really that striking point, as you were mentioning before, of accumulation of changes, also physiological changes that can potentially drive a higher frailty index, which was also higher when looking at these survivors compared to their siblings.

One outcome that was really not that worse when we look at survivors of childhood cancer was actually mental health. And as I read the paper, it was something that really surprised me a little bit because you would imagine that going through such a harsh diagnosis, such very complex treatment, very early in their life could potentially lead to some worse health outcomes also in terms of mental health over time. But this was not seen. And just a comment on this, because I think it's a very surprising data.

Dr. Rusha Bhandari: Yes, I appreciate that question. So, as you mentioned, mental health is such an important issue for patients, both those undergoing treatment as well as those in long-term survivorship. And in our study, we found that survivors were not more likely, as you mentioned, to report poor mental health compared to their siblings. And I think there's a few possible reasons for this.

You know, again, this is self-reported data amongst siblings and survivors who survived to at least 50 years of age and completed a questionnaire. And so that is the group of individuals that we were able to evaluate this in, so we have to keep that in mind. But I think our findings may also reflect the resilience of this particular cohort of aging survivors that we included. This finding has been reported in other studies of survivors as well, and so I think it very well may speak to the resilience of the cohort that we're looking at.

Dr. Davide Soldato: Going back just a little bit, you mentioned that the majority potentially of these survivors who were included in the current analysis were treated between 1970s and 1980s. So, as you were mentioning before, radiotherapy was seen as a significant contributor to second neoplasm and also to the increase of this chronic health condition. So, do you believe that there is still a role for these survivorship studies as we are approaching treatment modalities where radiotherapy is administered less frequently or with lower doses or omitted at all in the treatment course of these survivors?

Dr. Rusha Bhandari: Absolutely. I think you mentioned a very important point, which is these findings are most applicable to the patients who were included in this cohort or similar cohorts, those who were treated in the 1970s and 80s who now are 50 years or older at this point in time. And as you know, treatment modalities have really changed. You know, as you mentioned, we'll use less radiation in many cases whenever possible, but there are so many new modalities, so many different chemotherapeutic agents, immunotherapy. There's so much more we need to learn about the long-term effects of some of these newer treatment modalities. And also, we've been able to really intensify our treatment regimens with improvements in both treatment approaches and supportive care. And so I think we have a lot to learn about those late effects, and ongoing studies are certainly needed as we continue to have this growing population of older survivors.

Dr. Davide Soldato: And now a more general question which builds on the results of the study but goes a little bit beyond what was the scope of the research. So we have just discussed that there is an excess mortality in general, there is a higher risk for secondary malignancies in this population, we see higher accumulation of chronic comorbid conditions that need to be treated. So building on these results, in your opinion, what would be the best framework to follow up these patients over time? Because I imagine that for some of these patients who have been treated 30, 40 years before the moment where we see this type of events, they can be potentially also discharged from more specialistic medical care. So what is the best course of action? Should we keep all of these patients under observation in a very specialistic environment under the care of the oncologist or the pediatric oncologist? Should we create a stronger bond with general practitioners so they know that there is this problem?

Dr. Rusha Bhandari: Yes, I mean, I think you're reading my mind. We thankfully do have evidence-based guidelines. We utilize the Children's Oncology Group Long-Term Follow-Up Guidelines, which include screening recommendations for secondary cancers, chronic health conditions, everything based on the underlying diagnosis and treatment that these patients received. But we recognize that a large proportion of these survivors do not continue to have lifelong follow-up at a survivorship center, but really do need that specialized screening based on their treatment that they received. And I think for that reason, it's so important that we continue to build relationships with their primary care providers and really make sure that both patients and their providers have this information at hand regarding what their treatment is and what the screening is that they need and that we be able to have this community whereby we are able to help inform the screening in our own survivorship clinics, but also help guide some of the primary care providers who are going to be seeing these patients in the long run.

Dr. Davide Soldato: Do we have any data showing what is the adherence rate of these patients to this type of continuous screening and monitoring over time? Because I imagine that that might also be a point for improvement in terms of quality of care. Can we retain as much childhood cancer survivors as we want as we are learning that there are all these potential negative health outcomes over time?

Dr. Rusha Bhandari: We definitely within the survivorship community do want to help make sure as many survivors as possible are being engaged, again, whether it's at their specific cancer center or whether it's in the community, recognizing that for many reasons, it's not feasible to always return to that cancer center for your regular survivorship care. I think there's a lot we can do. Going a little bit outside the scope of your question, but I think there's a lot that we can do nowadays in terms of telehealth and being able to communicate with patients and their providers even if they're geographically not located right near us. But we do have data that shows that the further out many patients get from their initial diagnosis and treatment, the less often they might follow up with a survivorship provider. Some of this varies by different treatment.

Dr. Davide Soldato: So, basically the final question is that we need more education and potentially more resources for survivorship clinics and in general to better inform patients and providers about these potential long-term outcomes.

Dr. Rusha Bhandari: That's certainly a focus of our survivorship program, for example, is to make sure that we're able to educate patients, inform them of their risks, and why certain screening tests are recommended at certain times in their survivorship journey. And then I think again, thankfully nowadays with all of the electronic medical records and different methods for us to communicate, there's a lot of opportunity for us to continue building these relationships with those primary care providers and making sure they have the information at their fingertips as well as to be able to work in conjunction with these patients to continue to formulate their plans and carry out these screenings and then again, like I was saying, have an easy open line of communication with the oncology centers if they do have any questions.

Dr. Davide Soldato: Thanks so much.

This brings us to the end of this episode. I would like to thank again Dr. Bhandari for joining us today.

Dr. Rusha Bhandari: Thank you so much. It's been a real pleasure speaking with you.

Dr. Davide Soldato: And we appreciate you sharing more on your JCO article titled "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study."

If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO author, Professor Sundar Jagannath, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and the Tisch Cancer Institute. He also serves as Network Director for the Center of Excellence for Multiple Myeloma, and he is an internationally recognized expert in the field of multiple myeloma.

Today, we will be discussing the article titled, "Long-Term Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma." Thank you for speaking with us, Professor Jagannath.

Dr. Sundar Jagannath: Thank you for having me, Dr. Davide Soldato. It is a pleasure to be here. JCO is a highly recognized journal among the oncologists, so I am very happy and privileged to be here today.

Dr. Davide Soldato: Thank you so much for being with us.

So, I wanted to start a little bit with the rationale of the study and the population that was included in the study. So, the trial that we are discussing, CARTITUDE-1, was already published before, and we observed very good results with a single infusion of cilta-cel. So we had previously reported a median progression-free survival of 30 months, and median overall survival was not reached. So, I just wanted to ask you if you could guide us a little bit into the population that was included in the study and also explain a little bit to our listeners what is the drug that we are discussing, cilta-cel.

Dr. Sundar Jagannath: It is a CAR T-cell. This is a patient's own lymphocytes, which goes through apheresis and is sent to the company, where they modify it and introduce the B cell receptor. In this case, you know, there is a heavy chain gene receptor for the BCMA, and in cilta-cel, there are actually two receptor sites on each molecule, or there are two binding domains on each receptor molecule. So, it is considered to be quite efficacious. As you reported, the earlier results that the patients who participated, 97% of the patient responded.

Now, you asked about the patients who participated in the clinical trial. This clinical trial was conducted between July of 2018 and October of 2019. At that time, this was a phase 1b/phase 2 trial, and the whole idea was to take patients who had relapsed all the available treatment regimen so that these patients were considered to have, in the unmet medical need situation. So, what does that entail? That means the patient should have been exposed to a proteasome inhibitor, to an immunomodulatory molecule, and to an anti-CD38 monoclonal antibody and should have received at least three or more prior lines of therapy and should be actually progressing on their last line of therapy. So with that requirement, if you look at it, the median number of prior therapy on the patients who participated was actually six.

So patients were heavily pretreated. They had exhausted all available treatment options. So, they can participate in this clinical trial. And if not, there have been real-world evidence, such as LocoMMotion, which had reported what is the outcome for such a patient if they were treated outside of this clinical trial, if they were treated with the then available regimen. Their median progression free survival would have been only 3 months, and most patients would have lost their life within a year. So, this was truly an unmet medical need with patients in a very difficult clinical situation. Let's put it that way. So, those were the patients who participated in this particular trial.

Dr. Davide Soldato: Thank you very much. And as we mentioned before, the results that were obtained in this clinical trial were really very interesting.

And now, in this issue of the Journal of Clinical Oncology, you are reporting data with a longer follow up. So we are actually at more than 5 years of follow up for the patients included in this trial. So, I just wanted a little bit of insight into why you decided to report these long-term outcomes and what type of information do you think you could provide with this study to the medical community?

Dr. Sundar Jagannath: This is very important because this was a clinical trial that was done in patients who were, as I said, in unmet medical need. Most of the patients had prior stem cell transplantation, had gone through a proteasome inhibitor. Many of them have had both Velcade and carfilzomib treatment. Most of them had been exposed to lenalidomide and pomalidomide. And as required, all of the patients had to have had prior exposure to anti-CD38 monoclonal antibody or daratumumab. So, the patients were heavily pretreated.

Typically, TIL CAR T-cells came into the field at this particular moment, until then, we were developing small molecules, and they usually would have a PFS of 3 months and median life expectancy of a year, the overall response rate of 30%, and that is how, if you look back, that is how carfilzomib was approved, that is how pomalidomide was approved. So, the drugs which were approved, including daratumumab, you know, the response rate was in the same ballpark. So you would see that most agents, single agents, would have had a response rate in the neighborhood of 30%, the progression-free survival would have been between 3 to 5 months or 6 months at the most, and the life expectancy was short.

And here comes a drug, and when I was following the patients at Mount Sinai, I found that there were a subset of patients, they got one-time treatment and they were in complete remission, no trace of cancer with annual evaluation with PET CT and bone marrow evaluation for MRD. So, I said this is remarkable, and this needs to be reported. And I went to the Janssen and company, and they agreed to review the entire experience. This is remarkable that 32 of the 97 patients, or one third of the patients, were alive and progression-free. This is unheard of for any clinical trial until now, that the patient will be progression-free, one third of the patients on a clinical trial will be progression-free, in the late stage of their disease. So that is the most important impact. And that is why this 5-year follow-up results were presented.

Dr. Davide Soldato: Thank you very much. That was very clear. And as you said, we are speaking about a population that was heavily pretreated, that had exhausted all type of treatment options outside of a clinical trial. And as you said, one third of the patients was alive and progression-free after 5 years from being included and infused inside of the study. So, considering this population that, as we said, had received all treatment options, I was wondering if you observed any kind of differences in terms of disease characteristics when looking at these patients that had exceptional response, so, alive and progression-free at 5 years, and the patients that sadly had developed a progression after the infusion in the study.

Dr. Sundar Jagannath: This is very important because we wanted to see who are the patients who are having this exceptional outcome. And we looked at all the 97 patients. If we look at all the patients, we saw that there were initially, out of the 97, 17 patients died earlier in the disease course due to treatment related complications, etc. But there were about 46 patients who had progression of disease and 32 patients, or one third, were alive without progression of disease. Then we looked at the 46 patients who had progression of disease. Of them, we found that 30 had disease progression and its complication, and there were actually 13 patients who were still alive even after progression of disease. So we decided to compare these 46 patients who had progression of disease versus 32 patients who had no progression of disease to see what is the difference. To our surprise, the age was similar, male, female distribution was similar. High-risk cytogenetics, which we would have thought, you know, that is why we say high-risk disease, the term, high-risk cytogenetics was equally distributed. That was really a surprise. Number of lines of prior therapy, number of exposure to drugs, all of that was the same. So that was also interesting.

But a theme did emerge. Patients, in general, tend to have lower burden of disease who had the exceptional outcome. But there is one which we considered as bad, the extramedullary disease. Multiple myeloma being a blood cancer, it is usually in the bone marrow. When it starts growing outside of the bone marrow, the extramedullary disease, usually it portends poor prognosis. But we were surprised that actually there were an equal number of extramedullary disease patients even in the long-term survivor as those who had progressed of disease. So the most important takeaway was patients who had lower burden of disease, they had less number of myeloma cells in their bone marrow, percentage wise, and the soluble BCMA level was lower. Soluble BCMA is an indirect measure of the amount of plasma cells in the patient's body. It is like a tumor burden. So they were low.

So, this was an important finding because it has future ramification, as you can understand. If this treatment is made available earlier in the disease course of the patients, where we are able to control the disease better, then more patients are likely to have such wonderful outcomes as one third of the patient experience in the late stage of the disease.

Dr. Davide Soldato: So, you already mentioned soluble BCMA as a marker of potentially better prognosis as being correlated to a lower volume of disease. I was wondering if you could give us some more information about the biomarkers that you evaluated in the study. For example, you evaluated a little bit the CAR T expansion kinetics and also some others that I think could be interesting and could point to some population that experienced such important benefit.

Dr. Sundar Jagannath: That is a very important point because CAR T-cell, it is a live cell and its efficacy depends upon how well the CAR T-cell is going to function. And then, you know, the patient undergoes apheresis. This is a patient's own lymphocyte. So first and foremost is who would generate good CAR T-cell. Those who have plenty of lymphocytes at the time they are coming for apheresis. This is likely to happen earlier in the course of the disease than in patients who have gone through numerous lines of therapy and exhausted. So, in this particular trial, of course this was in late stage of the disease, and so we were able to show patients who had lower number of T cell in circulation, and the way to measure is if they had more neutrophils and less lymphocytes. So that is what is called as a higher T cell over neutrophil, they did better. If they have more neutrophil than T cells, then they did not do well. So, procurement.

The second one is also whether the T cells are more naive, you know, not exhausted T cells. So more naive T cells, if you are able to procure from the patient, they did very well. Now, after the CAR T-cell manufacture, then the expansion, when you put it back into the patient, if the T cells expand very well, so that the effector, that is the CAR T-cells to the tumor ratio is good, so there are more effector cells, the CAR T was able to expand and the amount of tumor was less, then the efficacy was very, very good. As I said, the patients in this group, those who had a lower burden of disease, they did better, and that is because of the CAR T-cell expansion, so the effector to the target ratio was favorable. So that is another important.

And then there are also the type of CAR T-cells, having CD4 T cells with central memory phenotype at the peak expansion also makes a difference. So all of that matters. But this is important because the efficacy of the CAR T-cell, it is persistent, long persistent and keeping the cancer down. Its ability to get rid of the cancer completely at the first go around because usually we are not able to detect the CAR T-cells beyond 6 months in the majority of patients and very rarely after a year or two. So it is very uncommon to find the CAR T-cells in circulation or even in the regular bone marrow evaluation.

So, efficacy, the expansion, having naive T cells, having good effector to target ratio and more central memory kind of T cell, because if it is all effector T cell, they will get quickly utilized and get exhausted, whereas the central memory cells can expand more and give more effective CAR T-cells.

Dr. Davide Soldato: Thank you very much.

I was wondering if you could guide us a little bit into what is your opinion regarding the positioning of CAR T-cells given all of these logistics that is necessary compared, for example, with bispecific antibodies against BCMA, which have the same target, but they do not have all of these logistics before being administered to the patient.

Dr. Sundar Jagannath: That is a very important question, how to sequence these treatments now that we have two BCMA-directed CAR T-cells available. We have three BCMA-directed bispecific and one GPRC5D-directed bispecific antibodies are available. And so the question comes in for at least the currently approved CAR T-cell therapy, there is an obligatory time. You have to go through apheresis and you have to ship to the company, and there is a manufacturing time, roughly about 2 months before they can receive it. During that time, you want to make sure the patient's disease is under control. So that is a given. There are several ways to look at it when we evaluate the patient and talk to the patient.

One good thing is now the two CAR T-cells which are approved, one is cilta-cel we talked about, and the other one is ide-cel. Ide-cel is approved in earlier line of therapy, two or more prior lines of therapy, and cilta-cel is approved in patients who have failed one line of therapy and who are lenalidomide refractory. So, the treatment of CAR T-cell is available earlier. And as I said, when you administer CAR T-cell earlier, you are able to keep the disease burden down, and it is a one and done deal. There is a better quality of life for the patient, and you are able to produce long, durable remission and potentially a cure.

Now coming to the bispecific, they are currently available in later lines of therapy. So if you look at it from a patient's perspective, you can use the CAR T-cell earlier and then go through the bispecific therapy. But if the patient comes with relapsed refractory myeloma and has not used the CAR T-cell therapy and has not used the bispecific therapy, then the physicians have to decide which one they want to use. If somebody's disease is rapidly progressing and they need immediate tumor reduction and they have already exhausted all available therapy, then going through BCMA bispecific therapy is quite appropriate.

And secondly, CAR T-cell therapy is generally given to somewhat physically more fit patients, whereas bispecific therapy, because you are giving antibody at step-wise dosing in this patient, and you have the ability to stop at any particular dose and then come back and redose, whereas CAR T is, you just give it to them one time, you have a lot more control. So intermediate frail or even frail patients can go through bispecific therapy, whereas it would not be in the best interest of the patient to go through a CAR T-cell therapy when they are frail. So that is another important point.

But from the information available, when the patient goes on a BCMA bispecific therapy and they start progressing on treatment, usually it is their T cells are exhausted or the BCMA is no longer expressed on the tumor cells. So coming with CAR T-cell later on is usually not effective, whereas giving CAR T-cell earlier, if the patient relapses later, they have good T-cell function and most of the time the BCMA is still expressed. So you are able to give the BCMA to the maximum benefit by using the CAR T first and BCMA later. So if somebody asked me how to sequence this, just off the bat, you will say CAR T first, BCMA bispecific second. But as I said, there are unique situations.

Then there is another potential that is happening. You can change the target. You can use a BCMA against GPRC5D to reduce the tumor, and then go ahead and consolidate it with a CAR T-cell therapy. That is also possible. You are changing the target from GPRC5D to BCMA, the tumor is already down, so the patient is likely to benefit. So these are all newer treatment options which have become available to the physician. So they will have to look at individual patients and decide what is the best course of action for that patient.

Dr. Davide Soldato: So, I just wanted to close a little bit with your opinion about how these results translate into clinical practice. So considering this outstanding 5-year data that we have seen, one third of the patients who are alive and progression-free after a single infusion of cilta-cel, do you think that we could start to think about functional cure even in patients who have a diagnosis of relapsed refractory multiple myeloma?

Dr. Sundar Jagannath: My feeling is this is important because in this particular study which is published, 12 patients who were followed at Mount Sinai out of the 32 patients who are alive and progression-free, 12 were followed at Mount Sinai. And they were evaluated every year with bone marrow MRD testing by clonoSEQ in 11 of the 12 patients, and one was by multiparametric flow cytometry. So most of them were 10 to the minus 6, not even one in a million cancer cells, and all of them had functional imaging, which is called PET CT every year. So these were patients who had no evidence of disease that we could detect with the technology available today, serologically, in the bone marrow, or anywhere else in the body with a PET CT. They were found to be disease free after a single infusion of cilta-cel. So, that would be almost to the definition of a cure because if you look at cure as a definition for any cancer, cure is defined as a state of complete remission with no trace of cancer that persists over a period of 5 years or longer without maintenance. And that will be applicable for breast cancer, lymphoma, leukemia. So it is a general statement. And if we use that in myeloma too, then I could say that these 12 patients from my center, we proved that they are cured of their myeloma. They are not functionally cured. You've got to remember, there is only cure. That was the definition across all diseases. So there is nothing like a functional cure. They are cured of myeloma.

So is myeloma curable? This is the first time we are looking at that. We do know, every physician treating myeloma that there are patients out there, 10 year and beyond, without evidence of disease. This has been published by University of Arkansas, Bart Barlogie's group, who has been saying that myeloma is a curable disease for a long time. And many others have shown long-term follow up. But this one in a late stage disease, we were able to show that they were one treatment with no maintenance. All other studies have been in newly diagnosed myeloma patients. Nobody has shown in late relapse patients on a clinical trial a third of the patient will be progression-free. And 12 of them who were studied were actually disease free. So they were cured of the disease.

So if we accept that, then the next question is, first step towards cure is achieving complete remission. They should have no monoclonal protein by any technology you want to use, no measurable residual disease using next gen sequencing or clonoSEQ, and functional imaging whole body PET CT or whole body MRI. So that is important, definition of the complete remission. And then it has to be sustained. That is something the IMWG and IMS, International Myeloma Society, they will have to come together for a consensus. How many years should they be followed and should be in this kind of status with no trace of cancer? Is it, 3 years are enough? 4 years enough? 5 years is enough? For me, I said in this paper, 5 years is a good definition for achieving a potential cure.

Then you use the term 'functionally cured'. I have a problem with functionally cured and operationally cured or whatever. Functionally cured was originally put out by Paiva from Spain. There were 8% of newly diagnosed myeloma patients who have, after they go get treated, they will have an MGUS like phenomenon, a small amount of paraprotein detectable, and they are only 8%. And he said that these patients could be off treatment and the disease does not progress. But the problem is when you are giving treatment like maintenance therapy continuously until progression, you do not know exactly who is in the MGUS situation. So you have to have done sophisticated flow cytometry like Paiva did, and it is not quite clinically applicable. So functionally cured applies only for 8% of the people, so it should go out of the vocabulary.

Then you can say 'operationally cured'. These are the patients traditionally Bart Barlogie and others showed that they have a large number of patients who have been followed for 10 years with no recurrence of disease, not on treatment. But in those days, they did not have MRD PET CT and all of them done systematically. So that is why they had to come up with a situation where they said they were operationally cured. So yes, myeloma patients have been cured since auto transplant was introduced. I completely agree. It is not new to the CAR T-cell therapy. But the beauty of the CAR T-cell therapy was it was in relapsed refractory myeloma, unmet medical need, number one. Number two, they were studied systematically. It was a clinical trial adjudicated by FDA and EMA for drug approval, cilta-cel was approved. So these patients were carefully followed, and it was a multi-center study. And in that group of patients, we were able to show patients- So, I think this would indicate cure is a reality in myeloma, and as these kind of treatments, immunologic treatment, either it is a CAR T-cell therapy or BCMA bispecific or whatever, there is a chance more patients are likely to be cured, and these treatments have to move forward and so that we are looking towards a cure.

That is the beauty of it, and I just thank you for asking and also throwing in this so-called functionally cured, which people like to use casually, and I say it is time to talk more cure and not stuck with functionally cured because that does not allow the field to progress.

Dr. Davide Soldato: Thank you very much. That was very interesting.

Dr. Sundar Jagannath: And provocative.

Dr. Davide Soldato: A little bit, but I think that we needed to close the podcast with this kind of reflection coming from someone who is an expert in the field, as you are.

So, I really wanted to thank you for joining us today and for sharing more on your article, which is titled, "Long-Term Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma."

If you enjoy our show, please leave us a rating and a review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.

Dr. Sundar Jagannath: Thank you.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Shannon Westin: Hi everybody and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts that are published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, social media editor of JCO and gynecologic oncologist extraordinaire.

I'm so very excited to talk to you today. We're going to speak about "Long-Term Dynamic Financial Impacts Among Adolescents and Young Adults With Cancer: A Longitudinal Matched-Cohort Study." And I'm joined today by Dr. Giancarlo Di Giuseppe. He has a PhD in epidemiology that he actually just defended with this very work you're going to hear about today at the Dalla Lana School of Public Health at the University of Toronto. He is now a research fellow at the Hospital for Sick Children. 

Welcome, Dr. Di Giuseppe. It's so exciting to have you.

Dr. Di Giuseppe: Thank you so much for having me.

Dr. Shannon Westin: So we'll get right to it. Let's level set. Can you talk a little bit about the financial impact of cancer on survivors in general? I think this has been a growing area of interest and research, certainly.

Dr. Di Giuseppe: Yeah, and I think that's a very important question, and I'm so happy that this research is now becoming more popular in the research world because it really addresses a critical issue that cancer survivors and their families must face. You know, you're diagnosed with cancer, and now you need to take time off work because you're hospitalized for chemotherapy. You're going back and forth to the hospital, and that all requires time away from your employment, and as a result of that, that has a significant financial strain, both on you and your family. And that's during therapy.

Now, in survivorship, in the years after you've survived your cancer, you still need to deal with all the late effects associated with your treatment and your disease, and that can be psychological, physical, and that impacts your workability as well. So, it's not just exclusive to individuals undergoing treatment but also in survivorship afterwards. It really gets the financial strait that you face as a cancer survivor because you're time away from work and your lost productivity.

Dr. Shannon Westin: Yeah, that makes sense. Then I think it would be great to talk a little bit specifically about the patient population that you studied in this particular manuscript. Can you talk a little bit about the adolescent young adult cohort, you know, why you singled out this particular group of people?

Dr. Di Giuseppe: Absolutely. Adolescents and young adults, or AYAs, which I'll now refer to them as - I'm one of them - we're at a unique crossroads of our life and in our developmental stage of life. We are finishing our post-secondary education. We're entering the workforce. We're forming romantic relationships, and we're really achieving financial autonomy. It's because of this unique developmental stage in life where we've become quite susceptible to health shocks such as cancer. Really, does a cancer and the associated negative financial impacts affect our long term trajectory?

So, I'm just finishing my PhD. If I was diagnosed with cancer, I would require a year or two away from my studies. I may or may not finish my education that could then impact my employment and then my financial outcomes later on in life. So it's really this unique population who are going through so many transitions and changes in their lives. How does that cancer really impact that life course trajectory? I think it's unique from an adult who might have, you know, large savings where they can bear the brunt of their cancer financial impacts, whereas AYAs may not have that same financial stability, provide a safety net for the financial impact resulting from their disease.

Dr. Shannon Westin: You broke my heart a little bit. I realized I'm no longer in that group, so I guess it's time to move on. Okay.

So, let's talk a little bit about the overall design of the study. Can you just kind of walk us through how you set everything up?

Dr. Di Giuseppe: Yeah, absolutely. So it's a matched cohort study at the population level here in Canada. We have large national administrative databases, and we have this really unique set of data at the national level through Statistics Canada that we can link our cancer registry to tax records. It really provides this unique opportunity to longitudinally follow individuals from their disease forward in time.

The main overall design is the matched cohort study. At the time of diagnosis of a cancer case, they're matched to someone from the population on certain characteristics. I follow these individuals from the index date of their cancer case forward in time. The crux of the study itself is a quasi-experimental two-group pre-post study design where I have information before the cancer diagnosis, I have information from their income after their cancer diagnosis, and it's really quantifying how much does that total income change from before the cancer to the after-cancer period.

Dr. Shannon Westin: I'm always intrigued about hearing more about financial toxicity in general, certainly very multi-dimensional. Can you speak a little bit about the different ways that you can assess this and measure this and kind of what you chose?

Dr. Di Giuseppe: Yeah, so financial toxicity really has two main spheres of measurement. There's a direct and the indirect measurements of financial toxicity. So your direct financial toxicities could be related to actually paying for medical treatment and any sort of financial burden as a direct consequence of your disease. Fortunately here in Canada, we have a universal health care system, so patients don't have to pay directly for most of their treatment.

There's also indirect financial toxicities, which are not a direct result of the disease. So in this study here, one of the, or the indirect financial toxicity that I measured was the financial impact to income. That's not the only indirect financial toxicity. There could be out-of-pocket expenses for drugs that may not be covered in the universal health care system here. It could be lost productivity at work. There's really this direct and indirect financial toxicities that together result in a significant financial burden and hardships for cancer patients and survivors.

Dr. Shannon Westin: Okay, so you guys did a lot of matching. It was extensive. Can you speak a little bit about the factors you used to match your patients and your controls and kind of why you chose them?

Dr. Di Giuseppe: Yeah, absolutely. The matching I think is a really critical aspect of the study, and it really establishes this baseline period of individuals who are cancer-free, who look as similar as possible to the individuals who would eventually develop cancer. So I matched on birth year, sex, marital status, whether or not they had children, if they were born here in Canada or not, as well as a geographic measurement of census division. So it's really in the city or in a rural town. Then I also matched on a 5% buffer of their total income in the year prior to the cancer diagnosis. All this matching was really done in the year before they were diagnosed, and it's to establish this comparator cohort of individuals from the general population who looked as similar as possible to the individuals, or the AYAs, who would develop cancer. It's again to establish this baseline period of a control cohort who looks as similar as possible.

So any differences that we might see after the cancer can be attributed to the effects of the AYA who would develop cancer. It's quite powerful, I think, from a study design perspective because it establishes causal inference methods through the study design and through the matching itself. Fortunately, I was able to match on an extensive list of covariates given the large population-based data that I used, particularly the tax records. Tax records contain a whole wealth of information, your marital status, your sex, your income, where you live. So it really provided this rich opportunity to match as closely as possible the AYAs who would develop cancer to someone from the population who wouldn't.

Dr. Shannon Westin: Yeah, and I mean I think that's the only way to do this type of research and really make it generalizable and actually, you know, know that you can trust the results that you've got. So I just want to again congratulate you because I think this was just- when I read the design, I was so impressed.

So now that we know the design and we understand everything, let's talk a little bit about the characteristics of the actual patient population that you studied.

Dr. Di Giuseppe: Yeah, for sure. So average age of diagnosis was in their early 30s, so around 32 years old. The breakdown of the population was mostly females, so I think two-thirds of the cohort were actually females who were diagnosed with cancer. Really, a lot of the cancers were thyroid and the breast cancers. These cancers are more common in women than they are in men. So it's really reflective of the different distribution of cancer in AYAs compared to other populations like in children or in older adults.

Dr. Shannon Westin: All right, bottom line. What did your primary analysis demonstrate and how was the income different based on the types of cancer that people might have been diagnosed with?

Dr. Di Giuseppe: Yeah, the bottom line is actually quite a disturbing message, I would say, and it's really that cancer causes this long, prolonged financial hardship in survivors. That's, I think, a very important result from the study, and I think it has far-reaching implications. This study demonstrates that these individuals who were diagnosed with this disease that is unforeseen also pay a financial price, and that sustains for many years after their diagnosis. That's overall on average. Once I dove deeper, actually looking at the different cancer types, the message actually gets even more disturbing, I would say, particularly in some disease subgroups. So the central nervous system cancer survivors really have a large reduction in their income, which sustains over 25%, 10 years after their diagnosis, and they never really recover financially from their disease. There are some groups of cancer survivors who really pay a large financial price for their disease.

Dr. Shannon Westin: I don't know if you're able to tease this out. This is just me thinking off the top of my head. Do you think it's the long-lasting side effects?

Dr. Di Giuseppe: I think you hit the nail on the head there, absolutely. I think what we're seeing here is a direct result of the late effects that cancer survivors experience. CNS cancer survivors, whether that is a surgical resection, radiation to the head for their tumor, the late effects really impact these individuals in the post-cancer survivorship period. So I think what we're really seeing are these late effects here.

Dr. Shannon Westin: The other thing I was kind of struck by is the differential and income loss over time. Can you speak a little bit about that in your work?

Dr. Di Giuseppe: Yeah, absolutely. There really is this period of financial vulnerability in the first couple years of diagnosis. So that's year zero, one, two, and three, these first couple years when these individuals are diagnosed with cancer, they are significantly impacted by their disease financially. Some of these reductions in their income is 15%, 20% in the year of diagnosis and the year afterwards. It's unsurprising because this is when these individuals typically are undergoing their treatment. They're not working. They may have even lost their job or quit their job. So it's really reflective in the results in that first few years of their diagnoses where these financial impacts are the largest. I think it provides an opportunity where certain interventions might alleviate some of these large reductions in their income.

Dr. Shannon Westin: Well, I really was disturbed by your work, and I hate to kind of say it that way because it's such important work. So I'm really- congratulations on everything that you're able to achieve and especially your PhD. But I think shining a light on these types of things is always pretty rough when you really look at the nitty-gritty details. So any thoughts about where we go from here, how do we support these people?

Dr. Di Giuseppe: I think we can support them at multiple different levels. So at the individual level, I think within the clinic setting, financial screening for financial toxicity, financial literacy, I think all these things can be incorporated into cancer care continuum to kind of educate AYAs with cancer about the financial implications of their disease, both in the short and the long term. So I think educating these cancer patients is important.

I think at the employer level, really working at the institutional level to incorporate workplace accommodations that might facilitate the return to work process for cancer survivors after their treatment or during, I think would also make the financial burden slightly less if cancer survivors are able to return to work or not have to quit their job because of their disease. And then return to work easier, I think might alleviate some of the employment consequences that these individuals face, which then lead to their adverse financial effects.

Then I think also at the policy level, at the governmental level, whether that's incorporating any sort of fiscal stimulus for cancer survivors, whether they're under treatment or in survivorship, any sort of tax breaks that they might be available to them to kind of alleviate some of that financial stress. The reality of it is being diagnosed with cancer and having your income reduced by even 5% - cost of living is expensive, especially now - so I can't even imagine what cancer survivors who are in this economy are facing with rising inflation and cost of living going up. So I think really having tax breaks as well as financial aid for these cancer survivors could really support them both in their cancer journey while they're undergoing treatment as well as some of the sustained effects that they experience afterwards.

It's particularly important, as we touched on earlier, for CNS cancer survivors, right? These individuals have this sustained effect that never really returns back to normal, and I think having  sort of disability pension or kind of financial aid for these individuals to support them, I think is important.

Dr. Shannon Westin: We see this all the time in gynecologic cancers, these young women that support their families, young children, and then lose their ability to do so due to their diagnosis and the treatment they have to receive. So I can't say this enough how important this work was and how honored I am to get to speak with you today. I learned a ton.

And thank you to all of you listeners. We're just so excited to have you. This has been long term dynamic financial impacts among adolescents and young adults with cancer: a longitudinal matched cohort study. Thanks again for listening to JCO After Hours, and please do check out our other offerings wherever you get your podcasts. Have an awesome day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

The disclosures for guests on this podcast can be found in the transcript.

Dr. Ece Cali: Welcome to this episode of JCO Article Insights. This is Dr. Ece Cali, JCO editorial fellow, and today I am joined by Dr. Martin Wermke, Professor for Experimental Cancer Therapy at Dresden University of Technology, to discuss the manuscript "Phase 1 Dose-Escalation Results for the Delta-Like Ligand 3/CD3 IgG-like T-Cell Engager Obrixtamig in Patients with DLL3+ Small Cell Lung Cancer or Neuroendocrine Carcinomas."

Obrixtamig is a bispecific T-cell engager that binds to DLL3 on tumor cells and CD3 on T-cells. This manuscript presents the phase 1A dose escalation results of Obrixtamig in patients with DLL3+ small cell lung cancer and neuroendocrine carcinomas. In this study, 168 patients were treated with Obrixtamig across four different dosing regimens. 49% of the patients had small cell lung cancer, 42% had extrapulmonary neuroendocrine carcinoma, and 8% had large cell neuroendocrine carcinoma of the lung. Patients received a median of two prior lines of therapy. 33% of the patients had brain metastases at baseline. Of note, this trial did not mandate baseline brain imaging. Maximum tolerated dose was not reached. 88% of the patients experienced a treatment-related adverse event, however, only 3.6% of the patients had to discontinue treatment due to treatment-related AEs, and dose reduction due to treatment-related AEs was documented in 2.4% of the patient population. Similar to the other DLL3-targeted bi-therapies, the most common adverse events included CRS in 57%, dysgeusia in 23%, and pyrexia in 21% of the patients. CRS events were mostly mild. They occurred more frequently in the first two to three doses. 9% of the patients experienced ICANS, of which 3% were graded as Grade 3 or higher.

And let's review the efficacy results. Responses were only seen in patients who received 90 microgram per kg or more once weekly or once every three weeks dosing. The objective response rate in patients who received an effective dose was 28%. If we review by tumor type, 21% of the small cell lung cancer patients, 27% of the extrapulmonary neuroendocrine carcinoma patients, and 70% of the large cell neuroendocrine carcinoma patients had objective response. Median duration of response was 8.5 months, though this data is immature due to short follow-up.

Dr. Wermke, DLL3-targeted bispecific T-cell engagers are reshaping the treatment landscape of small cell lung cancer. This trial investigates Obrixtamig in other high-grade neuroendocrine tumors as well. Can you put this trial into context for us and explain why it may represent an important step forward?

Dr. Martin Wermke: Yeah, thank you for providing me with the opportunity to discuss our data today. I think the data with Obrixtamig in small cell lung cancer are largely similar to what has been observed with other bispecific T-cell engagers such as tarlatamab with respect to the response rate and duration. It has, however, been to be mentioned that BI 1438001 had a bit more liberal inclusion criteria than other trials around. You already mentioned the fact that we allowed the inclusion of patients without mandatory brain imaging, which led to some patients having their brain mets been diagnosed during the treatment with obrixtamig and then adding to the progressive disease patients. That is something which was not the case with the tarlatamab trials where you really had to have a brain imaging before, and in the Phase 1 trial you were even required to treat the brain mets before you included the patient. So it is a bit different, more poorest patient population.

I think the trial adds on existing data by being the first trial to also include non-SCLC neuroendocrine carcinoma of other origin, for example from the gastrointestinal tract, and also by including large cell neuroendocrine carcinoma of the lung, which is a really hard to treat pulmonary neoplasm which currently lacks any standardized treatment. So that is really a step forward which we will build on in the future.

Dr. Ece Cali: And one thing I would note in this trial, only patients with tumor expressing DLL3 were enrolled. Can you tell us a little bit more about this target, DLL3 in the context of neuroendocrine tumors, and does DLL3 expression predict clinical outcomes after treatment with DLL3 BiTEs, or do we actually need other predictive biomarkers for these novel agents?

Dr. Martin Wermke: Yeah, thank you. That's a pretty interesting question. First of all, DLL3 is an atypical notch ligand, which is expressed by the majority of neuroendocrine carcinomas, virtually absent on healthy adult tissues. Therefore, turning it really into a bona fide target for T-cell engaging therapies, pretty low risk for on-target off-tumor side effects. We found that in all the patients we screened, we had an expression rate of about 94% in small cell lung cancer, 80% of large cell neuroendocrine carcinoma of the lung were positive, and also about 80% of the extrapulmonary neuroendocrine carcinoma. So it's really a high prevalence. So the fact that we only included DLL3+ tumors still means we included most of the patients that presented with these diseases.

I think at the moment there are no data suggesting a clear-cut association between DLL3 expression levels and outcome on DLL3 CD3 T-cell engagers. There's also not a lot published. If you want to find this out for tarlatamab, you have to look into their patent to really see the data, but it's not clear-cut and I'm sure we need other markers to complement that. And I think what probably plays a major role is intrinsic T-cell fitness. So the question how really diseased your T-cells are, how old you are, because age also correlates with the fitness of the immune system, and other patient characteristics such as tumor burden, we've seen all across the board that the higher the tumor burden, the lower the rate of prolonged response is in such trials. And I also think we need to focus on other components of the tumor microenvironment. So see how high the T-cell infiltration with obrixtamig is and how abundant suppressive elements like regulatory T-cells or myeloid-derived suppressive cells are. That is work which is currently being done. Data are emerging, but I don't think that at the moment we have any clear biomarker helping us to select who should not receive DLL3 T-cell engagers.

Dr. Ece Cali: Those are great points and there is a lot we need to learn about how to use these novel agents in the future.

I'd like to highlight the results in large cell neuroendocrine carcinoma of the lung. The response rate in this group was remarkably high at 70%. Though we should note the small sample size of only 14 patients in this trial. After first line chemoimmunotherapy, current approved options for this population have very modest clinical activity. Given these trial results, how do you envision the field moving forward for patients with large cell neuroendocrine carcinoma?

Dr. Martin Wermke: Yeah, I think LCNEC is really an area which urgently needs further improvement of therapeutic standards. At the moment, as I said, there is no real standard. We are usually extrapolating from results we have in small cell lung cancer or non-small cell lung cancer, but I don't think we have too many prospective trials really informing this. Of course, 14 patients is a small sample size, but I think it's still fair to say that we can claim that DLL3 T-cell engagers are not doing worse in LCNEC than they do in SCLC. And that's why I think we really need to move forward clinical trials that are specifically targeting this population. Although I fear a bit that, given the rareness of this disease and the aggressiveness of its phenotype, that this is probably not the main focus of the pharmaceutical industry. So I think it's up to us academic investigators to really come up with investigator-initiated trials trying to fill the knowledge gaps we have here.

Dr. Ece Cali: And one more thing that I want to talk about is the accessibility for these drugs. These novel agents are showing real promise in improving outcomes for patients with high-grade neuroendocrine tumors, an area where progress has been limited until very recently. However, as DLL3 BiTEs become more widely used, issues of logistics and access come into sharper focus. With unique toxicities and the specialized monitoring, their use is restricted to certain centers. Looking ahead, what kinds of strategies could help mitigate some of these adverse events or make these treatments more broadly available?

Dr. Martin Wermke: Yeah, I think if you look at countries like the United States where tarlatamab has already been approved, we can see how the management strategies are evolving. I've heard about a colleague equipping their patients with thermometers and a pill of Dexamethasone, alongside with a temperature control protocol and clearly instructing them, "If you measure a temperature above a certain level then start taking the Dexamethasone and come back to our office and we're going to take care of you." I think that's one way to move forward.

I think we are lucky in a way that CRS usually manifests within the first 24 hours. This was the same in our study, like in the tarlatamab studies. So we really know when the time of trouble is for our patients. And in this time, I think we need to instruct the patients to stay close to the hospital. I don't think we need to hospitalize all of them, but we probably need them to stay in a nearby hotel to be able to reach the emergency room if needed in a short period of time.

And I think we can also learn in this strategy how to manage bispecific antibodies from the experience our colleagues in hematology had because they have been using bispecific T-cell engagers for quite some years right now and they developed strategies and networks that were able to successfully treat these patients also on an outpatient basis. And I think that is clearly an experience we need to follow, acknowledging that we are talking about diseases which are much more frequent than the standard hematology indications.

Dr. Ece Cali: Thank you so much, Dr. Wermke, for this informative discussion and for sharing your perspective on this evolving field.

Dr. Martin Wermke: Yeah, thank you for providing me with the opportunity to talk about data. It was really great being able to share that, and I really think that we are just at the beginning of a new exciting area for the treatment of neuroendocrine carcinomas, and I think much improvement is yet to come for our patients.

Dr. Ece Cali: Yes, that's really exciting.

And thank you everyone for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Martin Wermke's Disclosures

Honoraria: Lilly, Boehringer Ingelheim, SYNLAB, Janssen, Merck Serono, GWT, Amgen, Novartis, Pfizer,  BMS GmbH & Co. KG, Regeneron, MJH/PER, Takeda

Consulting or Advisory Role: Bristol-Myers Squib, Novartis, Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, Amgen, immatics, Bayer, ImCheck therapeutics, AstraZeneca, Tacalyx, Regeneron, Daiichi Sankyo Europe GmbH, Zymeworks, PharmaMar, Iovance Biotherapeutics, T-Knife, Genentech

Research Funding: Roche

Patents, Royalties, Other Intellectual Property

Travel, Accommodations, Expenses: Pfizer, Bristol-Myers Squibb, AstraZeneca,  Amgen,  GEMoaB, Sanofi/Aventis, immatics,  Merck Serono, Janssen Oncology, Iovance Biotherapeutics, Daiichi Sankyo Europe GmbH"

TRANSCRIPT

TTFields in Locally Advanced Pancreatic Adenocarcinoma

Dr. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with manuscripts that have been published in the Journal of Clinical Oncology. I am your host, gynecologic oncologist Shannon Westin, social media editor at the JCO, and just excited to be here to learn today about pancreatic cancer.

None of our participants have conflicts of interest related to this podcast, and it is my honor to introduce Dr. Hani Babiker. He is an associate professor of medicine, consultant in oncology at the Mayo Clinic in Jacksonville, Florida.

Welcome, Dr. Babiker.

Dr. Hani Babiker: Hi, Dr. Westin. Thank you for the great opportunity to discuss our trial, and thank you for having me here. I really appreciate it, and I am excited.

Dr. Shannon Westin: All right, so are we. So we are going to be talking about "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: A Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study." This was simultaneously published and presented in the JCO and at the annual meeting of ASCO on 5/31/2025.

So, let's level set. Can you speak to us just a little bit about pancreatic cancer? What is the survival, and what is the typical treatment for locally advanced disease? This gynecologic oncologist has not kept up in this field.

Dr. Hani Babiker: Absolutely, Dr. Westin, and thank you for that question. Pancreatic adenocarcinoma is a lethal cancer. When I first started my career, the 5-year survival, per the Surveillance, Epidemiology, and End Results, was at 4.5%. I always, whenever I was giving talks, say that I really hope that I will see it in the double digit. Now, the 5-year survival for all pancreatic adenocarcinoma is 13.3%. And the 5-year survival, and although it is a double digit, I still hope that I will see it in a higher double digit in the future. It is even worse in patients with metastatic cancer, about 3% 5-year survival for metastatic pancreatic cancer. It is a dismal diagnosis. I really hope in the future we will find a better therapeutic approach to this lethal cancer.

Dr. Shannon Westin: Yes, I just lost a very dear friend and colleague to this disease, so I completely agree with you.

Well, now that we are settled kind of with the basics here, I would love to talk a little bit about kind of the primary piece of this intervention, the Tumor Treating Fields. So, how does this work? And what diseases has it gotten indications in as yet?

Dr. Hani Babiker: Absolutely. So, Tumor Treating Fields is alternating frequency electrical fields that have been studied preclinically and shown that it abrogates cancer cell proliferation. Earlier on, we knew that it inhibits polymerization of tubulin, and hence, it affects cancer cells from proliferating. Later, we are learning that there are multiple mechanisms of action. It affects permeability, allowing for better drug delivery. It also inhibits cancer cell proliferation through affecting autophagy mechanisms that pancreatic cancer cells will use for proliferating and becoming more aggressive. There is also some early data preclinically in colorectal cancer cell lines and lung cancer cell lines and in vivo models showing that it potentially could activate the microenvironment to make it more pro-immunogenic. We recently published papers showing that it could also affect the nanomechanical properties of the tumor microenvironment within pancreatic cancer, hinting towards affecting, potentially, the stroma.

So, there are multiple mechanisms to Tumor Treating Electric Fields. It is a new, novel therapeutic approach. Sometimes when I speak with my trainees, I say, "Well, we have surgery, we have radiation and chemotherapy, and this is something new." Tumor Treating Fields initially was studied in refractory GBM and got an indication there. Subsequently, frontline treatment of GBM in a randomized clinical trial, and then malignant pleural mesothelioma and non-small cell lung cancer. We have studied it in pancreatic cancer.

Dr. Shannon Westin: I don't think I have ever heard it described so perfectly. That was brilliant. So thank you, and I hope everyone listening knows that you just got a masterclass on this mechanism. You know, they dabbled in it a little bit in ovarian cancer and it didn't quite make the grade, so I was a little definitely disappointed. But very excited about the data we're going to talk about today.

So let's get into the PANOVA-3 study. Can you highlight the overall design and also the key eligibility criteria that would be helpful for our listeners?

Dr. Hani Babiker: Absolutely. So, it started off with preclinical work in pancreatic cancer showing Tumor Treating Fields with chemo abrogate cancer cell perforation. It led to a trial, the PANOVA-2 trial, that was run in Europe that showed efficacy for OS and PFS in patients with locally advanced pancreatic cancer, which included metastatic and locally advanced pancreatic cancer, more so in locally advanced that led to the PANOVA-3 trial, which was an international, global study. This was in more than 190 centers, 20 countries in Latin America, North America, Europe, and Asia. It was a randomized trial. Patients were randomized 1 to 1 to either chemotherapy with gemcitabine plus nab-paclitaxel per drug label. The other arm was with Tumor Treating Fields at 150 kHz for a recommendation for patients to wear it 18 hours per day.

The primary end point of the trial was OS, overall survival. The secondary end point included other efficacy landmarks such as local PFS, pain control, quality of life, and safety. And there was a post hoc that looked at distant PFS.

Dr. Shannon Westin: That's a pretty common secondary end point in pancreatic studies of looking at the pain-free interval. I thought that was really brilliant because, you know, I think in gyn cancers, we see resolution of symptoms as being a really big deal, but it's not necessarily something that we always look at. So I thought that was really nice that you included that.

Okay, talk to us a little bit about the population. So, the population that actually got treated in PANOVA-3 is pretty generalizable to what people are treating in the clinic.

Dr. Hani Babiker: So, in pancreatic cancer, unfortunately, most of our patients present, approximately 80%, with metastatic disease. Local is divided to resectable, borderline, and locally advanced. We studied this trial, a randomized trial, in locally advanced and unresectable, which is really an unmet need. Most of our patients with locally advanced and unresectable are grouped up with other trials in the metastatic setting without a focus on locally advanced and unresectable, save for a few trials. This year, a trial that we were looking for for a long time, the LAPLACE trial, unfortunately, that we were very excited about, this is a molecule that targeted connective tissue growth factor, that showed earlier efficacy in a randomized trial, did not meet up the median OS end point. And hence, PANOVA-3 is the first trial in locally advanced and unresectable that did meet its primary end point.

So, it's a very unmet need in locally advanced and unresectable. A lot of the times, our patients in clinic are treated with frontline chemotherapy that was studied in metastatic disease and locally advanced and unresectable, which include either FOLFIRINOX, NALIRIFOX, or gemcitabine/abraxane. I do have in my clinic multiple patients that would stay on the regimen for such a long time, and then we would have to devise a mechanism of maintenance, although this is not studied really in details, either with capecitabine or dropping the oxaliplatin to continue FOLFIRI. And then we also approach chemoradiotherapy. So the trial was in a disease in pancreatic cancer that really is an unmet need.

So the inclusion criteria included a patient with locally advanced and unresectable. These were done at multiple centers. Most of them academic centers were discussed at the tumor board, and if it's unresectable, they will be meeting specific metrics of appropriate liver function tests, kidney function tests, and blood counts. We excluded patients that obviously had, given that these are electric fields, patients that have, for example, stimulators or pacemakers, knowing that this could potentially affect some of these devices. But for the most part, it was locally advanced and unresectable patients with a very good performance status and good counts.

Dr. Shannon Westin: That's great. I think everyone's excited to hear about the primary outcome of overall survival. What did you find, and how does it compare to some of the recent trials?

Dr. Hani Babiker: We're very excited that it did meet its primary end point of median overall survival. It was very exciting knowing that a lot of us were disappointed a little bit of some of the trials that were presented at ASCO GI, such as the LAPLACE trial that I alluded to. Just before the presentation, the PRODIGE 29 trial that is in locally advanced and unresectable that randomized patients with locally advanced disease to either FOLFIRINOX or single-agent gemcitabine, allowing for a crossover, although it did meet its primary end point of PFS, there was no overall survival benefit. So that kind of got us a little bit disappointed, but having the PANOVA-3 trial being positive in median OS got us all excited.

In addition, the 12-year overall survival rate was increased in both the intention-to-treat and modified intention-to-treat. The modified intention-to-treat were patients that have had at least one cycle of therapy with TTFields daily and/or one cycle with chemotherapy, which was gemcitabine plus nab-paclitaxel. There was a trend to improvement in PFS and local PFS, although that did not have statistical significance, but the 12-year PFS rate in both the intention-to-treat and modified intention-to-treat was significant. For me, as one of the investigators, that told me that there might be a specific biomarker that would tell me that patients could respond greater than others, more exceptional than others, given that 12-month PFS rate was improved. On a post hoc analysis, the distant PFS was improved with the intervention of Tumor Treating Fields with gemcitabine plus nab-paclitaxel. In addition, there was an improvement in global health status and quality of life in addition to pain-free survival, which is a strong hurdle in our patients with pancreatic adenocarcinoma that most present with significant abdominal pain.

Dr. Shannon Westin: One of the other questions that I think has come up is around central review. So did you all use central review in this study?

Dr. Hani Babiker: Most of the centers were academic centers. These were discussed in tumor boards, which included radiation oncologists and surgeons. I wanted to point out that it's very important to note that the primary end point was overall survival. So the primary end point was not PFS. Hence, the central review would help us, for example, with elaborating and making sure patients were actually locally advanced disease, but in a setting where the primary end point is overall survival, that was the key point of the clinical trial. This trial was discussed at academic centers, and all included tumor boards to decide if patients were locally advanced or not. In the trial, there was a good proportion of patients, or percentage, that had a CA 19-9 more than 1000. That could indicate that potentially there are a fraction of patients that actually had metastatic disease, micrometastatic disease. So that could hint towards why the median OS was slightly lower then in both arms when compared to, for example, the trial that was presented at ASCO GI, the LAPLACE trial. However, having said that, we were very excited about the trial. It was the first positive trial in locally advanced and unresectable to meet median OS survival.

Dr. Shannon Westin: It's so awesome. So congratulations. Okay, so let's talk a little bit about your very detailed secondary end points because you had a lot of really prudent choices there. So anything that was interesting or informative in those end points?

Dr. Hani Babiker: One major hurdle back we have for most of our patients with pancreatic adenocarcinoma, like I mentioned earlier, is pain. We try to approach it, obviously, with narcotics. If it doesn't work, we try to do celiac axis block interventionally, and that sometimes is successful and sometimes is not. So actually, to see the pain-free survival end point to be met was very exciting for us. And as for me, as a scientist that studies TTFields in clinic and lab as also to develop a mechanism and understanding really how that works. That was very important for us that in addition to chemotherapy, it improved pain-free survival or deterioration of pain. And most importantly, our patients with pancreatic cancer, this disease is very aggressive. It affects quality of life of patients. Patients feel fatigued, tired. It's a procoagulant tumor that causes clots and strokes, etcetera, marantic endocarditis. And one big problem we deal with when we're seeing patients in clinic is obviously that quality of life. Although data have shown with treatment, with frontline regimens, that quality of life improves with treatment and chemotherapy, it's actually great to see that that improvement happens early in addition to Tumor Treating Fields.

The other interesting point was that it was not only pain and quality of life, but also digestive symptoms that are improved with this intervention, knowing that a lot of our patients do have pancreatic cancer, pancreatic exocrine insufficiency that affect also with digestion, and a lot of our patients have abdominal pain after eating and diarrhea. So it was interesting to see that also improved with the intervention.

Dr. Shannon Westin: You have touched a little bit on some of the adverse events, kind of with the TT mechanisms, but I'd love to hear a little bit more detail around adverse events in general in this study, as well as specific AEs related to the Tumor Treating Fields.

Dr. Hani Babiker: Absolutely. So when we compared both arms, there was a similar toxicity related to the regimen, mostly with chemotherapy, but in specifically to Tumor Treating Fields, there was a rash, and that included dermatitis and rash. Most of the side effects were grade 1 and grade 2. Grade 3 toxicities related to skin was less than 10%, approximately 7% to 8%, and hence did not affect many patients. But it was something to note, and it's something that in the future, when we develop a mechanism of treating patients to note early. We in our clinic have learned to treat patients in the clinical trial early with topical steroids to each patient, of shifting the arrays to mitigate some toxicity and rash. We do advise our patients in hot areas, we keep them aware that sweating, for example, can lead to higher conductivity of electrical fields with a predisposition for rash. So if there's an opportunity to stay in a little bit of a cold area, make sure that the arrays are shifted, use topical steroids early. If it's a significant rash, to hold treatment for at least 48 hours and speak to the investigators. And through these mechanisms, we have learned that we were able to mitigate the rash quite a bit.

Dr. Shannon Westin: That's awesome. Thank you so much. Yeah, I'm, it's summer right now, and I think- I'm in Texas, you're in Florida, like we know.

Okay, so I guess, again, you have been kind of touching on this, but I would love to know, like if in the quality-of-life assessments or if just in your discussions with patients, like how easy is this to use? How easy is the Tumor Treating Fields device to use, and what do patients really think?

Dr. Hani Babiker: Absolutely. We have learned that whenever we speak with patients, it's always good to discuss with them briefly the science of it. A lot of patients would want to know if it's interventional, is that something that goes, is delivered percutaneously or not, and we explain that these are delivered through arrays that are through the skin. We always touch base with them about a lot of question I get about mechanism of action and then about compliance. So I think one important thing to note is that compliance with the use of the device is a lot of the question we'll get quite a bit. Patients know there's going to take an effort from them, and some of my patients enjoyed it because they felt like they also are fighting the disease by wearing the device. I have learned very quickly that having a team, surrounded by a team that knew how to mitigate some of the side effects and knew how to explain how to use the device helped quite a bit. And this included some of our nurses and our nurse practitioners and our clinical research coordinators who've done a wonderful job of showing these arrays actually to patients before they start on the trial, look at it, know how it works.

The other point to know is that the sponsor provided Device Support Specialist, we call them DSS, they have been instrumental in helping us, helping the patients know how to use the device, how to use the generator, how to change the batteries, and that helped us conduct the trials and enroll very well. I would envision in the future with education and relying on the Device Support Specialist and having a team that knows how to use the device and mitigate some of the side effects will go a long way for patients to learn about this treatment. Many of the times our patients said while they are on the clinical trial felt like they are also being part of this team in applying the device and fighting the cancer.

Dr. Shannon Westin: That's awesome.

Well, I guess the bottom line. Is it ready for prime time? Is this something you are going to use for your patients in the clinic?

Dr. Hani Babiker: Absolutely. In a disease that has poor prognosis, and we are trying our best to find new treatments to fight this cancer and treatment modalities, presenting patients with all the treatment options that are out there would be recommended. It's what I would do it for in my clinic. And you know, it's funny that I am mentioning that right now. I had a patient who was seen internationally asking about the trial and the device and had locally advanced and unresectable before they start frontline treatment. I do think that there is going to be an educational piece. Obviously, this is not a pill, it's not an intravenous chemotherapy that we're very well and accustomed to. And some of us in academic centers know it very well. I usually joke that whenever I am talking about it in pancreatic cancer, if there is a radiation oncologist in the room, they will be like, "Yeah, we know all about it. We have been treating patients with GBM over there." So a lot of the times, when we first went to trial, if I had any questions, I would call them and ask them. So from their perspective, they, because they use it as a standard of care in treatment of GBM, they develop significant expertise in it. I think in the GI world, specifically and with oncologists that treat pancreatic cancer and specifically oncologists in the community, learning about the device and how to use it, how to recommend it, how to mitigate side effects, will be hopefully for prime time in the future.

Dr. Shannon Westin: That's great. Sounds like some real educational opportunities there.

Well, this has been awesome. Thank you so much, Dr. Babiker. I mean, I learned a ton, and I wish that we could find a way to use this in gynecologic cancers, but really, really just want to commend you on the design of the trial and the success in this really devastating disease.

So again, this was "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: A Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study."

And as always, I am your host, Shannon Westin. Please go check out our other offerings wherever you get your podcasts and have an awesome day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Babiker Disclosures

Consulting or Advisory Role: Endocyte, Celgene, Idera, Myovant Sciences, Novocure, Ipsen, Caris MPI, Incyte, Guardant Health

Speakers' Bureau: Guardant Health

Research Funding:  Spirita Oncology, Novocure, AstraZeneca, JSI, Incyte, Qurient, HiFiBiO Therapeutics, Revolution Health Care, Elevation Oncology, Dragonfly Therapeutics, Zelbio, BMS, Mirati Therapeutics, Strategia

TRANSCRIPT

Dr. Ece Cali: Hello, and welcome to our series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's most important oncology meetings. I am your host, Dr. Ece Cali, JCO editorial fellow, and I am joined by Dr. Tom Stinchcombe, JCO associate editor, to discuss the Journal of Clinical Oncology article and 2025 World Conference on Lung Cancer abstract presentation, "Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non–Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations."

The WU-KONG1B trial is a multinational, phase II study that investigated the efficacy and safety of different doses of sunvozertinib in patients with metastatic non-small cell lung cancer and EGFR exon 20 insertion mutations after progression on platinum based chemotherapy. Tom, before we dive into the results, could you walk us through the rationale for this study, and how does it fit into the current treatment options for patients with EGFR exon 20 insertion?

Dr. Tom Stinchcombe: Thank you, Dr. Cali. I think the clinical context is always important. We have known that EGFR exon 20 insertions exist and that they are resistant to our currently available EGFR tyrosine kinase inhibitors, and I think there have been attempts in the past to develop a tyrosine kinase inhibitor, but there is a very narrow therapeutic window between the dose you need to inhibit the EGFR mutation in the cancer and the EGFR receptor on normal tissues, most notably the mucosa, the gut, and the skin. And so, our previous attempts have failed largely because the dose required was not tolerable for patients and they could not really stay on the drug for a long time or they were not very active.

And so, I think there was a real desire to develop an EGFR tyrosine kinase inhibitor, and then, historically, the standard had been a platinum based doublet as the standard of care. And more recently, platinum based doublet with amivantamab has proven to be superior to platinum based chemotherapy alone. I think the context is also important that amivantamab is not necessarily available in all the countries, and so, there are patients who do not have access to amivantamab. Going to the rationale, I think that this drug had shown preliminary promise of having activity but without that being encumbered by those EGFR wild type toxicities, and, therefore, it was really explored in this larger study.

Dr. Ece Cali: And what are some key findings from this trial?

Dr. Tom Stinchcombe: So, I think that we should look at the study design. It is a little quirky, for lack of a better term, in that there is a randomization to 200 versus 300 mg, and then, there was a nonrandomized cohort of 300 mg. So, when you look at the study, if you are a purist, you will just look at the randomized patients. If you are sort of an aggregator, you look at all patients. So, it shows reporting on three cohorts, but I think the key findings are that the 200 mg and the 300 mg treatments had similar toxicities in terms of response rate, duration of response, and progression free survival. And as you know going through the review, there was a lot of queries from the reviewers as to which would be the preferred dose, and to me, I think this really illustrates a dose finding component to a trial design because there is a lot of debate about what the minimal effective dose is or the optimal dose. And in this case, having the two dose cohorts did provide us some valuable efficacy and toxicity information. And then, when I look at the study, I want to make sure it reflects my patient population, and about a quarter of patients had brain metastases, and about 15% had previous amivantamab, and about 5% to 10% had another EGFR tyrosine kinase inhibitor.

Dr. Ece Cali: And what is the objective response rate and the duration of response? These are pretty good numbers for this patient population.

Dr. Tom Stinchcombe: In the 200 mg cohort, it was about 46%. The duration of response was around 11 months, and the PFS was around 8 months. The 300 mg cohort was 46%, duration of response 9.8, and the median PFS is 6.9 months, and I think that this is greater activity than we have seen with our previous attempts at EGFR tyrosine kinase inhibitors.

Dr. Ece Cali: And based on these data, FDA granted accelerated approval for sunvozertinib very recently at 200 mg once daily dosing in this setting. So, that is a major step forward for our patients. Dr. Stinchcombe, how does this impact your clinical practice, and what side effects should oncologists be watching for if they prescribe this medication?

Dr. Tom Stinchcombe: So, I think it was very interesting that they chose the 200 mg dose, which I think was more tolerable, and when we kind of look at this, there still was a rate of diarrhea, all grade, rash, paronychia, which are the EGFR related toxicities. There can be some decreased appetite, stomatitis, and then, it can lead to some lab abnormalities, like increased CPK and creatinine that physicians have to be aware of.

You know, how it will affect my practice is that all these patients had received a platinum based chemotherapy as the first line therapy. I think that this would become my preferred second line therapy for patients outside the context of a trial because of the activity and the tolerability.

Dr. Ece Cali: And lastly, several other tyrosine kinase inhibitors are being evaluated for EGFR exon 20 insertion, including in the frontline setting. So, what are some of the outstanding questions in this space, and what data should our listeners keep an eye on moving forward?

Dr. Tom Stinchcombe: I think you are right that now, there is going to be another EGFR tyrosine kinase that may become available in the next year, and there is another drug, furmonertinib, that is being investigated.

I think, for the clinical question, is, well, can we move these into the first line setting? And actually, the development path has two ways of doing this. There is EGFR tyrosine kinase compared to platinum based chemotherapy, and then, platinum based chemotherapy with an EGFR tyrosine kinase versus platinum based chemotherapy, and both have their merits and strengths. And so, I think it is going to be very interesting as we see if those first line trials, one, can they be demonstrated to be superior to platinum based chemotherapy, and then by what magnitude and what the side effects are. But I think we are hoping that in the next couple of years, we will have an additional first line option for our patients.

Dr. Ece Cali: Yeah, it is always great to have more options for our patients.

Thank you, Dr. Stinchcombe, for speaking about the JCO article, "Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations."

Join us again for the latest JCO simultaneous publications. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of World Lung Conference.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Davide Soldato: Hello, and welcome to JCO After Hours, the podcast where we sit down with authors of the latest articles published in the Journal of Clinical Oncology. I'm your host, Dr. Davide Soldato, a medical oncologist at Ospedale San Martino in Genoa, Italy.

Today, we are joined by Dr. Lin, assistant professor in the Department of Health Services Research at the University of Texas MD Anderson Cancer Center. Dr. Lin and I will be discussing the article titled, "Racial and Ethnic Disparities Along the Treatment Cascade Among  Medicare Fee-for-Service Beneficiaries With Metastatic Breast, Colorectal, Lung, and Prostate Cancer."

Thank you for speaking with us, Dr. Lin.

Dr. Lin: Thank you so much for having me. I appreciate it.

Dr. Davide Soldato: So, just to start, to frame a little bit the study, I just wanted to ask you what prompted you and your team to look specifically at this question - so, racial and ethnic disparities within this specific population? And related to this question, I just wanted to ask how this work is different or builds on previous work that has been done on this research topic.

Dr. Lin: Yeah, absolutely. Part of the impetus for this study was the observation that despite people who are black or Hispanic having equivalent health insurance status - they all have  Medicare Fee-for-Service - we've known that treatment and survival differences and disparities have persisted over time for patients with metastatic breast, colorectal, lung, and prostate cancer. And so, the question that we had was, "Why is this happening, and what can we do about it?"

One of the reasons why eliminating racial and ethnic disparities in survival among Medicare beneficiaries with metastatic cancer has been elusive is because these disparities are occurring along a lot of dimensions. Whether or not it's because the patient presented late and has very extensive metastatic cancer; whether or not the patient has had a difficult time even seeing an oncologist; whether or not the patient has had a difficult time starting on any systemic therapy; or maybe it's because the patient has had a difficult time getting guideline-concordant systemic therapy because, more recently, these treatments have become so expensive. Disparities, we know, are occurring along all of these different facets and areas of the treatment cascade. Understanding which one of these is the most important is the key to helping us alleviate these disparities. And so, one of our goals was to evaluate disparities along the entire treatment cascade to try to identify which disparities are most important.

Dr. Davide Soldato: Thank you very much. That was very clear. So, basically, one of the most important parts of the research that you have performed is really focusing on the entire treatment cascade. So, basically, starting from the moment of diagnosis up to the moment where there was the first line of treatment, if this line of treatment was given to the patient.

So, I was wondering a little bit, because for this type of analysis, you used the SEER-Medicare linked database. So, can you tell us a little bit which was the period of time that you selected for the analysis? Why do you think that that was the most appropriate time to look at this specific question? And whether you feel like there is any potential limitation in using this type of database and how you handled this type of limitations?

Dr. Lin: Yeah, absolutely. It's a great question. And I want to back up a little bit because I want to talk about the entire treatment cascade because I think that this is really important for our research and for future research. We weren't the first people to look at along the treatment cascade for a disease. Actually, this idea of looking along the treatment cascade was pioneered by HIV researchers and has been used for over a decade by people who study HIV. And there are a lot of parallels between HIV and cancer. One of them is that with HIV, there are so many areas along that entire treatment cascade that have to go right for somebody's treatment to go well. Patients have to be diagnosed early, they have to be given the right type of antiretrovirals, they have to be adherent to those antiretrovirals. And if you have a breakdown in any one of those areas, you're going to have disparities in care for these HIV patients.

And so, HIV researchers have known this for a long time, and this has been a big cornerstone in the success of getting people with HIV the treatment that they need. And I think that this has a lot of parallels with cancer as well. And so, I am hoping that this study can serve as a model for future research to look along the entire treatment cascade for cancer because cancer is, similarly, one of these areas that requires multidisciplinary, complex medical care. And understanding where it is breaking down, I think, is crucial to us figuring out how we can reduce disparities.

But for your question about the SEER-Medicare linked database, so we looked between 2016 and 2019. That was the most recent data that was available to us. And one of the reasons why we were excited to look at this is because there were some new treatments that were just released and FDA-approved around 2018, which we were able to study. And this included immunotherapy for non–small cell lung cancer, and then it also included androgen receptor pathway inhibitors, the second-generation ones, for prostate cancer. And the reason why this is important is because for some time, as we have developed these new therapies, there's been a lot of concern that there have been disparities in access to these novel therapies because of how expensive they are, particularly for the Medicare population. And so one of the reasons why we looked specifically at this time period was to understand whether or not, in more recent years, these novel therapies, people are having increasing disparities in them and whether or not increasing disparities in these more expensive, newer therapies is contributing to disparities in mortality. That being said, obviously, we're in 2025 and these data are by now six years old, and so there are additional therapies that are now available that weren't available in the past. But I think that, that being said, at least it's sort of a starting point for some of the more important therapies that have been introduced, at least for non–small cell lung cancer and prostate cancer.

And the database, SEER-Medicare, is helpful because it uses the population cancer registry, which is the SEER registry cancer registry, linked to Medicare claims. So, any type of medical care that's billed through Medicare, which is going to basically be all of the medical care that these patients receive, for the most part, we're going to be able to see it. And so, I think that this is a really powerful database which has been used in a lot of research to understand what kind of care is being received that has been billed through Medicare.

So, one of the limitations with this database is if there is care that's received that was not billed through Medicare, we're not going to be able to see that. And this does not happen probably that frequently, particularly because most patients who have insurance are going to be receiving care through insurance. However, we may see it for some of the oral Part D drugs. Some of those drugs are so expensive that patients cannot pay for the coinsurance during that time. And it's possible that some of those drugs patients were getting for free through the manufacturer. We potentially missed some of that.

Dr. Davide Soldato: So, going a little bit into the results, I think that these are very, very interesting. And probably the most striking one is that when we look at the receipt of any type of treatment for metastatic breast, colorectal, prostate, and lung cancer - and specifically when we look at guideline-directed first-line treatments - you observed striking differences. So, I just wanted you to guide us a little bit through the results and tell us a little bit which of the numbers surprised you the most.

Dr. Lin: So, what we were expecting is to see large disparities in receiving what we called guideline-directed systemic therapy. And guideline-directed systemic therapy during this time kind of depended on the cancer. So, we thought that we were going to see large disparities in guideline-directed therapy because these were the more novel therapies that were approved, and thus they were going to be the more expensive therapies. And so, what this meant was for colorectal cancer, this was going to be any 5-FU–based therapy. For lung cancer, this was going to be any checkpoint inhibitor–based therapy. For prostate cancer, this was going to be any ARPI, so this was going to be things like abiraterone or enzalutamide. And for breast cancer, this was going to be CDK4 and 6 TKIs plus any aromatase inhibitor. And so, for instance, for breast, prostate, and lung cancer, these were going to be including more expensive therapies. And so, what we expected to see was large disparities in receiving some of these more expensive, novel therapies. And we thought we were going to see fewer disparities in receiving some of the cheaper therapies, such as aromatase inhibitors, 5-FU, older platinum chemotherapies for lung cancer, and ADT for prostate cancer.

We were shocked to find that we saw large racial and ethnic disparities in seeing some of the older, cheaper chemotherapies and hormonal therapies. So for instance, for breast cancer, 59% of black patients received systemic therapy, whereas 68% of white patients received systemic therapy. For colorectal, only 23% of black patients received any systemic therapy versus 34% of white patients. For lung, only 26% of black patients received any therapy, whereas 39% of white patients did. And for prostate, only 56% of black patients received any systemic therapy versus 77% of white patients. And so, we were pretty shocked by how large the disparities were in receiving these cheap, easy-to-access systemic therapies.

Dr. Davide Soldato: Thank you very much. So, I just wanted to go a little bit deeper in the results because, as you said, there were striking differences even when we looked at very old and also cheap treatments that, for the majority of the patients that were included inside of your study, were actually basically available for a very small price to these patients who had the eligibility for Medicare or Medicaid. And I think that one of the very interesting parts of the research was actually the attention that you had at looking how much of these disparities could be explained by several factors. And actually, one of the most interesting results is that you observed that low-income subsidy status was actually a big determinant of these disparities in terms of treatment. So, I just wanted to guide us a little bit through these results and then just your opinion about how these results should be interpreted by policymakers.

Dr. Lin: Yeah, absolutely. I'm going to explain a little bit about what low-income subsidy status is and dual-eligibility status. Some of the listeners may not know what low-income subsidy status or dual-eligibility status is. Low-income subsidy status is part of Medicare Part D. Medicare Part D is an insurance benefit that allows patients to receive oral drugs. So these are drugs that are dispensed through the pharmacy, such as the CDK4/6 inhibitors, as well as second-generation ARPIs in our study. For patients who have Medicare Part D and whose income is low enough - falls below a certain federal poverty level threshold - those patients will receive their oral drugs for much cheaper. And this is really important for some of these more novel therapies because for some of these more novel therapies, if you don't have low-income subsidy status, you may be paying thousands of dollars for a single prescription of those drugs. Whereas if you have low-income subsidy status, you may be paying less than $10. And so that difference, greater than $1,000 or $2,000 versus less than $10, one would think that the patient who's paying less than $10 would be much more likely to receive those therapies. So that's low-income subsidy status.

Low-income subsidy status, importantly, doesn't apply for infused medications like immunotherapy. But it's important to know that most people with low-income subsidy status - about 88% - are also dual-eligible. What dual-eligible means is that they have both Medicare and Medicaid. Medicare being the insurance that everybody has in our study who's greater than 65. And Medicaid is the state-run but federally subsidized insurance that patients with low incomes have. And so patients who are dual-eligible - and about 87% of those with low-income subsidy status are dual-eligible - those patients have both Medicaid and Medicare, and they basically pay next to nothing for any of their medical care. And that's because Medicare will reimburse most of the medical care and the copays or coinsurance are going to be covered by Medicaid. So Medicaid is going to pick up the rest of the bill. So, most of the patients who have low-income subsidy status who are dual-eligible, these patients pay almost nothing for their medical care - Part B or Part D, any of their drugs.

And so, one would expect that if cost were the main determinant of disparities in cancer care, then one would expect that dual-eligibles, most of them would be receiving treatment because they're facing minimal to no costs. What we found is that when we broke down the racial and ethnic disparity by a number of factors - including LIS status/dual eligibility, age, the number of comorbidities, etcetera - what we found was that the LIS or dual-eligibility status explained about 20% to 45% of the disparities that we saw in receiving treatment. And what that means is despite these patients paying next to nothing for their drugs, these are the most likely patients to not be treated for their cancer at all. So they're most likely to basically be diagnosed, survive for two months, see an oncologist, and then never receive any systemic therapy for their cancer. And this is not just chemotherapies for colorectal or lung cancer. This includes cheaper, easier-to-tolerate hormonal therapies that you can just take at home for breast cancer, or you can get every six months for prostate cancer, that people who even have poorer functional status are able to take. However, for whatever reason, these dual-eligible or LIS patients are very unlikely to receive treatment compared to any other patient. The low likelihood of treating this group of patients, that explains a large portion of the racial and ethnic disparities that we see.

Dr. Davide Soldato: And one thing that I think is very interesting and might be of potential interest to our listeners is, did you compare survival outcomes in these different settings? And did you observe any significant differences in terms of racial and ethnic disparities once you saw that there was a significant difference when looking at both receipt of any type of treatment and also guideline-directed treatments?

Dr. Lin: We saw that there were large disparities in survival by race and ethnicity when you look overall. However, when you just account for the patients who received any systemic therapy at all - not just guideline-directed systemic therapy - those differences in survival essentially disappeared. And so, what that suggests is that if black patients were just as likely to receive any systemic therapy at all as white patients, we would expect that the survival differences that we were seeing would disappear. And this is not even just looking at guideline-directed systemic therapy. This was looking just at systemic therapy alone. And so, while guideline-directed systemic therapy should be a goal, our research suggests that if we are to close the gap in disparities in overall survival among black and white patients, we must first focus on patients just receiving any type of treatment at all. And that should be the very first focus that policymakers, that leaders in ASCO, that health system leaders, that physicians, that we should focus on: just trying to get any type of treatment to our patients who are poorer or black.

Dr. Davide Soldato: Thank you very much. And this was not directly related to the research that you performed, but going back to this very point - so, increasing the number of patients that receive any kind of systemic treatment before looking at guideline-directed treatments - what would you feel would be the best way to approach this in order to decrease the disparities? Would you look at interventions such as financial navigation or maybe improving referral pathways or providing maybe more culturally adapted information to the patients? Because in the end, what we see is disparities based on racial and ethnicity. We see that we can reduce these disparities if we get these patients to the treatment. But in the end, what would you feel is the best way to bring patients to these types of treatments?

Dr. Lin: I think the most important thing is to understand that these disparities are not primarily happening because of the high cost of cancer treatment. These disparities are happening because of other social vulnerabilities that these patients are facing. And so these vulnerabilities could be a lot of things. It could be mistrust of the medical system. It could be fear of chemotherapy or other treatments. It could be difficulty taking time off of work. It could be any number of things.

What we do know is when we've looked at the types of interventions that can help patients receive treatment, navigation is probably the most effective one. And the reason why I think that is because when patients don't receive treatment because of social vulnerability, I sort of look at social vulnerability like links in a chain. Any weakest link is going to result in the patient not receiving treatment. This may be because they have a hard time taking time off of work. This may be because they had a hard time getting transportation to their physician. It may be because they had an interaction with a physician, but that interaction was challenging for the patient. Maybe they mistrusted the physician. Maybe they're worried about the medical system. If any of these things goes wrong, the patient is not going to be treated. The patient navigator is the only person who can spot any of those weak links within the chain and address them.

And so, I think that the first thing to do is to get patient navigation systems in place for our vulnerable patients throughout the United States. And this is incredibly important because in Medicare, patient navigation is reimbursable. And so this is not something that's 'pie in the sky'. This is something that's achievable today.

The second thing is that it's really important that we see these vulnerabilities happening for patients who are dual-eligible, who have both Medicare and Medicaid. One of the reasons why this is important is because there has been a lot of research outside of what we've done that has shown vulnerabilities for dual-eligible patients who have Medicare for a number of different diseases. And the reason why is because, although patients are supposed to have the benefits of both Medicare and Medicaid, usually these two insurances do not play nicely together. It creates a huge, bureaucratic, complex mess and maze that most of these patients are unable to navigate. And so many of these patients are unable to actually receive the full reimbursement from both Medicare and Medicaid that they should be getting because those two insurers are not communicating well. And so the second thing is that national cancer organizations need to be supporting policies and legislation that is already being discussed in Congress to revamp the dual-eligible system so that it facilitates these patients getting properly reimbursed for their care from both Medicare and Medicaid and these systems working together well.

The third thing is that Medicaid itself has many benefits that can allow patients to receive care, like they have transportation benefits so that patients can get to and from their doctor's appointments with ease. And so I think this will be additionally very, very helpful for patients.

The last thing is, you know, it's possible that future innovations such as telemedicine and tele-oncology and cancer care at home can also make it easier for some of these patients who may be working a lot to receive care.

But what I would say is that our study should be a call for healthcare delivery researchers to start piloting interventions to be able to help these patients receive systemic therapy. And so what this could look like is trying to get that care navigation and implement that in clinics so that patients can be receiving the care that they need.

Dr. Davide Soldato: Thank you very much. That was a very clear perspective on how we can tackle this issue. So, I just wanted to close with a sort of personal question. I was wondering what led you to work specifically in this research field that is very challenging, but I think it's particularly critical in healthcare systems like in the United States.

Dr. Lin: Yeah, absolutely. One of the most important things for me as an oncologist and a researcher is being able to know that all patients in the United States - and obviously abroad - who have cancer should be able to receive the kind of care that they deserve. I don't think that patients, because their incomes are lower or because their skin looks a certain color or because they live in rural areas, these shouldn't be determinants of whether or not cancer patients are receiving the care that they need. We can develop and pioneer the very best treatments and breakthroughs in oncology, but if our patients are not receiving them - if only 20% of our patients with colon cancer or lung cancer are receiving any type of systemic therapy, who are black - this is a big problem. But this is something that I think that our system can tackle. We need to get these breakthroughs that we have in oncology to every single cancer patient in America and every single cancer patient in the world. I think this is a goal that all oncologists should have, and I think that this is something that, honestly, is achievable. I think that research is a powerful tool to give us a lens into understanding exactly why it is that certain patients are not getting the care that they deserve. And my goal is to continue to use research to shed light on why our system is not performing the way that we all want it to be.

Dr. Davide Soldato: Circling back to your research, actually the manuscript that was published was supported by a Young Investigator Award by the American Society of Clinical Oncology. So, was this the first step of a more broad research, or do you have any further plans to go deeper in this topic?

Dr. Lin: Yeah, absolutely. First, I want to thank the ASCO Young Investigator Award for funding this research because I think it's fair to say that this research would not have happened at all without the support of the ASCO YIA. And the fact that ASCO is doing as much as it can to support the future generation of cancer researchers is incredible. And it's a huge resource, and having it come at the time that it did is critical for so many of us. So I think that this is an unbelievable thing that ASCO does and continues to do with all of its partners.

For me, yeah, this is definitely a stepping stone to further research.  Medicare Fee-for-Service is only one part of the population. I want to spread this research and extend it to patients who have other types of insurances, look at other types of policies, and also try to conduct some of the cancer care delivery research that's needed to try to pilot some interventions that can resolve this problem. So hopefully this is the first step in a broader series of studies that we can all do collectively to try to eliminate racial and ethnic disparities in cancer care and survival.

Dr. Davide Soldato: So, I think that we've come at the end of this podcast. Thank you again, Dr. Lin, for joining us today.

Dr. Lin: Thank you so much. It was a pleasure to be a part of this.

Dr. Davide Soldato: So, we appreciate you sharing more on your JCO article, "Racial and Ethnic Disparities Along the Treatment Cascade Among Medicare Fee-for-Service Beneficiaries With Metastatic Breast, Colorectal, Lung, and Prostate Cancer."

If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

Joseph Mathew: Welcome to the Journal of Clinical Oncology Article Insights episode for the August issue of the JCO. This is Joseph Mathew, editorial fellow for JCO, and today, it is my pleasure to have with us Dr. Haiquan Chen and Dr. Yang Zhang, authors of the recently published manuscript, "Phase 3 Study of Mediastinal Lymph Node Dissection for Ground-Glass Opacity-Dominant Lung Adenocarcinoma," which we will be discussing today. Dr. Chen is the Director of the Institute of Thoracic Oncology at Fudan University and the Chief of Thoracic Surgery at Fudan University Shanghai Cancer Center, where he is also the Head of Thoracic Oncology MDT and the Director of the Lung Cancer Center. Dr. Chen is a surgeon-scientist and a pioneer in developing individualized surgical strategies for early-stage non-small cell lung cancer. Dr. Zhang is a surgical oncologist and a member of the team which Dr. Chen leads at the Fudan University Shanghai Cancer Center.

Welcome Dr. Chen and Dr. Zhang. Thank you very much for accepting our invitation and joining us today as part of this podcast episode.

To summarize the salient points, this study presented the interim analysis of a multi-center, open-label, non-inferiority, randomized controlled trial investigating the necessity of systematic mediastinal lymph node dissection at the time of segmentectomy or lobectomy in patients with clinical stage T1N0M0 ground-glass opacity-dominant invasive lung adenocarcinoma, as defined by a consolidation-to-tumor ratio of 0.5 or less on thin-section computed tomography and a maximum tumor diameter of 3 cm or less. Eligible participants with intraoperatively confirmed invasive adenocarcinoma on frozen section analysis were randomized to either the systematic mediastinal lymph node dissection arm or to no mediastinal lymph node dissection. In the latter experimental group, mediastinal lymph nodes comprising the N2 nodal stations were not dissected, and the hilar nodes were variably addressed at the discretion of the operating surgeon.

The primary endpoint of the trial was disease-free survival at 3 years. Secondary endpoints included perioperative outcomes, the status of lymph node metastasis in the systemic lymph node dissection arm, and 3-year overall survival. Before the trial reached its accrual target, a pre-planned interim safety analysis set for the time point when enrollment reached 300 patients was performed. It was noted that while none of the patients in either arm had nodal metastasis on postoperative pathological evaluation, lymph node dissection-related intraoperative and postoperative complications were more commonly observed in the systematic lymph node dissection arm, including one life-threatening episode of massive bleeding. Since this met the predefined criteria for trial termination, and in accordance with the principle of non-maleficence, further recruitment was stopped and the trial terminated.

Although the 3-year disease-free survival and the overall survival for the enrolled patients were comparable, operative outcomes, including the duration of surgery, blood loss, chest tube duration, length of postoperative stay, and the rate of clinically significant complications, were significantly lower in the experimental arm compared with the systematic lymph node dissection group. The authors concluded that for well-selected patients, mediastinal nodal dissection could be omitted without adversely affecting oncological outcomes, representing a significant shift in current surgical practice, given that guidelines the world over recommend systematic lymph node dissection or sampling for all invasive lung cancers.

In summary, this study addressed a clinically relevant question with regard to the extent of nodal dissection, especially in the light of recent evidence recommending less extensive parenchymal dissections for early-stage non-small cell lung cancer, with the findings suggesting that invasive lung adenocarcinoma associated with ground-glass opacities of consolidation-to-tumor ratio up to 0.5 was an excellent predictor of tumor biology, and in clinical T1N0M0 lesions, a reliable predictor of negative mediastinal lymph node involvement.

So Dr. Chen and Dr. Zhang, could you tell us some more about what led you to do this research and the challenges which you faced while recruiting patients for this trial?

Dr. Yang Zhang: Dr. Mathew, thank you for your summary. The current clinical guidelines recommend systematic lymph node dissection or sampling for every patient with early-stage lung cancer, regardless of their lymph node status. And in our clinical practice, we observe that this procedure causes a lot of surgical complications including chylothorax and recurrent laryngeal nerve injury. Furthermore, dissecting the tumor-draining lymph nodes actually may potentially damage the body's anti-tumor immunity. So, Dr. Chen proposed the concept of selective lymph node dissection, which we aimed to dissect the metastatic lymph nodes, while at the same time we try to preserve as many uninvolved lymph nodes as possible.

So previously, we have conducted a series of retrospective studies to identify reliable predictors of nodal negative status in certain mediastinal zones, and we have performed a prospective observational phase 2 clinical trial to validate that the six criteria we proposed are 100% in predicting node-negative status. And this forms the basis for our phase 3 clinical trial.

Dr. Haiquan Chen: This trial is only one of the series of trials. The meaning of this trial you already said. And for a long time, from the surgeon's point of view, we considered minimally invasive surgery. It minimizes the size of the incision and minimizes the number of the holes we made. So, the true and the high-impact of minimally invasive, we make a concept of minimal dissection, that means organ-level minimally invasive. So we proposed the concept of minimally invasive 3.0, that means minimal incision, minimal dissection (that means organ-level minimal), and systemic minimally invasive.

So at first, we judged from the point of minimally invasive surgery. As long as immunotherapy is widely used in the clinical practice, we know immunotherapy, that means you use drugs to stimulate and activate the lymph node site. If we dissect all the metastatic lymph nodes, cut them out, how can we restimulate that lymph node site? So, from minimally invasive trauma and second, from the functional aspect, to try to save as many uninvolved lymph nodes as possible.

Joseph Mathew: Thank you, Dr. Chen. That's a very interesting concept that you alluded to even in the discussion of this paper, as to the potential role of the non-metastatic lymph nodes as immune reservoirs.

So, coming back to this paper, were there any challenges which you faced while recruiting patients for this trial?

Dr. Haiquan Chen: The criteria is very clear. That means invasive adenocarcinoma, that means most of the centimeter is 3.0 centimeter and also CTR ratio less than 0.5. And we can see that, you know, we did study about that. Even the invasive component of the subsolid nodule, it's bigger than the solid part. That means even the pure GGO, we can find out that there's still some invasive component. From this point of view, pure GGO and subsolid GGO, from this part of invasive carcinoma, that means it's a special clinical subtype that we, from retrospective study and also prospective study, we find out this group of patients, there are no mediastinal lymph node metastasis. So I think it's very important for this kind of group that we can avoid doing the mediastinal lymph node dissection. And we can do organ-level minimally invasive surgery. And also, we try to keep the patient's immune function as normal as possible.

Dr. Yang Zhang: Well, Dr. Mathew, we believe that the biggest challenge when we are enrolling these patients is that there needs to be a paradigm shift in the mind because systematic lymph node dissection has long been the standard of care. And some patients may misunderstand. Before the enrollment, we have to give them informed consent, but if the patient hears that they may be enrolled in the no-lymph-node-dissection group, they may feel that they do not receive radical, curative-intent surgery. So we believe, as Dr. Chen has said, after the release of our results, the no-lymph-node dissection may be incorporated in the future guideline for those patients without lymph node involvement, we can just omit the lymph node dissection.

Joseph Mathew: The study described two pre-planned interim points during the course of subject enrollment when the data was analyzed. So Dr. Chen and Dr. Zhang, could you please explain a little more about these two interim points of analysis that were planned and the rationale behind it?

Dr. Yang Zhang: When conducting this trial, we have two concerns. One is if there is any lymph node metastasis, there may be omission of metastatic lymph nodes not dissected in the no-lymph-node-dissection group. And there is another concern is that if all these lymph nodes are uninvolved, then dissecting these lymph nodes may cause life-threatening complications. So, we set the 150 interim analysis to ensure that there is no lymph node involvement in this group. And the other early termination criteria is set because if there is no lymph node involvement found in both groups, then a severe complication which is life-threatening is unacceptable because it threatens the patient's safety.

Joseph Mathew: So, although you did briefly allude to in the paper, what was the basis for selecting DFS as the primary endpoint when the objective of this trial was to assess nodal involvement in this subset of tumors?

Dr. Yang Zhang: Well, previously, we have done a series of retrospective studies and one prospective phase 2 trial. And in these studies, we have identified that GGO-dominant lung adenocarcinoma, even if it's invasive, it has no lymph node involvement. So this phase 3 trial was primarily designed to compare the survival outcomes. But as the trial went on, as Dr. Chen has concerns that if the patients have no lymph node metastasis at all, it may be unfair to dissect the lymph nodes for patients enrolled in the systematic lymph node dissection group. So there is one life-threatening complication that happens due to dissecting the lymph nodes and injury to the superior vena cava, which leads to massive bleeding. It is at this point that we decided to terminate this trial for patient safety concerns.

Joseph Mathew: Yeah, that's a very fair point. So you made sure that the ethical considerations were kept intact.

So another point was, there was a mention in the study of the historical data from your institution suggesting a 3-year disease-free survival of 96.6% for patients with clinical T1N0M0 ground-glass opacity-dominant invasive lung adenocarcinoma. So could you please elaborate on the patterns of recurrence which you noted for this group of patients who had developed a recurrence?

Dr. Haiquan Chen: Yeah, I think over 90% 3-year DFS, that's the least. From our retrospective data for this kind of group of patients, their DFS is so good. To the best of my knowledge, almost 100%. So this is very conservative, 94, 90% is very conservative. I think the trial eventually would have been positive. It's a special clinical subtype, even for invasive adenocarcinoma, their prognosis is much better than the other type of invasive adenocarcinoma.

Joseph Mathew: So this question may be slightly outside the purview of this study, but in your clinical practice, would you advocate either segmentectomy or lobectomy for all patients meeting the trial criteria, that is, lesions measuring 3 cm or less with a CTR of up to 0.5? Or is there a subgroup of patients you would recommend a wedge dissection for?

Dr. Haiquan Chen: I think CTR ratio is one parameter and also the location is another very important parameter. So we put it together to make a decision, the patient should do a lobectomy or segmentectomy. Even for an ongoing trial, for even the patient, invasive adenocarcinoma, we can do in the right location, even wedge, it can achieve enough negative margin in the ongoing trial to verify the comparable result for the patient, we can do the wedge dissection. So not just the CTR ratio, that's not the only parameter to make a decision on what kind of procedure we'll do.

Joseph Mathew: Yeah, great point, Dr. Chen. So from my perspective, this study was a well-designed, randomized control trial based on a relevant and clinically valid research question. So what, in your opinion, are the main strong points of this study?

Dr. Yang Zhang: We believe that this study represents the first randomized clinical trial published, yet, regarding the topic of selective lymph node dissection. It basically offers the highest level of evidence. We believe our results should be incorporated in the future clinical guideline.

Joseph Mathew: Given the increasing incidence of these lesions, I think it was- a randomized control trial in this arena was much awaited. And the other point is that GGO-dominant lung adenocarcinomas, the specific clinical guidelines are not very clear. So I think your study brought out that lymph node dissection for these tumors which satisfy the eligibility criteria could be omitted safely. Important consideration here is that the conclusions of the trial were based on an interim analysis, and this analysis was not planned for an early assessment of the primary endpoint. In other words, the study was not adequately powered to detect a significant difference in DFS at 3 years.

So Dr. Chen and Dr. Zhang, what do you perceive are the most important limitations of this study which you feel should be addressed in future research?

Dr. Haiquan Chen: So the surgery now is more individualized. I think the surgery from the last two decades, from the maximum tolerable intervention to minimum effective treatment, there's a big shift. So I think that the consensus, we can preserve normal lung parenchyma as much as possible. For the lymph nodes, I think that the big shift, we should shift it to keep as many as uninvolved lymph nodes as possible. So that's very important, not just to reduce the intraoperative trauma, but also to keep the immune environment as normal as possible.

Joseph Mathew: Another point was the limited long-term follow-up data to determine the actual impact of omitting lymph node dissection on local-regional disease control. So is any future follow-up planned to assess the long-term survival outcomes for the 302 patients which were enrolled in this trial?

Dr. Haiquan Chen: Yeah, I think that's very important for us. This trial we terminated just because if we keep the trial going, it's unfair for the mediastinal lymph node dissection group. We tried to just stop here, and we shifted to the single-arm trial. So, 2 or 3 years, this trial and another trial, they will give our final result to demonstrate more if selective mediastinal lymph nodes have a better result than ever before. And we will support the mediastinal lymph node dissection. That's one way.

And the American College just asked me, how can we put this policy into clinical practice in the United States? Because most of the patients they meet have solid tumors. So we have another trial, try to figure out how we can make sure before and intraoperative the lymph node status is negative or positive, and then we can solve that problem and put this policy into clinical practice in the Western society.

Joseph Mathew: Great. So that would be something we should all be looking forward to. So, this brings me to the final point of discussion on future research in this field. Dr. Chen, you commented in the paper that future studies should focus on improving the reproducibility of CTR evaluation. What are your thoughts on this subject?

Dr. Haiquan Chen: The CTR ratio, the concept from the JCOG 0201, just a concept from that prospective study, the phase 2 study, only subgroup analysis they give the concept of CTR ratio and the diameter. How can we reproduce? In our group and also I believe in Japan and in China, in Korea, and in our daily practice, I think CTR ratio is not a big issue. There are two very important things. One, you make sure the CTR ratio, not in a common CAT scan, but in a high-resolution CAT scan. So the imaging, that's the first thing. And the second, not from the single section and a two or three section, you make sure that your calculation is accurate. That's not just the single section, you make sure that you got the conclusion, the CTR ratio is the same number. We make sure that totally we, from the top to the bottom of the whole lesion, we make sure that the CTR ratio is accurate.

Joseph Mathew: Thank you, Dr. Chen. I think that would involve training our radiologists also to be aware of the CTR ratio and how it should be interpreted.

So another very interesting concept which you had alluded to in the discussion was the potential role of non-metastatic lymph nodes as immune reservoirs. So how do you think we could preserve these nodes and do you think sentinel node biopsies would play a role in future?

Dr. Yang Zhang: Actually, Dr. Chen has also led some basic research on this topic. We are investigating the immunological role of the tumor-draining lymph nodes. And our preliminary results have already shown that the tumor-draining lymph nodes of lung cancer, especially those uninvolved lymph nodes, have a vital role in the anti-tumor immunity and also effective response to the current anti-PD-1 immunotherapy. In the future, we believe that by incorporating our clinical evidence and those findings from our basic research, we will be able to provide very strong rationale to support selective lymph node dissection.

Joseph Mathew: So lastly, what are the questions that still remain to be answered and what do you perceive as the next step in this field?

Dr. Haiquan Chen: I think for the lung cancer surgery, especially for the cT1N0M0, they are more individualized. We can, based on the patient, the location, the CTR ratio, we can do wedge dissection, or segmentectomy, or lobectomy. For the lymph node dissection, we can do no mediastinal lymph node dissection or selective, only to dissect the positive one, or we have to do the systemic mediastinal lymph node dissection. So we can see there are too many combinations. So in the near future, for the surgery perspective, we have it more individualized. In the future, we just try to make sure we do not cut as many as possible. We just make sure that we can avoid over-diagnosis or overtreatment or over-dissected. I think that in the near future, that goal will come true.

Joseph Mathew: That's a great point, Dr. Chen. So that would be something also for the thoracic oncology community to work towards.

This wraps up today's episode of JCO Article Insights. Dr. Chen and Dr. Zhang, thank you very much for taking the time to join us today in what has been a very insightful session.

Dr. Haiquan Chen: Thank you.

Dr. Yang Zhang: Thanks.

Joseph Mathew: To our audience, thank you for listening. Please stay tuned for more interviews and articles, summaries, and be sure to leave us your comments and ratings. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

Michael Hughes: Welcome to this episode of JCO Article Insights. This is Michael Hughes, JCO's editorial fellow. Today I am interviewing Dr. Nikhil Munshi on the "International Myeloma Society and International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma" by Avet-Loiseau et al.

At the time of this recording, our guest has disclosures that will be linked in the transcript.

While some patients with multiple myeloma live for decades after treatment, others exhibit refractory or rapidly relapsing disease irrespective of treatment administered. We term this "high-risk myeloma." Multiple risk stratification systems have been created, starting with the Durie-Salmon system in 1975 and evolving with the advent of novel therapeutics and novel treatment approaches.

In 2015, the Revised International Staging System (R-ISS) was introduced, which incorporated novel clinical and cytogenetic markers and remained, until recently, a mainstay of risk stratification in newly diagnosed disease. Myeloma as a field has, just in the past few years, though, undergone explosive changes. In particular, we have seen groundbreaking advances not only in treatments - the introduction of anti-CD38 agents and the advent of cellular and bispecific therapies - but also in diagnostic technology and our understanding of the genetic lesions in myeloma.

This has led to the proliferation of numerous trials employing different definitions of high-risk myeloma, a burgeoning problem for patients and providers alike, and has prompted attempts to consolidate definitions and terminology. Regarding cytogenetic lesions, at least, Kaiser et al's federated meta-analysis of 24 therapeutic trials, published here in the JCO in February of 2025 and recently podcasted in an interview with associate editor Dr. Suzanne Lentzsch, posited a new cytogenetic classification system to realize a shared platform upon which we might contextualize those trial results.

This article we have here by Dr. Avet-Loiseau, Dr. Munshi, and colleagues, published online in early June of this year and hot off the presses, is the definitive joint statement from the International Myeloma Society (IMS) and the International Myeloma Working Group (IMWG). What is high-risk multiple myeloma for the modern era?

The IMS and IMWG Genomics Workshop was held in July 2023 and was attended by international myeloma experts, collaborating to reach consensus based on large volumes of data presented and shared. The datasets included cohorts from the Intergroupe Francophone du Myélome (IFM); the HARMONY project, comprised of multiple European academic trials; the FORTE study, findings from which solidified KRd as a viable induction regimen; the Grupo Español de Mieloma Múltiple (GEM) and the PETHEMA Foundation; the German-Speaking Myeloma Multicenter Group (GMMG); the UK-based Myeloma XI, findings from which confirmed the concept of lenalidomide maintenance; Emory 1000, a large, real-world dataset from Emory University in Atlanta; the Multiple Myeloma Research Foundation Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile (CoMMpass) dataset; and some newly diagnosed myeloma cohorts from the Mayo Clinic.

Data were not pooled for analyses and were assessed individually - that is to say, with clear a priori understanding of whence the data had been gathered and for what original purposes. Consensus on topics was developed based on the preponderance of data across studies and cohorts.

In terms of results, substantial revisions were made to the genomic staging of high-risk multiple myeloma, and these can be sorted into three major categories: A) alterations to the tumor suppressor gene TP53; B) translocations involving chromosome 14: t(14;16) (c-MAF overexpression), t(14;20) (MAFB overexpression), and t(4;14) (NSD2 overexpression); and C) chromosome 1 abnormalities: deletions of 1p or additional copies of 1q.

In terms of category A, TP53 alterations: Deletion of 17p is present in up to 10% of patients at diagnosis and is enriched in relapsed or refractory disease. This is well-documented as a high-risk feature, but the proportion of the myeloma cells with deletion 17p actually impacts prognosis. GEM and HARMONY data analyses confirmed the use of 20% clonal cell fraction as the optimal threshold value for high-risk disease. That is to say, there must be the deletion of 17p in at least 20% of the myeloma cells on a FISH-analysis of a CD138-enriched bone marrow sample to qualify as high-risk disease.

TP53 mutations can also occur. Inactivating mutations appear to have deleterious effects similar to chromosomal losses, and the biallelic loss of TP53, however it occurs, portends particularly poor prognosis. This effect is seen across Myeloma XI, CoMMpass, and IFM cohorts. Biallelic loss is rare, it appears to occur in only about 5% of patients, but next-generation sequencing is nevertheless recommended in all myeloma patients.

Category B, chromosome 14 translocations: Translocation t(14;16) occurs in about 2% to 3% of patients with newly diagnosed disease. In the available data, primarily real-world IFM data, t(14;16) almost always occurs with chromosome 1 abnormalities. Translocation t(4;14) occurs in about 10% to 12% of newly diagnosed disease, but only patients with specific NSD2 alterations are, in fact, at risk of worse prognosis, which clinically appears to be about one in every three of those patients. And so together, the CoMMpass and Myeloma XI data suggest that translocation t(4;14) only in combination with deletion 1p or gain or amplification of 1q correlates with worse prognosis.

Translocation t(14;20) occurs in only 2% of newly diagnosed disease. Similar to translocation t(4;14), it doesn't appear to have an effect on prognosis, except if the translocation co-occurs with chromosome 1 lesions, in which case patients do fare worse.

Overall, these three translocations - t(14;16), t(4;14), and t(14;20) - should be considered high-risk only if chromosome 1 aberrations are also present. In terms of those chromosome 1 aberrations, category C, first deletions of 1p: Occurring in about 13% to 15% of newly diagnosed disease, deletion 1p eliminates critical cell checkpoints and normal apoptotic signaling. In the IFM and CoMMpass dataset analyses, biallelic deletion of 1p and monoallelic deletion of 1p co-occurring with additional copies of 1q denote high-risk.

In terms of the other aberration in chromosome 1 possible in myeloma, gain or amplification of 1q: This occurs in up to 35% to 37% of newly diagnosed disease. It upregulates CKS1B, which is a cyclin-dependent kinase, and ANP32E, a histone acetyltransferase inhibitor. GEM and IFM data suggest that gain or amplification of 1q - there was no clear survival detriment to amplification - is best considered as a high-risk feature only in combination with the other risk factors as above.

Now, in terms of any other criteria for high-risk disease, there remains one other item, and that has to do with tumor burden. There has been a consensus shift, really, in both the IMS and IMWG to attempt to develop a definition of high-risk disease which is based on biologic features rather than empirically observed and potentially temporally dynamic features, such as lactate dehydrogenase. Beta-2 microglobulin remains an independent high-risk indicator, but care must be taken when measuring it, as renal dysfunction can artificially inflate peripheral titers. The consensus conclusion was that a beta-2 microglobulin of at least 5.5 without renal failure should be considered high-risk but should not preclude detailed genomic profiling.

So, in conclusion, the novel 2025 IMS-IMWG risk stratification system for myeloma is binary. It's either high-risk disease or standard-risk disease. It's got four criteria. Number one, deletion 17p and/or a TP53 mutation. Clonal cell fraction cut-off, remember, is 20%. Or number two, an IGH translocation - t(4;14), t(14;16), t(14;20) - with 1q gain and/or deletion of 1p. Or a monoallelic deletion of 1p with 1q additional copies or a biallelic deletion of 1p. Or a beta-2 microglobulin of at least 5.5 only when the creatinine is normal.

This is a field-defining work that draws on analyses from across the world to put forward a dominant definition of high-risk disease and introduces a new era of biologically informed risk assessment in myeloma.

Now, how does this change our clinical approach? FISH must be performed on CD138-enriched samples and should be performed for all patients. Next-generation sequencing should also be performed on all patients. Trials will hopefully now begin to include this novel definition of high-risk multiple myeloma. It does remain to be seen how data from novel therapeutic trials, if stratified according to this novel definition, will be interpreted. Will we find that therapies being evaluated at present have differential effects on myelomas with different genetic lesions?

Other unanswered questions also exist. How do we go about integrating this into academic and then community clinical practice? How do we devise public health interventions for low-resource settings? To discuss this piece further, we welcome the esteemed Dr. Nikhil Munshi to the podcast. Dr. Munshi is a world-renowned leader in multiple myeloma and the corresponding author on this paper. As Professor of Medicine at Harvard Medical School, Director of the Multiple Myeloma Effector Cell Therapy Unit, and Director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center of the Dana-Farber Cancer Institute, he has presided over critical discoveries in the field. 

Thank you for joining us, Dr. Munshi.

Dr. Nikhil Munshi: Oh, it's my pleasure being here, Michael, to discuss this interesting and important publication.

Michael Hughes: I had a few questions for you. So number one, this is a comprehensive, shall we say, monumental and wide-ranging definition for high-risk myeloma. How do you hope this will influence or impact the ways we discuss myeloma with patients in the exam room? And how do we make some of these components recommended, in particular next-generation sequencing, feasible in lower-resource settings?

Dr. Nikhil Munshi: So those are two very important questions. Let's start with the first: How do we utilize this in our day-to-day patient care setting?

So, as you know well, we have always tried to identify those patients who do not do so well with the current existing treatment. And for the last 30 years, what constitutes a myeloma of higher risk has continued to change with improvement in our treatment.

The current definition basically centers around a quarter of the patients whose PFS is less than 2 to 3 years. And those would require some more involved therapeutic management. So that was a starting point of defining patients and the features.

As we developed this consensus amongst ourselves - and it's titled as "International Myeloma Society, International Myeloma Working Group Consensus Recommendation" - this IMS-IMWG type of recommendation we have done for many years, improvising in various areas of myeloma care. Now, here, we looked at the data that was existing all across the globe, utilizing newer treatment and trying to identify that with these four-drug regimens, with transplant and some of the immunotherapy, which group of patients do not do as well. And this is where this current algorithm comes up. So before I answer your question straight, "How do we use it?" I might like to just suggest, "What are those features that we have identified?"

There are four features which constitute high-risk disease in the newer definition. Those with deletion 17p with 20% clonality and/or TP53 mutation. Number two, patients with one of the translocations - t(4;14), t(14;16), or t(14;20) - co-occurring with 1q amplification or deletion 1p32. And that's a change. Previously, just the translocation was considered high-risk. Now we need a co-occurrence for it to be called high-risk. The third group is patients having biallelic deletion 1p32 or monoallelic deletion 1p32 along with 1q amplification. And finally, patients with high beta-2 microglobulin, more than or equal to 5.5 mg/dL, with normal creatinine less than 1.2 mg/dL.

And the question, "How do we use this?" There are multiple areas where we incorporate high-risk features in our treatment algorithm. One of the first areas is where we would consider the induction regimen. If a patient has a high-risk disease, we would definitely consider a four-drug regimen rather than a three-drug regimen, although we are beginning to incorporate four-drug for all groups. That's one important thing. Number two, those are the patients where we do consider consolidation with transplant or maybe in the new world, considering some of the immunotherapeutic consolidation more early or more aggressively. Number three, these are the patients who get a little bit more maintenance therapy. So normally, lenalidomide might end up being our standard maintenance regimen. In patients who have high-risk disease, we incorporate either addition of daratumumab or the anti-CD38 targeting antibody and/or addition of proteasome inhibitor, either bortezomib or carfilzomib. So you would have multi-drug maintenance therapy in these patients. And in high-risk patients, we follow them with maintenance longer periods of time.

One very critically important point to keep in mind is that to get the better outcome in high-risk disease, we must try to get them into MRD negativity because there is clear data that patients who do achieve MRD negativity, despite having high-risk disease, have a much superior outcome. They become near to standard-risk disease. And so, in high-risk patients, I would try to do whatever various options I have to try and get them into MRD-negative status. And when these patients relapse, we do not wait for the classic progression criteria to be met before we intervene. We would propose and suggest that we intervene earlier before the disease really blasts off. And so there are a number of areas in our setting where this high-risk definition will help us intervene appropriately and also with appropriate aggressiveness to achieve better outcome, to make this similar to standard-risk disease.

Michael Hughes: Thank you, Dr. Munshi. And thoughts on how to really integrate this not only into academic centers but also lower-resource settings?

Dr. Nikhil Munshi: So that's a very important question, Michael. And when we were developing this consensus, we were very cognizant of that fact. So wherever available, I think we are recommending that over a period of next 2, 3, 5 years, we should begin to switch over to sequencing-based methods because two components of this definition, one is TP53 mutation, which we cannot do without sequencing, and also reliably detecting deletion 1p requires sequencing-based method.

So in the low-resource countries - and there are many in this world, and also even in our own country, patients may not be able to afford it - the older method with FISH or similar such technology, which is more affordable, is also acceptable for current time. They may miss a very small number of patients, maybe 2% to 3%, where these finer changes are not picked up, but a majority of this would be captured by them. So the current practice might still be applicable with some limitation in those patient populations, and that's what we would recommend. What is happening, fortunately, is that actually sequencing-based method is becoming cheaper. And in many centers, it is cheaper to do the sequencing rather than to do the FISH analysis. And so my hope is that even in low-resource centers, sequencing might be more economical in the end. It's, I think, the access to technology, which is a little bit limited currently, but it's hopefully becoming available soon.

Michael Hughes: Thank you, Dr. Munshi. And staying for a minute and looking at the multiple myeloma subsets which might be missed by this really still very broad-ranging high-risk definition, at least by prior risk stratification systems, right, there is this group of patients who have standard-risk cytogenetics by R-ISS or R2-ISS, but they have primary refractory disease or they relapse early. We call these, as you are well aware, functionally high-risk disease. What proportion of previously FHR, functionally high-risk, myeloma patients do you expect to be captured by this novel definition?

Dr. Nikhil Munshi: So I think the newer definition - and we can look at it both ways, but the newer definition should capture most of the functionally high-risk definition. To put it differently, Michael, there are patients who we know are, as you mentioned, functionally high-risk. Those are the patients who might have plasma cell leukemia, those who might have extramedullary disease, those who might not respond to our four-drug induction. If you don't respond to the four-drug induction, almost by definition, they are high-risk. However, a majority of them have one of the abnormalities that we are describing here. There would be a very small proportion which may not have. And if they do not have, we know one of the important components of this definition here is also that the genome, we know, keeps on evolving. So there may be a very small clone with the high-risk feature which was not obvious in the beginning. Following treatments or following relapse, that clone predominates, and now the patient's disease becomes high-risk. 

So the definition would incorporate or would capture these functional high-risk patients, but as you said, in countries where resources are not available, using this functional high-risk would also be helpful and advantageous. Sometimes LDH ends up being a high-risk. In our studies, LDH has not come out to be high-risk anymore because the features we are describing captures most of those patients, but those alternatives, older, can still be considered if other newer techniques are not available.

Michael Hughes: Got you. And in terms of these older definitions, yes, that incorporate tumor burden, these empirical observations about how myeloma presents, do you foresee any additional tumor burden indicators being added to future definitions of high-risk disease? Or do you instead see this particular definition as a major waypoint on the journey towards a fully biologically grounded definition of high-risk disease?

Dr. Nikhil Munshi: I think your second part is what is going to happen. I think the tumor burden-related definition is being now replaced by the biological or genomic-based definition. And I think at some point, it will be quite fully replaced. One component not here, and it is because one thing, we don't have enough data; number two, we don't know how it will pan out, is also the influence of the microenvironment on the risk definition. For example, the immune system, the immune function, etc. But not enough data exists to suggest how it would change the current definition. So in future, would a definition be totally genomic or it could be more integrative? And my personal guess is that it would be more integrative and that some immune features might come into the picture, especially now that we are using immune-based therapy as a very important component of treatment - CAR T-cells, bispecific, and antibody-based treatments. What role the immune system plays in either supporting tumor or what role suppression of the anti-tumor immunity plays? They all will be important how patient outcomes end up being, and which in turn could translate into how patient's risk stratification might happen.

So I think the older tumor burden-related definitions probably will become things of the past. What we have currently proposed and consensus developed is the new path forward, and over time, some microenvironmental influences, if defined and found to be important, may get some more incorporation if it compares favorably with the genomic features.

Michael Hughes: Thank you, Dr. Munshi for that enlightening response. 

To conclude the podcast, I'd like to look to the future and to the immediate future, what are the next steps for high-risk disease definition between now and discussing an integrated genomic-microenvironment-based definition? Will we see attempts to refine? Will we see a multi-level system, things like this?

Dr. Nikhil Munshi: Yeah, so I think the current definition will be here to stay for the next 10 years or so. I think this has been developed using a large amount of data, so we do believe that this will remain fine. It has been validated now within the last six months by a few of the other studies. So there won't be a quick change. But we will try to, all of us will try to innovate. And as you very rightly bring up, the areas of research would include looking at the expression or transcriptomic component. Does that matter? And we do believe a small number of patients will have transcriptomic changes, not looked at the DNA changes, and may play a role. There are newer components, so long non-coding RNA, for example, is going to be an important component to look at, how it impacts the disease outcome, etc. There are also some of the proteomic-related changes which may become important in our studies. And then as we discussed, microenvironment and immunological changes. So these are the future areas of ongoing research where we all should collect data, and then in the next 5 to 10 years, we'll have another group meeting to see has anything changed or any of the features have become more important. 

Most of the time, some of the older features are lost because they are not as critically high-risk, and the newer features come in. And so the historical background for just one second, there was a time when chromosome 13 was considered a high-risk disease. We now don't even mention it because it's not high-risk. The newer treatments have improved the outcome. t(4;14) used to be a high-risk disease. Now by itself today, in this definition by itself is not; it needs to be with something else. And so I think this is a great sign of progress. As we improve the treatment and outcomes, some of the features will become less important, new features will come up, and we'll need to keep on evolving with time and with technology and make it better for patients.

Michael Hughes: Thank you so much, Dr. Munshi, for your wisdom, for your sagacity, for your historical perspective as well. 

Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries. And be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

The disclosures for guests on this podcast can be found in the show notes.

Dr. Peter Li: Welcome to this episode of JCO Article Insights. I am Dr. Peter Li, JCO's editorial fellow, and today I am joined by Dr. Maurice Pérol on "Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST," by Pérol et al.

At the time of this recording, our guest has disclosures that will be linked in the transcript.

Before we start our interview, I want to give our listeners a quick summary of the TRUST study.
For those tuning in, the TRUST study is a phase II, single-arm, open-label, nonrandomized, multicenter trial looking at the efficacy and safety of a novel, next-generation ROS1 TKI, taletrectinib, in advanced ROS1-mutated non–small cell lung cancer. While a relatively rare mutation, the prevalence of ROS1 mutations ranges from 0.9% to 2.6% of patients, with a third of patients presenting with brain mets at diagnosis.Current FDA-approved therapies include crizotinib, entrectinib, and repotrectinib, which have varying degrees of efficacy, in-coming with trade-offs in CNS penetrance and safety with newer generations, particularly in the realm of neurological side effects, highlighting an unmet need in this arena.

A total of 273 patients with advanced non–small cell lung cancer with confirmed ROS1 mutation were recruited for this study. 160 patients were TKI-naive, while 113 were TKI-experienced with either crizotinib or entrectinib. Patients with asymptomatic brain mets were also allowed to enroll. In the TKI-naive arm, the median age was 57, with 91% of patients having stage IV disease, 20% having no more than one cycle of chemo, and 23% having brain mets at baseline. In the TKI-experienced arm, the median age was 53, with 97% having stage IV disease, 37% having received prior chemo, and about 50% having brain mets. Furthermore, about 10% of the study population had received entrectinib, while more than 90% had received crizotinib. About 10% had a known G2032R acquired resistance mutation. Taletrectinib was dosed at 600 mg daily until disease progression or unacceptable toxicities. The primary endpoint was overall response rate, with secondary endpoints being disease control rate, duration of response, time to response, and progression-free survival. For those with brain mets, intracranial overall response rate and disease control rate were also assessed. Median follow-up time was about 21 months in both cohorts.

In the TKI-naive cohort, the overall response rate was 89%, with 8 patients achieving a complete response. Disease control rate was 95%, with a median duration of response of 44.2 months. Time to treatment response was about 1.5 months. Median progression-free survival was 45.6 months, with 52.6% not having progressed at 3 years. While overall survival data were immature, 66% of patients were still alive at 3 years.

In the pretreated cohort, overall response rate was 56%, with 5 patients achieving a complete response. Overall response rate was 53% for those who were crizotinib-pretreated and 80% for the entrectinib-pretreated patients. Disease control rate was 88%, and median duration of response was about 16.5 months. Time to treatment response was also 1.5 months, and median progression-free survival was 9.7 months. Median overall survival was not reached, but 77.5% of patients were still alive at 1 year.

Responses were consistently seen across subgroup analyses. 17 TKI-naive and 32 TKI-pretreated patients had measurable brain mets. In the TKI-naive arm, intracranial overall response rate was 77%. Disease control rate was 88%, and duration of response was 15 months. In the TKI-pretreated arm, intracranial overall response was 66%, with one patient achieving complete response. The disease control rate was 94%, and duration of response was about a year.

For the 13 patients who had a known G2032R mutation, a 62% response rate was noted.

Most common treatment-related side effects were AST/ALT elevation, nausea, and vomiting, with most being grade 1 or 2. Most common neurological side effects were dizziness, dysgeusia, and headache. Again, most were grade 1. QTc prolongation is another important adverse event to note, occurring in about 18% of all patients. Discontinuation rate from treatment was only 7%. There were three treatment-related deaths in this study: one from hepatic failure, one from pneumonia in the naive arm, and one from liver dysfunction in the pretreated arm.

Dr. Peter Li: Maurice, thank you so much for joining us today to talk about your paper. Would you mind just giving yourself a brief introduction to the listeners out there of who you are?

Dr. Maurice Pérol: So, my name is Maurice Perol. I'm a thoracic oncologist working in the Cancer Center of Lyon in France. And I'm involved in clinical research in thoracic oncology. I've been involved for many years now.

Dr. Peter Li: Okay. And for listeners out there, don't forget, he's also the primary author of the paper that we just talked about.

So, Maurice, let's begin. Can you tell our listeners what is the significance of your study?

Dr. Maurice Pérol: Well, the results of these two large phase II studies - TRUST-I, which has been conducted in China, and TRUST-II, which was a global, worldwide phase II study - so, the results place taletrectinib as the TKI with the most favorable efficacy-tolerability ratio of the available ROS1-targeting TKIs, especially in frontline therapy. And this is based on the response rate, which was very impressive, the CNS penetration with a great CNS activity, the duration of response with a compelling 45 months median PFS in frontline setting.

The level of activity in pretreated patients after crizotinib or entrectinib was also impressive and similar to that of repotrectinib, for example, but with a more favorable neurological tolerance profile. The toxicity is mainly represented with grade 1 or 2 transaminase elevation, but without clinical symptoms, and GI toxicity, but mainly grade 1 and 2. The neurological toxicity is low, especially for dizziness, showing that taletrectinib spares TrKB in a large part.

And finally, there is also a decrease in toxicity over time, especially for GI toxicity and liver toxicities, which allows a very long and a prolonged administration, which is very important in this setting.

Dr. Peter Li: These are all excellent points. Can you tell the listeners if there are any limitations that we should be concerned about, about this study?

Dr. Maurice Pérol: Sure. This data comes from single-arm phase II studies. So, this is not comparative data. And a phase III trial, which compares taletrectinib to crizotinib, is ongoing to evaluate the superiority of taletrectinib over the standard of care. Another limitation comes from the lack of systematic brain imaging at each tumor evaluation in patients without brain metastases at baseline, not allowing to assess the intracranial PFS in all patients, and which did not allow us to assess the CNS protective issue from taletrectinib, especially in patients without brain metastases at baseline.

Dr. Peter Li: Another question that I have is, with this novel TKI now available, how would you recommend the sequencing of these drugs? Would you start with someone on an alternate TKI and then reserve taletrectinib second line or later? Or would you use it upfront? Or does it depend?

Dr. Maurice Pérol: Well, it is a very important question, as we have now different available TKIs. Looking at the efficacy-toxicity balance, I would strongly favor the use of taletrectinib in frontline setting, in first line. The response rate, the CNS activity, the duration of response with a very compelling 45 months median PFS, and moreover, the good tolerance profile over time are strong arguments in favor of giving taletrectinib in frontline. Generally speaking, the use of the most active agent as frontline treatment in lung cancer depending on an oncogenic addiction is probably the best way to improve the patient's outcome. This is true for patients with EGFR mutation, for patients with ALK fusions, and this is probably also true for patients with ROS1 fusion. So, I would probably argue in favor of a frontline use of taletrectinib.

Dr. Peter Li: Listeners are going to ask, well, if you use taletrectinib upfront, then what are you going to use second line once they progress?

Dr. Maurice Pérol: Well, we have some new compounds which are under development today. For example, the NVL-520, which is a very interesting compound, which seems also to be active in case of resistance mutation. But I do think that we have to use the best-in-class TKI in frontline because, you know, the extension of PFS after acquired resistance you can obtain with a second-line TKI is always shorter than the benefit you can obtain by using the most active agent in frontline. And this is true for the majority of oncogenic addiction in lung cancer.

Dr. Peter Li: That makes sense. I also noticed that cognitive impairment wasn't listed in the safety table. Is that not an issue that you've observed at all with taletrectinib, or is it still an issue but less so because, like you mentioned earlier, because of its higher selectivity?

Dr. Maurice Pérol: Well, this is a good question because we have some ROS1-targeting TKIs like repotrectinib, entrectinib, and even lorlatinib, with some neurological adverse events and some cognitive issues. Taletrectinib is a very selective ROS1-targeting TKI, and it spares very well the TrKB, for example, explaining that we did not observe any cognitive impairment with taletrectinib in the TRUST study, showing also with the low level of other neurological adverse events, dizziness, dysgeusia, for example, the high selectivity of the compound and the preservation of TrKB.

So, this is very important when you consider the long duration of treatment in those patients with ROS1 fusion. If you have to take a drug for more than 2, 3, or 4 years, of course, the neurological adverse events are very important, and they can clearly impair the quality of life. So, this is a very important point, the very low level of neurological toxicity of taletrectinib.

Dr. Peter Li: And I think that goes to say why you would favor using it frontline as well compared to entrectinib or repotrectinib.

Last question that we have for you is: well, what's next? You mentioned there's a phase III trial comparing it to crizotinib. I think one of the questions that a lot of us would have is: why not compare it to one of the newer agents as a comparator arm?

Dr. Maurice Pérol: Well, this is a good question. Crizotinib remains the standard of care in many countries for ROS1-positive advanced non–small cell lung cancer outside of the US, especially in Europe, and in particular in patients who do not have brain metastases at diagnosis. Entrectinib has a better CNS penetration, but it did not achieve a better PFS than crizotinib in phase I/II trials, and clearly, it has a less favorable tolerance profile with weight gain, edema, and neurological adverse events. Repotrectinib has overall a level of activity which seems close to that of taletrectinib. So, it makes it difficult to consider a comparative trial that would, for example, test taletrectinib in comparison with repotrectinib because this kind of study would need a very large number of patients and a very late readout. Considering if you have a median PFS of more than 3 or 4 years, it would be very difficult to have results in before 4-5 years.

So, from a pragmatic point of view, the comparison of taletrectinib to crizotinib is probably the best way to evaluate in a phase III setting the level of activity of taletrectinib, especially in the CNS, because this study will probably allow us to assess the CNS protective effect of the compound for patients without brain metastates at baseline. So, I think probably it's a pragmatic study that will allow us to confirm the high level of activity and the good tolerance profile of taletrectinib.

Dr. Peter Li: Well, thank you, Maurice, so much for speaking about the JCO article, "Taletrectinib in ROS1-Mutated Non–Small Cell Lung Cancer: TRUST," and for all your valuable input today.

Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries, and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript

The guest on this podcast episode has no disclosures to declare.

Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series, where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, JCO Editorial Fellow, and I am joined by JCO Associate Editor, Dr. Tom Stinchcombe. In this episode, we will discuss the Journal of Clinical Oncology article and abstract presentation "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer."

NeoADAURA is a randomized global phase III study investigating the efficacy of neoadjuvant osimertinib-containing regimens in patients with resectable EGFR-mutated stage II to IIIB non–small-cell lung cancer. 358 patients were randomized 1:1:1 to receive osimertinib plus chemotherapy, osimertinib monotherapy, or placebo plus chemotherapy in the neoadjuvant setting. The primary endpoint was major pathological response. Osimertinib plus chemotherapy and osimertinib alone demonstrated MPR rates of 26% and 25%, respectively, compared to 2% in the chemotherapy plus placebo arm with a p-value of less than 0.001.

Tom, can you please explain to our listeners how you interpret this data?

Dr. Thomas Stinchcombe: Great question. Yeah, I think to give a little context, obviously, chemotherapy and immunotherapies preoperatively is becoming the standard of care. However, patients with EGFR-mutant lung cancer generally have not responded to immunotherapy, and many of the trials excluded patients with known EGFR mutation. There have been smaller phase II trials that had looked at EGFR TKIs preoperatively, but none of these were definitive. So I think that this trial is a big trial, and I think some of the strengths are that it has osimertinib alone and chemotherapy with osimertinib arms as compared to the standard of chemotherapy.

I think it's going to be really interesting at the meeting to see how this is discussed by the discussant and also what the reaction is to its public presentation. And I think that's largely because there's an alternative paradigm now, surgical resection adjuvant osimertinib, that's available to patients. So I think this will be interesting to see what the reaction is to the induction therapy. For patients with known N2 disease, I've generally given some form of induction therapy prior to surgical resection. So I think that's the subgroup of patients that I'm most likely to employ this approach with based on the results.

Dr. Ece Cali: So, in this trial, more than 90% of the patients on the osimertinib-containing regimens underwent curative-intent surgery. So, this speaks to the feasibility of the approach, and the higher MPR rate with osimertinib-containing regimens is encouraging. Event-free survival data is currently immature. You have already touched upon some of the strengths of the trial, but what are the weaknesses and the strengths of this trial?

Dr. Thomas Stinchcombe: So, I mean, I think there are some weaknesses. A major pathological response was chosen as an endpoint, and there could be an argument that path CR is more of a prognostic marker. However, the rates of path CR are relatively low, so it would have been very hard to design a trial such as that. And then I think the trial started off as a preoperative trial but effectively became a perioperative trial with preoperative EGFR-TKI, postoperative osimertinib. And so I think it's going to be very hard to determine what the contribution of the components are.

And then you've hit on another part that I think is very important when we interpret the data that the maturity on the event-free survival is only 15%, and most people are still on therapy. So the event-free survival, which is an important endpoint, is very immature right now.

Dr. Ece Cali: And this trial was designed to compare the neoadjuvant approaches, hence the comparator arm here is neoadjuvant chemotherapy followed by surgery. So, considering the ADAURA trial results with upfront surgery followed by osimertinib as adjuvant, so how do you see this trial's impact on the current clinical practice?

Dr. Thomas Stinchcombe: Well, very good question, I think one that we're still struggling with as we kind of look at this data. I think, for me, stage II patients will most likely go to surgery and then get adjuvant osimertinib, and then maybe the N2 patients will get an osimertinib-containing regimen as an induction therapy. I think one of the questions is does it really matter when you get the osimertinib as long as you get it at some point? And I think that's going to be the critical interpretation of some of the data at this point.

Dr. Ece Cali: And how do you think this trial shapes the future research for patients with resectable EGFR-mutated lung cancer?

Dr. Thomas Stinchcombe: Well, I mean, I think it shows that chemotherapy was really modestly active with an MPR rate of 2%, no pathological responses. And then I think you're going to have to look at an osimertinib plus another targeted therapy component. I think, you know, when I looked at the osimertinib versus the chemo-osimertinib arm, I also was sort of surprised that the MPR rate and the path CR rate were very, very similar. So I think that the question is would a double targeted therapy approach or some other approach matter? And I think it also sets a safety standard. And you touched on this in your comments, that there was not a disparity in terms of the rate of going to surgery or R0/R1 resections. So patients were not having progressive disease events or toxicities that prevented surgery. So I think it does give us good safety data.

Dr. Ece Cali: Tom, thank you so much for sharing your insights on the JCO article, "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer."

Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting, and please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript

The guest on this podcast episode has no disclosures to declare.

Dr. Lauren Shih: Hello, and welcome to our 2025 ASCO annual meeting series where we cover some of the top JCO papers published simultaneously with their abstract presentations at this year's meeting. I'm your host, Dr. Lauren Shih, JCO editorial fellow, and I'm joined by JCO Associate Editor Dr. Stephanie Wheeler to discuss the Journal of Clinical Oncology article and abstract presentation "Use of Low-Value Cancer Treatments in Medicare Advantage Versus Traditional Medicare."

Let's start with the relevance of the article. Dr. Wheeler, can you explain this to our listeners?

Dr. Stephanie Wheeler: Thank you so much. Let's get right into it. So this article is really about understanding different types of Medicare plans and what we should expect to see in terms of their use of low-value treatments for cancer patients. So, as Medicare really is focused on trying to limit the use of low-value cancer treatments, we really need to better understand the drivers of variability. So we know that many cancer patients have multiple treatment options available to them. We also know that the vast majority of older adults beyond age 65 are insured by Medicare, and about half of them are on Medicare Advantage plans, which are serviced by private insurance. And private insurance companies in this case are receiving capitated payments for Medicare beneficiaries to manage their service utilization and reduce costs. So, with respect to Medicare Advantage versus the traditional fee-for-service Medicare, it's not really been known to what extent low-value treatments are differentially used by these types of plans for cancer patients. And so that was really the focus of this article.

What the authors found is that across six different types of treatments, in general, the folks who were enrolled in Medicare Advantage plans had reduced use of low-value treatment. So that's a good sign for Medicare beneficiaries. And although the relative difference in that use was somewhat low, this translates to a significant number of Medicare enrollees across the country not receiving these low-value treatments. And of course, this translates to considerable savings at the society level.

Dr. Lauren Shih: Are there any additional key results that we should review?

Dr. Stephanie Wheeler: Yeah. So I'll tell you just a little bit more about the methods and also their findings. So they looked at six different low-value treatments, and this was in, again, 100% of national Medicare enrollees from 2015 through 2021. So the six low-value treatments that they examined were the use of G-CSFs among patients receiving low-risk chemotherapy and denosumab for those who had castration-sensitive prostate cancer. Then they also looked at four high-cost treatments, including using nab-paclitaxel instead of paclitaxel for patients with breast or lung cancer; second, adding bevacizumab to carboplatin plus paclitaxel for ovarian cancer; third, using brand-name drugs instead of generics when generics were available; and fourth, using biologics instead of biosimilars when biosimilars were available. And these are all, by the way, non-recommended treatments according to a variety of guidelines, including NCCN and ASCO's Choosing Wisely guidelines.

So they used the Medicare claims data to examine use of these regimens. They also analyzed results by type of Medicare Advantage plan, whether people were enrolled in a health maintenance organization plan, or an HMO, or a preferred provider organization plan, or a PPO. They also looked at the largest Medicare Advantage insurers—including Aetna, Blue Cross Blue Shield, Cigna, Humana, and UnitedHealth—and limited their analyses to those that had complete encounter data. And what they found across the board is that the enrollees in Medicare Advantage plans generally had lower use of these low-value treatments. And the largest differences between Medicare Advantage and traditional Medicare plans were in the outcomes, including G-CSF use and using denosumab for castration-resistant prostate cancer, and then the combination of bevacizumab, carboplatin, and paclitaxel versus carboplatin and paclitaxel. And all of these had a change in use ranging from about 19% change to 24% change in use. This is significant as a field as we look at ways in which different plan organization can influence use of treatments, particularly given the excess cost of cancer care. This is something we really want to pay attention to.

So I'd encourage folks to look more closely at the results by treatment type as well as the results by plan type to see a little bit more about what was going on across different plan types.

Dr. Lauren Shih: Great. And are there any outstanding questions that need to be answered?

Dr. Stephanie Wheeler: Yes, there always are, of course. I think the study has several strengths that are worth noting.

First, they have 100% of Medicare enrollees, so there's national coverage there, which is, you know, quite outstanding. They also use an appropriate choice of analysis to help deal with some of the selection. So they use inverse probability of treatment weights, and they control for practice and county indicators to try to get some realistic adjustment for the selection that happens in terms of how patients are enrolled in different Medicare Advantage versus traditional fee-for-Medicare plans. These statistical approaches are a good idea, but they are limited by the observed variables that we can use for these kinds of adjustments. And so any unobserved—confounding or any unobserved factors that would influence selection in these plans aren't going to be captured well. So preferences, for example, that patients may have about different types of plans when they're insuring themselves and their families may not be captured.

Second, the data that are used are only encounter data from those plans with complete records. That may mean that smaller Medicare Advantage insurers or those that don't have as comprehensive records are not included. So this may not be reflective of their practice patterns. And then third, of course, this only looked at six different low-value cancer treatments. It remains to be seen whether this kind of finding extends to other types of low-value cancer treatments, and that's an opportunity for future study.

Finally, I would say that we don't exactly know why these patterns exist. It could be that Medicare Advantage plans have different approaches to prior authorization. They could have more in-house quality control and management to really understand, among their population for whom they're receiving Medicare Advantage payments, to really look at care quality and assess Choosing Wisely guidelines. We don't know exactly how that's playing out. And so we need additional data to really figure out what's working here and what are opportunities for future policy and payment innovations that can further reduce low-value care.

Dr. Lauren Shih: Great. Thank you so much, Dr. Wheeler, for speaking to us about the JCO article, "Use of Low-Value Cancer Treatments in Medicare Advantage Versus Traditional Medicare." We really appreciate your insights.

Dr. Stephanie Wheeler: Thanks for having me.

Dr. Lauren Shih: Join us again for the latest simultaneous publications from the ASCO 2025 Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript

The guest on this podcast episode has no disclosures to declare.

Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, and I'm joined by JCO Associate Editor Dr. Grant McArthur. Today, we will discuss Journal of Clinical Oncology article and abstract presentation "A Phase II Randomized Trial of Avelumab Plus Cetuximab Versus Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma."

Let's start with a brief overview of the clinical trial. This is a randomized phase II trial that compared avelumab plus cetuximab to avelumab in PD-1/PD-L1 antibody-naive patients with advanced cutaneous squamous cell carcinoma. This is a cooperative group study conducted in the United States. Sixty patients were randomized one-to-one and stratified by PD-L1 and HIV status. The primary endpoint was progression-free survival. Patients on the cetuximab plus avelumab arm had a median PFS of 11.1 months, while patients on the avelumab arm had a median PFS of 3 months, corresponding to a hazard ratio of 0.48 with a p-value of 0.018. Grade III or higher treatment-related adverse events occurred in 48% of the patients on the combination arm versus 21% of patients on the avelumab arm.

Dr. McArthur, can you please explain to our listeners how you interpret this data?

Dr. Grant McArthur: These results are very important because they provide proof of concept for inhibiting PD-L1 as a target when combined with EGFR, so inhibiting PD-L1 with avelumab and inhibiting EGFR with cetuximab, in a randomized trial with a very significant impact in terms of efficacy. So, what this does is it provides proof of concept for inhibiting those targets in cutaneous squamous cell carcinoma of the skin. Avelumab is not approved for cutaneous squamous cell carcinoma of the skin, and so further studies would need to be done, particularly asking the question about combination with the approved PD-1 agents cemiplimab and pembrolizumab.

Dr. Ece Cali: I still find the difference in median PFS with various PD-1/PD-L1 inhibitors striking in this context. In this trial, avelumab, as you mentioned, the PD-L1 inhibitor, demonstrated a median PFS of 3 months, whereas PD-1 inhibitors cemiplimab and pembrolizumab have demonstrated longer median PFS in other trials.

So, what are some potential reasons for this, and do you think this difference impacts the interpretation of the results here?

Dr. Grant McArthur: So, the obvious reason for the differences is that avelumab targets PD-L1, where pembrolizumab and cemiplimab inhibit PD-1, so there could be simply a difference in the target to explain those differences in progression-free survival. However, as you point out, cross-trial comparisons, one has to do with caution because you can, in different phase II studies, enroll different patient populations, which would impact the progression-free survival. So, we have to be cautious about that interpretation. However, given that cemiplimab and pembrolizumab are the approved agents, I think they are the logical ones for further clinical development. Nonetheless, this is still a very important proof-of-concept trial showing that there is a strong clinical signal when you combine EGFR inhibition with inhibition of PD-L1 versus PD-L1 alone.

Dr. Ece Cali: I want to highlight some of the safety data presented in this trial as well. The treatment discontinuation rate due to adverse events was much higher in the combination arm, reaching 31% compared to the 14% in the single-agent avelumab arm. The most common grade III adverse events were infusion reaction, rash, and diarrhea in the combination arm. So, these adverse events may affect patients' quality of life significantly. So, what are your thoughts on this, Dr. McArthur?

Dr. Grant McArthur: So, the safety data is important. What we're seeing is safety related to each individual agent. So, we have diarrhea and skin rash from the cetuximab, and the infusion reactions is a common toxicity of avelumab. I think what's important, given this is proof of concept inhibiting these targets going forward to further studies, is that agents such as cemiplimab and pembrolizumab have a very low infusion reaction rate. So, the treatment discontinuations due to infusion reaction are unlikely to be an issue with cemiplimab and pembrolizumab when further clinical trials are done. Of course, there is still the issue of diarrhea and skin rash. Now, that can be managed in many patients with EGFR inhibition, you know. However, one would have to await safety data from a significant patient cohort with a combination of cetuximab with either cemiplimab or pembrolizumab, of course, to assess the clinical impact of those safety signals. But I would expect there to be definitely rash and diarrhea as predominant toxicities with those other combinations as well.

Dr. Ece Cali: And lastly, I think we touched upon this a little bit, but how do you think this trial impacts the clinical practice, and what are some outstanding questions that need to be addressed in this field in light of the data from this trial?

Dr. Grant McArthur: So, the most important outstanding question is - of course, we've already alluded to in our conversation - regarding using anti-PD-1 agents such as pembrolizumab or cemiplimab. So, that needs to be undertaken. Clearly, a randomized trial would be required combining cetuximab with those agents because they are quite active as single agents with impressive response rates and PFS. So, that is the way forward.

There's other important clinical questions as well, though. So, patients that get locally aggressive or metastatic cutaneous squamous cell carcinoma of the skin are often immunosuppressed. And so, we do need data in patients that are immunosuppressed, either due to treatment of immune-related disorders - and also organ transplantation. We see a lot of cutaneous squamous cell carcinoma in organ transplant patients. So, these are important patient subsets that would also need to be investigated in further clinical development. However, overall, you know, this is a strong signal, hazard ratio of less than 0.5, and very worthy of further investigation in randomized trials of inhibiting these targets.

Dr. Ece Cali: This was a great discussion. Thank you so much for your insight, Dr. McArthur, for speaking about the JCO article "A Phase II Randomized Trial of Avelumab Plus Cetuximab Versus Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma."

Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript

The guest on this podcast episode has no disclosures to declare.

Dr. Peter Li: Hello, and welcome to our 2025 ASCO Annual Meeting series, where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Peter Li, and I'm joined by JCO Associate Editor Dr. Eileen O'Reilly to discuss the Journal of Clinical Oncology article and abstract presentation "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal, Phase 3 PANOVA-3 Study."

Now, let's start with the relevance of the article. Eileen, can you explain this study to our listeners?

Dr. Eileen O'Reilly: Thanks very much, Peter, for the invitation today to discuss this. Yes, so this is a positive phase 3 trial that was conducted in locally advanced, unresectable pancreas cancer. Patients were randomized to receive either gemcitabine and nab-paclitaxel, international standard, with or without tumor-treating fields. And this is a device like a battery pack that you would wear with a goal to wear that approximately 18 hours a day. And the primary endpoint of this study was overall survival, with key secondary endpoints of tumor response, progression-free survival, looking at pain-free survival, and distant progression-free survival.

So, the primary endpoint was met with a median overall survival of 16.2 months compared to 14.2 months on the intervention versus control arm, with a hazard ratio of 0.82. And so that met the pre-specified boundary. There was not an increase in progression-free survival, but there was an increase in control of pain on the tumor-treating fields study. So, it was a large, global study, community, academic sites, randomized 570 people, and it supports what I think we've seen in other difficult-to-treat malignancies using tumor-treating fields, that there's a signal of interest.

Dr. Peter Li: Can you speak to some of the strengths and weaknesses of this study?

Dr. Eileen O'Reilly: So, strengths: it was a large study. It included community sites, it included academic sites. It included ECOG performance status 0, 1, and some patients with 2. The intent was locally advanced. It probably is fair to say that there were some patients who had more advanced disease based on early progression, based on relatively high CA 19-9 for a percentage of people. But likely that was, with random assignment, that would have presumably fallen out between the arms. The inclusion of patients with a lower performance status is nice to see in large phase 3 studies in pancreas cancer. So, they would be some of the strengths.

So maybe some of the limitations are the fact that it's an open-label study - so, always some biases inherent in that. Acknowledging that the primary endpoint was overall survival, presumably that wouldn't be directly influenced by that. And there was an imbalance of women on the control arm, and women do fare a little better in this disease, so possibly kind of weighted one of the study arms a little bit. But nonetheless, I think it was a rigorously designed and rigorously conducted phase 3 trial.

It's always hard to fully interpret the signal in locally advanced disease because of the fact that some patients go on to surgery, some patients have a treatment switch of cytotoxic therapy, some patients will go on to radiation. And the endpoint here of overall survival, to a degree, eliminates some of that. So, the benchmark, I think, was generally high here.

Dr. Peter Li: Gotcha. And then with these findings and this positive study, how do you foresee this research being implemented and how it will impact clinical practice moving forward?

Dr. Eileen O'Reilly: I think there'll be an educational need to introduce this approach to the community and to the pancreas cancer world. Again, there's a precedent in glioblastoma and data from other diseases, so there's some familiarity with this. I think people always want to understand how it works and why it works, and that's something that we'll look forward to hearing more about mechanistically, and also seeing how it can be built upon. And there's some intriguing data with the combination of tumor-treating fields and immunotherapy that's being evaluated in the PANOVA-4 study. So, we'll stay tuned to hear how that reads out in due course. But I think overall, it'll be educational and learning, managing the cutaneous impacts or some skin irritation effects from this, and building on this signal in locally advanced disease.

Dr. Peter Li: Well, thank you so much, Eileen, for your time and for speaking about the JCO article, "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal, Phase 3 PANOVA-3 Study."

Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript

The guest on this podcast episode has no disclosures to declare.

Dr. Peter Li: Hello, everyone, and welcome to our 2025 ASCO Annual Meeting Series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Peter Li, JCO Editorial Fellow, and I'm joined by Dr. Andrew Ko, JCO Associate Editor, to discuss the Journal of Clinical Oncology article and abstract presentation "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study."

Now, let's start off with the relevance of this article. Andrew, can you please explain this to our listeners?

Dr. Andrew Ko: Sure. Thanks, Peter. So, this was a very large international study evaluating the combination of lenvatinib and pembrolizumab. And just for context, that combination has been approved for use in other solid tumor types. It's FDA approved for renal cell carcinoma, for example, and endometrial carcinoma. But this study was looking specifically at this combination together with a chemotherapy backbone - so either FOLFOX or CAPOX - and comparing that to what at the time was a standard of care, which was just standard chemotherapy by itself. So, this very large study was intending to look at this particular novel combination. And we can get into some of the nuances of this study because the way that the experimental, the combination arm, was designed was perhaps a little bit more on the unusual side and led to maybe some imbalance in terms of how we think about the respective arms.

Dr. Peter Li: Okay. We can definitely talk more about that as we go on.

So, what are some of the key results of this study, and how do you think this will impact practice in the future?

Dr. Andrew Ko: That's a good question. Technically, it was not a positive study. Well, it was positive in the sense that the co-primary endpoints - which included both progression-free survival and overall survival - so, progression-free survival, it did technically meet its endpoint, both in terms of the overall population and the preplanned subgroup analysis of patients who had a PD-L1 CPS of greater than or equal to 1. So, there was a PFS benefit with the experimental combination - the lenvatinib, pembrolizumab, plus chemotherapy - compared to chemotherapy alone. I will say the benefit was on the more modest side. So, if you even look at the medians, it was not a marked difference. If you look at the hazard ratios, they did meet statistical significance. On the other hand, this did not translate into a benefit for overall survival.

So, when you ask, "Well, is this going to inform practice?" I'd have to say no. It highlights, I think, that JCO does want to publish articles that aren't necessarily going to be practice-changing, but that I think offer a lot of insights into trial design and important aspects of investigating novel treatments, even if they don't end up moving the needle in routine clinical practice.

Dr. Peter Li: I totally agree with you. I mean, it was significant in terms of progression-free survival, but again, not clinically significant. And then overall survival, the interventional arm actually appeared to do slightly worse overall.

Can you make some comments on the strengths and the weaknesses of this study, and where do you see us going from here?

Dr. Andrew Ko: So, I think a couple of things worth highlighting in this study, very well designed, more than 800 patients in total. So, first of all, as I mentioned at the beginning, the combination was a little bit unique in terms of patients enrolled to the experimental arm got the combination of lenvatinib, pembrolizumab, together with chemotherapy for a very finite duration. So, that period of chemotherapy they received was only three months. And per protocol, patients then just segued to, quote unquote "maintenance treatment" with just the lenvatinib and pembrolizumab combination. Whereas patients on the control arm, meaning chemotherapy alone, would continue chemotherapy basically in perpetuity until their disease progressed or intolerable toxicity. So, there really was an imbalance in terms of, if you think that chemotherapy or continuing chemotherapy beyond that initial three-month period of time may be significant, that could have had some impact on the robustness or the efficacy of the experimental arm. There were some other aspects in terms of perhaps some differences in the rates of post-progression treatment, in other words, patients going on to receive second-line treatment.

I think the other very relevant aspect, Peter, in this study was that the control arm - and no fault of the investigators - but the control arm at the time the study was ongoing just consisted of chemotherapy, FOLFOX CAPOX, by itself, without an immune checkpoint inhibitor, right? And we clearly know, based on results of several large phase III studies, and it's now in standard clinical practice, that we routinely use chemotherapy plus an immune checkpoint inhibitor. Certainly for patients with CPS PD-1/PD-L1 scores that are, well, you could argue greater than 1, or perhaps greater than 5 or 10. But the point being that the control arm of the study probably doesn't reflect what is currently used in clinical practice. And that's just always a challenge in clinical trial design, right? That when a study is designed and when it rolls out, you're always at risk in a rapidly changing and moving field that the standard of care may evolve during the lifetime of that particular trial, which is what I think you see in LEAP-015.

Dr. Peter Li: Totally understand. And the survival we see from this study is also roughly similar to the combination of immuno-chemotherapy that is the standard of care today, which is, the authors mentioned, 12 to 14 months.

Thank you so much, Andrew, for your input and for speaking about the JCO article "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study."

Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript

Michael Hughes: Welcome to this episode of JCO Article Insights. This is Michael Hughes, JCO's editorial fellow. Today I have the privilege and pleasure of interviewing Dr. Suzanne Lentzsch on the "Co-Occurrence of Cytogenetic Abnormalities and High-Risk Disease in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma" by Dr. Kaiser and colleagues.

At the time of this recording, our guest has disclosures that will be linked in the transcript.

The urge to identify patients with aggressive disease, which is the first step in any effort to provide personalized medical care, is intuitive to physicians today. Multiple myeloma patients have experienced heterogeneous outcomes since we first started characterizing the disease. Some patients live for decades after treatment. Some, irrespective of treatment administered, exhibit rapidly relapsing disease. We term this 'high-risk myeloma'.

The Durie-Salmon Risk Stratification System, introduced in 1975, was the first formal effort to identify those patients with aggressive, high-risk myeloma. However, the introduction of novel approaches in therapeutic agents—autologous stem cell transplantation with melphalan conditioning, proteasome inhibitors like bortezomib, or immunomodulatory drugs like lenalidomide—rendered the Durie-Salmon system a less precise predictor of outcomes.

The International Staging System in 2005, predicated upon the burden of disease as measured by beta-2 microglobulin and serum albumin, was the second attempt at identifying high-risk myeloma. It was eventually supplanted by the Revised International Staging System (RISS) in 2015, which incorporated novel clinical and cytogenetic markers and remains the primary way physicians think about the risk of progression or relapse in multiple myeloma.

Much attention has been focused on the canonically high-risk cytogenetic abnormalities in myeloma, typically identified by fluorescence in situ hybridization: translocation t(4;14), translocation t(14;16), translocation t(14;20), and deletion of 17p. Much attention also has been focused on the fact that intermediate-risk disease, as defined by the RISS, has been shown to be a heterogeneous subgroup in terms of survival outcomes. The RISS underwent revision in 2022 to account for such heterogeneity and has become the R2-ISS, published here in the Journal of Clinical Oncology first in 2022. Translocations t(14;16) and t(14;20) were removed, and gain or amplification of 1q was added. Such revisions to core parts of a modern risk-stratification system reflect the fact that myeloma right now is in flux, both in treatment paradigms and risk-stratification systems.

The field in recent years has undergone numerous remarkable changes, from the advent of anti-CD38 agents to the introduction of cellular and bispecific therapies, to the very technology we use to investigate genetic lesions. The major issue is that we're seeing numerous trials using different criteria for the definition of high-risk multiple myeloma. This is a burgeoning problem and speaks very much now to a critical need for an effort to consolidate all these criteria on at least cytogenetic lesions as we move into an era of response-adapted treatment strategies.

The excellent article by Kaiser and colleagues, published in the February 2024 edition of the JCO, does just that in a far-ranging meta-analysis of data from 24 prospective therapeutic trials. All 24 trials were phase II or III randomized controlled trials for newly diagnosed and relapsed/refractory multiple myeloma. The paper takes a federated analysis approach: participants provided summaries and performed prespecified uniform analyses. The high-risk cytogenetic abnormalities examined were translocation t(4;14), gain or amplification of 1q, deletion of 17p, and translocation t(14;16), if included in the original trials. All of these were collected into zero, single, or double-hit categories, not unlike the system currently present in diffuse large B-cell lymphomas. The outcomes studied were progression-free survival and overall survival, with these analyses adhering to modified ITT principles.

The authors also performed prespecified subgroup analyses in the following: transplant-eligible newly diagnosed myeloma, transplant non-ineligible newly diagnosed myeloma, and relapsed/refractory myeloma. They, in addition, described heterogeneity by the I² statistic, which, if above 50%, denotes substantial heterogeneity by the Cochrane Review Handbook, and otherwise performed sensitivity analyses and assessed bias to confirm the robustness of their results.

In terms of those results, looking at the data collected, there was an appropriate spread of anti-CD38-containing and non-containing trials. 7,724 patients were evaluable of a total 13,926 enrolled in those 24 trials: 4,106 from nine trials in transplant-eligible myeloma, 1,816 from seven trials in transplant non-ineligible myeloma, and 1,802 from eight trials in relapsed/refractory disease. ISS stage for all patients was relatively evenly spread: stage I, 34.5%; stage II, 37%; stage III, 24%. In terms of high-risk cytogenetic lesions, double-hit disease was present in 13.8% of patients, and single-hit disease was present in 37.4%.

In terms of outcomes, Kaiser and colleagues found a consistent separation in survival outcomes when the cohort was stratified by the number of high-risk cytogenetic lesions present. For PFS, the hazard ratio was for double-hit 2.28, for single-hit 1.51, without significant heterogeneity. For overall survival, the hazard ratio was for double-hit disease 2.94, single-hit disease 1.69, without significant heterogeneity except in patients with double-hit disease at 56.5%. By clinical subgroups, hazard ratios remained pretty consistent with the overall cohort analysis. In transplant-eligible newly diagnosed myeloma, the hazard ratio for progression is 2.53, overall survival 4.17. For transplant non-ineligible, 1.97 progression, 2.31 mortality. Relapsed/refractory disease progression 2.05, overall mortality 2.21, without significant heterogeneity.

Of trials which started recruitment since 2015, that is to say, since daratumumab was FDA approved and thus since an anti-CD38 agent was incorporated into these regimens, analysis revealed the same results, with double-hit myeloma still experiencing worse survival by far of the three categories analyzed. Risk of bias overall was low by advanced statistical analysis. In terms of subgroup analysis, double-hit results for transplant-eligible newly diagnosed myeloma may have been skewed by smaller study effects, where the upper bound of the estimated hazard ratio for mortality reached into the 15 to 20 range.

In conclusion, from a massive amount of data comes a very elegant way to think about the role certain cytogenetic abnormalities play in multiple myeloma. A simple number of lesions - zero, one, or at least two - can risk-stratify. This is a powerful new prognostic biomarker candidate and, somewhat soberingly, also may confirm, or at least suggests, that anti-CD38 agents are unable to overcome the deleterious impact of certain biologic characteristics of myeloma.

Where do we go from here? This certainly needs further a priori prospective validation. This did not include cellular therapies. The very scale at which this risk-stratification system operates, agnostic to specific genetic lesion, let alone point mutations, lends itself also to further exploration. And to discuss this piece further, we welcome the one and only Dr. Suzanne Lentzsch to the episode. Dr. Lentzsch serves as an associate editor for JCO and is a world-renowned leader at the bleeding edge of plasma cell dyscrasia research.

Dr. Lentzsch, there are several new investigations which suggest that translocation t(4;14), for example, is itself a heterogeneous collection of patients. There are other studies which suggest that point mutations in oncogenes like TP53, which were not assessed in Kaiser et al., carry substantial detrimental impact. Is this classification system - no-hit, single-hit, double-hit - too broad a look at tumor genetics? And how do you think we will end up incorporating ever more detailed investigations into the genetics of multiple myeloma moving forward?

Dr. Suzanne Lentzsch: Michael, first of all, excellent presentation of that very important trial. Great summary. And of course, it's a pleasure to be here with JCO and with you to discuss that manuscript.

Let me go back a little bit to high-risk multiple myeloma. I think over the last years, we had a lot of information on what is high-risk multiple myeloma, and I just want to mention a couple of things, that we separate not only cytogenetically high-risk multiple myeloma, we also have functional high-risk multiple myeloma, with an early relapse after transplant, within 12 months, or two years after start of treatment for the non transplant patients, which is difficult to assess because you cannot decide whether this is a high-risk patient before you start treatment. You only know that in retrospective. Other forms of high-risk: extramedullary disease, circulating tumor cells/plasma cell dyscrasia, patients who never achieve MRD positivity, extramedullary multiple myeloma, or even age and frailty is a high risk for our patients. Then we have gene expression and gene sequencing. So there is so much information currently to really assess what is high-risk multiple myeloma, that is very difficult to find common ground and establish something for future clinical trials.

So what Dr. Kaiser did was really to develop a very elegant system with information we should all have. He used four factors: translocation t(14;16), t(4;14), gain or amplification of 1q, and deletion of 17p. Of course, this is not the entire, I would say, information we have on high risk, but I think it's a good standard. It's a very elegant system to really classify a standard single-hit, double-hit, high-risk multiple myeloma, which can be used for all physicians who treat multiple myeloma, and especially, it might also work in resource-scarce settings.

So, ultimately, I think that system is an easy-to-use baseline for our patients and provides the best information we can get, especially with a baseline, in order to compare clinical trials or to compare any data in the future.

Michael Hughes: Thank you, Dr. Lentzsch.

To the point that you made about this isn't the full story. There does, as you said, exist this persistent group of functional high-risk multiple myeloma where we see standard-risk cytogenetics, but these patients ultimately either exhibit primary refractory disease or very early relapse despite aggressive, standard aggressive treatment. How do you see risk-stratification systems incorporating other novel biomarkers for such patients? Is it truly all genetic? Or is next-generation sequencing, gene expression profiling, is that the answer? Or is there still a role for characterizing tumor burden?

Dr. Suzanne Lentzsch: Excellent question, Michael, and I wish I would have the glass ball to answer that question. I see some problems with the current approach we have. First of all, to do the cytogenetics, you need good material. You only detect and identify what you have. If the bone marrow is of low quality, you have mainly peripheral blood in your bone marrow biopsy, you might not really fully have a representation of all cytogenetic changes in your bone marrow. So I think with a low-quality sample, that you might miss one or the other really cytogenetic high risk.

So, having said this, I think circulating tumor cells, that might be something we will look into in the future, because circulating tumor cells are readily available, can be assessed without doing a bone marrow biopsy. And what is even more exciting, in addition to the circulating tumor cells or plasma cells, using them is next-generation sequencing. I think at the moment, we are more in a collection phase where we really try to correlate sequencing with our cytogenetics and especially to establish next-generation sequencing in all of our patients. But I think after that collection phase, maybe in the future, collecting peripheral blood and doing sequencing on peripheral blood samples might be the way to go.

In addition, I don't want to forget the imaging. We started with a skeletal survey, and we know that you probably need to lose 30% of the bone before you see a lesion at all. So having imaging, such as diffusion-weighted imaging, whole-body MRI, is also, together with sequencing of the tumor cells, a step into the right direction.

Michael Hughes: Thank you, Dr. Lentzsch.

Bringing this back to the article at hand, how has Kaiser et al. changed the way we discuss myeloma with patients in the exam room?

Dr. Suzanne Lentzsch: I think we have more data on hand. So far, we talked about standard risk and high risk, but I think right now, with a very simple system, we can go into the room and we can tell the patient, "Listen, you don't have any of those cytogenetic abnormalities. I think you have a standard risk. We might give you a simple maintenance treatment with Revlimid." But we might also go into the room and say, "I'm really concerned. You have so-called double-hit multiple myeloma. You have high-risk and at least two of those abnormal cytogenetics which we discussed, and I think you need a more intense maintenance treatment, for instance, double maintenance." I think we know that a high-risk multiple myeloma can be brought into a remission, but the problem that we have is to keep those patients into a remission. So, I think a more intense treatment, for instance, with a double maintenance, or with consolidation after transplant, and a longer and more intense treatment is justified in patients who have that truly high-risk multiple myeloma described here.

Michael Hughes: Dr. Lentzsch, thank you so much for your time and your wisdom.

Dr. Suzanne Lentzsch: My pleasure. Thank you for having me.

Michael Hughes: Listeners, thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries, and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit ASCO.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript

The guest on this podcast episode has no disclosures to declare.

Dr. Davide Soldato

Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Harriet Kluger. Dr. Kluger is a professor of medicine at Yale School of Medicine, Director of the Yale SPORE in Skin Cancer, and an internationally recognized expert in immuno-oncology for melanoma and renal cell carcinoma. She leads early-phase and translational trials that pair novel immunotherapies with predictive biomarkers to personalized care.

Today, Dr. Kluger and I will be discussing the article titled "Phase 2 Trial of Pembrolizumab in Combination with Bevacizumab for Untreated Melanoma Brain Metastases." In this study, Dr. Kluger and colleagues evaluated four cycles of pembrolizumab plus the anti-VEGF antibody bevacizumab followed by pembrolizumab maintenance in patients with asymptomatic non-hemorrhagic melanoma brain metastases that had not previously received PD-1 therapy.

Thank you for speaking with us, Dr. Kluger.

Dr. Harriet Kluger

Thank you for inviting me. The pleasure is really all mine.

Dr. Davide Soldato

So to kick off our podcast, I just wanted to ask if you could outline a little bit the biological and clinical rationale that led you to test this type of combination for patients with untreated brain metastases from metastatic melanoma.

Dr. Harriet Kluger

Back in approximately 2012, patients who had untreated brain metastases were excluded from all clinical trials. So by untreated, I mean brain metastases that had not received local therapy such as surgery or radiation. The reason for it was primarily because there was this fear that big molecules wouldn't penetrate brain lesions because they can't pass the blood-brain barrier. Turns out that the blood-brain barrier within a tumor is somewhat leaky and drugs sometimes can get in there.

When PD-1 inhibitors were first identified as the next blockbuster class of drugs, we decided to conduct a phase 2 clinical trial of pembrolizumab monotherapy in patients with untreated brain metastases. We actually did it also in lung cancer, and we could talk about that later on. Responses were seen. The responses in the brain and the body were similar. They were concordant in melanoma patients.

Now, at approximately that time, also another study was done by the Australian group by Dr. Georgina Long, where they did a randomized trial where patients who didn't require immediate steroid therapy received either nivolumab alone or nivolumab with ipilimumab, and the combination arm was substantially superior. Subsequently, also, Bristol Myers Squibb also conducted a large phase 2 multicenter trial of ipilimumab and nivolumab in patients with untreated brain metastases. And there, once again, they saw that the responses in the brain were similar to the responses in the body.

Now, somewhere along the line there, we completed our anti-PD-1 monotherapy trial. And when we looked at our data, we still didn't have the data on ipilimumab and nivolumab. And our question was, "Well, how can we do better?" Just as we're always trying to do better. We saw two really big problems. One was that patients had a lot of perilesional edema. And the other one was that we were struggling with radiation necrosis in lesions that were previously Gamma Knifed. The instance of radiation necrosis was in excess of 30%.

So the rationale behind this study was that if we added bevacizumab, maybe we could treat those patients who had some edema, not requiring steroids, but potentially get them on study, get that PD-1 inhibitor going, and also prevent subsequent radiation necrosis. And that was the main rationale behind the study. We had also done some preclinical work in mouse models of melanoma brain metastases and in an in vitro blood-brain barrier model where we showed that bevacizumab, or anti-VEGF, really tightens up those leaky basement membranes and therefore would be very likely to decrease the edema.

Dr. Davide Soldato

Thank you very much for putting in context the combination. So this was a phase 2 trial, and you included patients who had at least one lesion, and you wanted lesions that were behind 5 and 20 millimeters. Patients could be included also if the brain metastasis was higher in dimension than 20 millimeters, but it had to be treated, and it was then excluded from the evaluation of the primary objective of the trial. So regarding, a little bit, these characteristics, do you think that this is very similar to what we see in clinical practice? And what does this mean in terms of applicability of these results in clinical practice?

Dr. Harriet Kluger

So that's an excellent question. The brain metastasis clinical research field has somewhat been struggling with this issue of inclusion/exclusion criteria. When we started this, we showed pretty clearly that 5 to 10 millimeter lesions, which are below the RECIST criteria for inclusion, are measurable if you use MRIs with slices that are 1 to 2 millimeters. Most institutions in the United States do use these high-resolution MRIs. I don't know how applicable that is on a worldwide scale, but we certainly lowered the threshold for inclusion so that patients who have a smattering of small brain metastases would be eligible.

Now, patients with single large brain metastases, the reason that we excluded those from the trial was because we were afraid that if a patient didn't respond to the systemic therapy that we were going to give them, they could really then develop severe neurological symptoms. So, for patient safety, we used 20 millimeters as the upper level for inclusion. Some of the other trials that I mentioned earlier also excluded patients with very large lesions. Now, in practice, one certainly can do Gamma Knife therapy to the large lesions and leave the smaller ones untreated. So I think it actually is very applicable to clinical practice.

Dr. Davide Soldato

Thank you very much for that insight, because I think that sometimes criteria for clinical trials, they have to be very restrictive. But then we know that in clinical practice, the applicability of these results is probably broader.

So, going a little bit further in the results of the study, I just wanted a little bit of comment from you regarding what you saw in terms of intracranial response rate and duration of response among patients who obtained a response from the combination treatment.

Dr. Harriet Kluger

So we were actually surprised. When we first designed this study, as I said earlier, we weren't trying to beat out ipilimumab and nivolumab. We were really just trying to exclude those patients who wouldn't have otherwise been eligible for ipilimumab and nivolumab because of edema or possibly even previous radiation necrosis. So it was designed to differentiate between a response rate of 34%, and I believe the lower bound was somewhere in the 20s, because that's what we'd seen in the previous pembrolizumab study.

What we saw in the first 20 patients that we enrolled was actually a response rate that far exceeded that. And so we enrolled another cohort to verify that result because we were concerned about premature publishing of a result that we might have achieved just by chance. The two cohorts were very similar in terms of the response rates. And certainly this still needs to be verified in a second study with additional institutions. We did include the Moffitt Cancer Center, and the response rate with Moffitt Cancer Center was very similar to the Yale Cancer Center response rate.

Now, your other question was about duration of response. So the other thing that we started asking ourselves was whether this high response rate was really because the administration of the anti-VEGF will decrease the gadolinium enhancement and therefore we might actually just be seeing prettier scans but not tumor shrinkage. And the way to differentiate those two is by looking at the duration of the response. Median progression-free survival was 2.2 years. That's pretty long. The upper bound on the 95% confidence interval was not reached. I can't tell you that the duration is as good as the duration would be when you give ipilimumab. Perhaps it is less good. This was a fairly sick population of patients, and it included some who might not have been able to receive ipilimumab and nivolumab. So it provides an alternative. I do believe that we need to do a randomized trial where we compare it to ipilimumab and nivolumab, which is the current standard of care in this patient population. We do need to interpret these results with caution.

I also want to point out regarding the progression-free survival that we only gave four doses of anti-VEGF. So one would think that even though anti-VEGF has a long half-life of three or four weeks, two years later, you no longer have anti-VEGF effect, presumably. So it does something when it's administered fairly early on in the course of the treatment.

Dr. Davide Soldato

So, in terms of clinical applicability, do you see this combination of pembrolizumab and bevacizumab - and of course, as we mentioned, this was a phase 2 trial. The number of patients included was not very high, but still you saw some very promising results when compared with the combination of ipilimumab and nivolumab. So do you see this combination as something that should be given particularly to those patients who might not be able to receive ipilimumab and nivolumab? So, for example, patients who are very symptomatic from the start or require a high dose of steroids, or also to provide a quicker response in terms of patients who have neurological symptoms, or do you think that someday it could be potentially used for all patients?

Dr. Harriet Kluger

The third part of your question, whether it can be used someday for all patients: I think we need to be very careful when we interpret these results. The study was substantially smaller than the ipilimumab/nivolumab trial that was conducted by Bristol Myers Squibb. Also going to point out that was a different population of patients. Those were all frontline patients. Here we had a mix of patients who'd had previous anti-CTLA-4 and frontline patients. So I don't think that we can replace ipilimumab and nivolumab with these results. But certainly the steroid-sparing aspect of it is something that we really need to take into consideration. A lot of patients have lesions in locations where edema can be dangerous, and some of them have a hard time coming off the steroids. So this is certainly a good approach for those folks.

Dr. Davide Soldato

And coming back to something that you mentioned in the very introduction, when you said that there were two main problems, which was one, the problem of the edema, and the second one, the problem of the radionecrosis. In your trial, there was a fair percentage of patients who received some type of local treatment before the systemic one. So the combination of pembrolizumab and bevacizumab. And most of the patients received radiosurgery. So I just wanted a brief comment regarding the incidence of radionecrosis in the trial and whether that specific component of the combination with bevacizumab was reduced. And how do you think that this fares in terms of what we see in clinical practice in terms of radionecrosis?

Dr. Harriet Kluger

I'm not sure that we really reduced the incidence of radiation necrosis. We saw radiation necrosis here. We saw less of it than in the trial of pembrolizumab monotherapy, but these were also different patients, different time. We saw more than we thought that we were going to see. It was 27%, I believe, which is fairly high still. We only gave the four doses of bevacizumab. Maybe to really prevent radiation necrosis, you have to continue to give the bevacizumab. That, too, needs to be tested. The reason that we gave the four doses of bevacizumab was simply because of the cost of the bevacizumab at the time.

Dr. Davide Soldato

Thank you very much for that comment on radionecrosis. And I really think that potentially this is a strategy, so continuing the bevacizumab, that really makes a lot of sense, especially considering that the tolerability of the regimen was really very, very good, and you didn't see any significant or serious adverse events related to bevacizumab. So just wondering if you could comment a little bit on the toxicities, whether you had anything unexpected.

Dr. Harriet Kluger

There was one patient who had a microperforation of a diverticulum, which was probably related to the bevacizumab. It was conservatively managed, and the patient did fine and actually remains alive now, many years later. We had one patient who had dehiscence of a previous wound. So there is some. We did not see any substantial hypertension, proteinuria, but we only gave the four doses. So it is possible that if you give it for longer, we would see some side effects. But still, relative to ipilimumab, it's very, very well tolerated.

Dr. Davide Soldato

Yeah, exactly. I think that the safety profile is really different when we compare the combination of ipilimumab/nivolumab with the pembrolizumab/bevacizumab. And as you said, this was a very small trial and probably we need additional results. But still, these results, in terms of tolerability and safety, I think they are very interesting.

So one additional question that I think warrants a little bit of comment on your part is actually related to the presence of patients with BRAF mutation and, in general, to what you think would be the best course of treatment for these patients who present with the upfront brain metastases. So this, it's actually not completely related to the study, but I think that since patients with BRAF mutation were included, I think that this warrants a little bit of discussion on your part.

Dr. Harriet Kluger

So we really believe that long-term disease control, particularly in brain metastases, doesn't happen when you give BRAF/MEK inhibitors. You sometimes get long-term control if you've got oligometastatic disease in extracranial sites and if they've previously been treated with a lot of immune checkpoint inhibitors, which wasn't the case over here. So a patient who presents early in the course of the disease, regardless of their BRAF status, I do believe that between our studies and all the studies that have been done on immunotherapy earlier in the course of disease, we should withhold BRAF/MEK inhibitors unless they have overwhelming disease and we need immediate disease control, and then we switch them very quickly to immunotherapy.

Can I also say something about the toxicity question from the bevacizumab? I have one more comment to make. I think it's important. We were very careful not to include patients who had overt hemorrhage from brain metastases. So melanoma brain metastases relative to other tumor types tend to bleed, and that was an exclusion criteria. We didn't see any bleeding that was attributable to the bevacizumab, but we don't know for sure that, if this is widely used, that that might not be a problem that's observed. So I would advise folks to use extreme caution and perhaps not use it outside of the setting of a clinical trial in patients with overt hemorrhage in the melanoma brain metastases.

Dr. Davide Soldato

Thank you very much. I think that one aspect that is really interesting in the trial is actually related to the fact that you collected a series of biomarkers, both circulating ones, but also some that were collected actually from the tissue. So just wondering if you could explain a little bit which type of biomarkers you evaluated and whether you saw any significant results that could suggest higher or lower efficacy of the combination.

Dr. Harriet Kluger

Thank you for that. So yes, the biomarker studies are fairly exploratory, and I want to emphasize that we don't have anything that's remotely useful in clinical practice at this juncture. But we did see an association between vessel density in the tumors and improved response to this regimen. So possibly those lesions that are more vascular are more fed by or driven by VEGF, and that could be the reason that there was improved response. We also saw that when there was less of an increase in circulating angiopoietin-2 levels, patients were more likely to respond. Whether or not that pans out in larger cohorts of patients remains to be determined.

Dr. Davide Soldato

Still, do you envision validation of these biomarkers in a potentially additional trial that will evaluate, again, the combination? Because I think that the signals were quite interesting, and they really make sense from a biological point of view, considering the mechanism of action of bevacizumab. So I think that, yeah, you're right, they are exploratory. But still, I think that there is very strong biological rationale. So really I wanted to congratulate you on including that specific part and on reporting it. And so the question is, really, do you envision validation of these biomarkers in larger cohorts?

Dr. Harriet Kluger

I would hope to see that, just as I'd like to see validation of the clinical results as well. The circulating biomarkers are very easy to do. It's a simple ELISA test. And the vessel density on the tumor is essentially CD34 staining and units per area of tumor. Also very simple to do. So I'd love to see that happen.

Dr. Davide Soldato

Do you think that considering the quality of the MRI that we are using right now, it would be possible to completely bypass even the evaluation on the tissue? Like, are we going in a direction where we can, at a certain point, say the amount of vessels that we see in these metastases is higher versus lower just based on MRI results?

Dr. Harriet Kluger

You gave me an outstanding idea for a follow-up study. I don't know whether you can measure the intensity of gadolinium as a surrogate, but certainly something worth asking our neuroradiology colleagues. Excellent idea. Thank you.

Dr. Davide Soldato

You're welcome. So just moving a step further, we spoke a lot about the validation of these results and the combination. And just wanted your idea on what do you think it would be more interesting to do: if designing a clinical trial that really compares pembrolizumab/bevacizumab with ipilimumab and nivolumab or going directly for the triplet. So we know that there has been some type of exploration of triplet combination in metastatic melanoma. So just your clinical impression: What would you do as an investigator?

Dr. Harriet Kluger

So it's under some discussion, actually. It's very difficult to compare drugs from different companies in an investigator-initiated trial. Perhaps our European colleagues can do that trial for us. In the United States, it's much harder, but it can be done through the cooperative groups, and we are actually having some discussions about that. I don't have the answer for you. It would be lovely to have a trial that compared the three drugs to ipi/nivo and to pembrolizumab/bevacizumab. So a three-arm trial. But remember, these are frontline melanoma patients. There aren't that many of them anymore like there used to be. So accrual will be hard, and we have to be practical.

Dr. Davide Soldato

Yeah, you're right. And in the discussion of the manuscript, you actually mentioned some other trials that are ongoing, especially one that is investigating the combination of pembro and lenvatinib, another one that is investigating the combination of nivolumab and relatlimab. So just wondering, do you think that the molecule in terms of VEGF inhibition, so bevacizumab versus lenvatinib, can really make a difference or is going to be just a mechanism of action? Of course, we don't have the results from this trial but just wondering if you could give us a general comment or your opinion on the topic.

Dr. Harriet Kluger

So that's a really great question. The trial of pembrolizumab and lenvatinib was our answer to the fact that bevacizumab is not manufactured by the same company as pembrolizumab, and we're trying to give a practical answer to our next study that might enable us to take this approach further. But it does turn out from our preclinical studies that bevacizumab and VEGF receptor inhibition aren't actually the same thing in terms of the effects on the blood-brain barrier or the perilesional tumor microenvironment in the brain. And these studies were done in mice and in in vitro models. Very different effects. The lenvatinib has stronger effect on the tumors themselves, the tumor cells themselves, than the bevacizumab, which has no effect whatsoever. But the lenvatinib doesn't appear to tighten up that blood-brain barrier.

Dr. Davide Soldato

Thank you. I think that's very interesting, and I think it's going to be interesting to see also results of these trials to actually improve and give more options to our patients in terms of different mechanism of action, different side effects. Because in the end, one thing that we discussed is that some combination may be useful in some specific clinical situation while others cannot be applicable, like, for example, an all immunotherapy-based combination.

Just one final comment, because I think that we focused a lot on the intracranial response and progression-free survival. You briefly mentioned this but just wanted to reinforce the concept. Did you see any differences in terms of intracranial versus extracranial response for those patients who also had extracranial disease with the combination of pembro and bevacizumab?

Dr. Harriet Kluger

So the responses were almost always concordant. There were a couple of cases that might have had a body response and not an intracranial response and vice-versa, but the vast majority had concordant response or progression. We do believe that it's a biological phenomenon. The type of tumor that tends to go to the brain is going to be the type of tumor that will respond to whatever the regimen is that we're giving. In the previous trial also, we saw concordance of responses in the body and the brain.

Dr. Davide Soldato

Thank you very much. Just to highlight that really the combination is worth pursuing considering that there was not so much discordant responses, and the results, even in a phase 2 trial, were very, very promising.

So thank you again, Dr. Kluger, for joining us today and giving us a little bit of insight into this very interesting trial.

Dr. Harriet Kluger

Thank you for having me.

Dr. Davide Soldato

So we appreciate you sharing more on your JCO article titled "Phase 2 Trial of Pembrolizumab in Combination with Bevacizumab for Untreated Melanoma Brain Metastases," which gave us the opportunity to discuss current treatment landscape in metastatic melanoma and future direction in research for melanoma brain metastasis.

If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Transcript

Joseph Mathew:

Hello and welcome to the Journal of Clinical Oncology Article Insights. I'm your host, Joseph Mathew, and today we will be discussing the article "Long-Term Survival in Resected Pancreatic Ductal Adenocarcinoma with Adjuvant Gemcitabine plus Capecitabine Compared to Modified FOLFIRINOX from the ESPAC-4 and the PRODIGE 24 Trials" by Dr. Palmer et al.

To summarize the relevant evidence, the ESPAC-4 was a European phase 3 multicenter randomized clinical trial published in 2017 comparing adjuvant gemcitabine and capecitabine (GemCap) with gemcitabine monotherapy following macroscopic margin-negative resections for operable pancreatic ductal adenocarcinoma (PDAC). The trial had included non-metastatic patients aged 18 years or older, World Health Organization (WHO) performance scores of 2 or less, creatinine clearance of at least 50 mL/min, and a life expectancy of over three months who had not received any prior anticancer treatment. Patients who had undergone R2 resections were selectively excluded.

Eligible participants were randomized 1:1 within 12 weeks of pancreatectomy to one of the two treatment arms, with chemotherapy initiated within two weeks from the date of randomization. The regimens involved six cycles, each lasting four weeks, for an overall duration of 24 weeks. In the monotherapy arm, gemcitabine dosed at 1 g/m² was given as an intravenous infusion once a week for three weeks, followed by one week off. In the GemCap arm, capecitabine dosed at 1660 mg/m² was added to gemcitabine, given daily for three weeks, followed by one week off. Patients were followed up every three months, with the primary endpoint being overall survival (OS). The study showed that at a median follow-up of 43.2 months, GemCap was associated with a significantly longer OS than gemcitabine alone.

Subsequently, in 2018, the Phase 3 randomized PRODIGE 24 trial was conducted in centers across France and Canada, comparing adjuvant modified FOLFIRINOX (mFOLFIRINOX) with gemcitabine in a similar subset of patients with resected PDAC and reported longer OS with the mFOLFIRINOX regimen. This study, however, had more restrictive eligibility criteria when compared to ESPAC-4, including patients aged under 80 years, WHO performance status of 0 or 1, with no significant cardiovascular disease, and a postoperative serum CA 19-9 of less than 180 U/mL. There was hence a subset of ESPAC-4 patients who did not meet the eligibility criteria for mFOLFIRINOX as set by the PRODIGE 24.

The present study was conducted to estimate the overall 5-year survival rates for patients of ESPAC-4 receiving GemCap and gemcitabine, further stratifying survival in either arm according to the status of the surgical margins (R status) and the resected nodes (N status), and also to investigate whether GemCap retained a survival benefit over gemcitabine in PRODIGE 24-ineligible patients.

A total of 732 patients, evenly distributed between both arms, were followed up for a median period of 104 months. Adjuvant GemCap was found to retain its survival advantage over gemcitabine, with a significantly longer median OS of 31.6 months when compared to 28.4 months with gemcitabine alone.

Further subgroup analysis was performed with reference to the resection margins and the nodal status. As a reminder, in the ESPAC-4 trial, 60% of patients were found to have microscopically positive margins (an R1 resection), and 80% were node-positive. The difference in survival was greater in patients undergoing microscopic margin-negative resections (R0) who experienced a median OS of 49.9 months with GemCap when compared to 32.2 months with gemcitabine. Node-negative patients also had a significantly greater 5-year OS rate with GemCap of 59% versus 53% with gemcitabine monotherapy. However, it is important to note that no significant difference in survival outcomes was observed in margin-positive (R1) or node-positive patients in the two arms.

The investigators also evaluated GemCap in the subgroup of 193 patients (comprising 26.4% of the ESPAC-4 cohort) who were not considered to have met the eligibility criteria for PRODIGE 24. The survival benefit of combination therapy was retained in this group, with patients receiving GemCap experiencing a median survival of 25.9 months compared to 20.7 months with adjuvant gemcitabine.

Although cross-trial comparisons have limited validity, good agreement was noted in adverse grade 3 or greater toxicity associated with the control gemcitabine arms of ESPAC-4 and PRODIGE 24, serving as the basis for a qualitative comparison of toxicities between mFOLFIRINOX and GemCap. Neutropenia was more prevalent in the GemCap arm, affecting 40.8% of patients compared to 28.4% with mFOLFIRINOX. However, granulocyte colony-stimulating factor (G-CSF) was administered to 62.2% of patients in PRODIGE 24. Palmar-plantar erythrodysesthesia (PPE) was also more prevalent with GemCap. Patients on mFOLFIRINOX were more likely to observe grade 3 or greater fatigue, diarrhea, nausea and vomiting, sensory peripheral neuropathy, and paresthesias.

The investigators concluded that GemCap was the standard adjuvant treatment for patients with PDAC undergoing an upfront resection who were not feasible for mFOLFIRINOX. Further exploratory analysis revealed that patients under the age of 70 who had undergone a microscopic margin-negative (R0) resection for node-negative PDAC were likely to derive an OS benefit from the addition of capecitabine to gemcitabine in the adjuvant setting. In contrast, mFOLFIRINOX would be more effective than gemcitabine in patients with positive margins (R1) or involved nodes, as per the PRODIGE 24 trial.

Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries, and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit ASCO.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Davide Soldato
Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy.

Today we are joined by JCO author Dr. Jessica Burris. Dr. Burris is an Associate professor of Psychology at the University of Kentucky and co leader of the Cancer Prevention and Control Research Program at the Markey Cancer Center. Her research focuses on smoking cessation among cancer survivors, health disparities, and behavioral interventions to promote health equity. She also leads the BIRDS Lab, which explores the intersection of smoking, social determinants of health, and cancer survivorship. Today I will be discussing with Dr. Burris on the article titled Longitudinal Results from the Nationwide Just Ask Initiative to Promote Routine Smoking Assessment in American College of Surgeons Accredited Cancer Program. So, thank you for Speaking with us, Dr. Burris.

Dr. Jessica Burris
Thank you for inviting me.

Dr. Davide Soldato
So today we'll be discussing an important study on the implementation of smoking assessment in cancer care and specifically through the Just Ask Initiative. So, we know that tobacco use is a critical factor in cancer treatment outcomes in general, and yet integrating systematic smoking assessment into oncology care has faced various challenges. So, Dr. Burris, to start off our interview, I would like to ask you to briefly introduce the Just Ask Initiative for those of our readers and listeners who may not be familiar with it. So, a little bit about the primary goals and why do you think that routine smoking assessment is such an important aspect of cancer care and why the Just Ask Initiative focuses on this specific issue?

Dr. Jessica Burris
Sure. So, as you mentioned before, smoking is a really critical factor in terms of cancer care and cancer outcomes. It impacts a lot of things, from complications after surgery up into cancer mortality, but it also impacts patient's quality of life. Their pain may be more severe, they're more tired, their distress levels are higher. So, there's just a lot of different reasons why we need to understand and address smoking in the context of cancer care. But like you said too, there's a lot of barriers as well. But in order to effectively treat nicotine dependence and tobacco use, we really need to know who is currently smoking. And so that was really the driver for Just Ask, wanting to make sure that we are asking every person with cancer at their diagnosis and as they go through treatment, what their smoking history is, if they are currently smoking, which we usually consider to be any smoking or other tobacco use in the past 30 days, so that once we can identify that person, then we know who we need to help.

Dr. Davide Soldato
Thank you very much. That was very clear. And in terms of methodology, Just Ask was really a quality improvement type of initiative that involved the programs that were contacted and approached to participate in this type of initiative. And the methodology is pretty standard for this type of implementation science, which is the Plan Do Study Act methodology. So just a little bit of background on this type of methodology and why do you think it might be so successful when implementing these types of changes at the structural level and when we are implementing these types of programs.

Dr. Jessica Burris
Right. So, the American College of Surgeons requires all the accredited cancer programs, both Commission on Cancer and the NAPBC or the ones that focus on breast cancer, to do at least one quality improvement project annually. And most of the programs do use the evidence-based Plan Do Study Act approach. I think it's a great one. It has a lot of evidence behind it, but it also is very practical or pragmatic. So, you're using data from your local healthcare system or clinic or program to inform what it is that you do. And then you're constantly pulling data out to see how well you're addressing the clinical practice change that you're hoping to achieve. And so, data is going in and coming out and you're using that to inform exactly what it is that you're doing over time. So, it's an iterative approach to practice change and again, one that has proven successful time and time again. And so that's the program that these programs and Just Ask used in order to increase the frequency by which they ask patients about smoking.

Dr. Davide Soldato
So as you were saying, the main objective of the initiative was really to understand if we are asking patients diagnosed with cancer and survivors if they are smoking. And how can we better report this information inside of the medical chart of the patient. So, what was the primary endpoint or the objective that you had for this type of intervention? And can you give us a little bit of results? So, what did you find the implementation of this quality improvement? How did it change the percentages of patients that were asked about smoking habits? And a little bit, what is your opinion on the results that you obtain in the study?

Dr. Jessica Burris
Sure. So, the goal was simple and that was to have an ask rate that was at least 90%. The way that we defined an ask rate is among all newly diagnosed cancer patients, how many were asked about their smoking history and their current status at that initial visit? And so, we wanted all of the participating programs who opted in to Just Ask in 2022 to achieve that 90% ask rate by the end of this one-year quality improvement project. And again, using the Plan Do Study Act approach, it was a very pragmatic study in some ways. So, what we did was we provided an intervention change package that we made available online. And programs could access that whenever they needed to and pull-down educational resources, patient facing materials, practical tools for changing the EHR or pulling data out of the EHR, any of those number of things. And then we also hosted webinars over the course of the year. And those webinars were great because half the time they were in response to questions that programs were asking as they went through the Just Ask QI project. And the other half of time we were really just reminding programs of the rationale and the reason for making sure that they're asking. And then of course, letting them know that they don't have to stop there, they should be advising patients to quit and assisting them with cessation. Even though that wasn't the goal of Just Ask, the goal again of Just Ask was getting that 90% rate. And so, we had over 750 programs who opted in to Just Ask and did this QI study with us, and it was successful. So, we met the goal, or rather the programs met the goal of that 90% ask rate. And that was maintained over time. And that was just fantastic. So again, we know that the end goal is really to assist patients with quitting, but we can't do that unless we know who to help. And so, you have to ask first. And again, they were able to do that.

Dr. Davide Soldato
So thank you very much. The quality improvement program was absolutely successful. And to go a little bit in the numbers, by the end of the one-year implementation of the program, you report a 98% rate of asking patients who first approached the centers or over time if they were or not smokers. So, you said before that you targeted a 90% ask rate in terms of smoking habits. But when looking at the data, I noticed that you already had in the baseline survey where you asked the programs about what were the practice before the implementation of the Just Ask initiative, already something that was quite close to the 90%. And yet, despite starting from such a good point, which was basically your endpoint, you still observed a major change over the years of the implementation. So, I wanted to just underline a little bit what is the value of this type of programs. And still starting from such a very high standard still, we managed to further improve. And as you were saying, this is pivotal and I think it's fundamental to really understand and see who are the patients that we need to refer and then to help in the smoking cessation. So, I just wanted a little bit of a comment on these very important results, despite already starting from a very good background from the centers.

Dr. Jessica Burris
Yeah, I'm glad that you brought up the baseline. So, I think one thing that's important about this study is that we looked at our ask rate or the asking as a clinical practice in two different ways. So, the 98% that you referred to that we found at the final survey is based on a response to a question on the frequency of asking. So, it's a Likert type question. And essentially what we did was we combined programs that reported usually asking or almost always asking into one, and that's where we arrived at the 98%. And at baseline it was 92%. What's interesting though is that we also asked them to report the specific number of patients who were seen in their cancer program during the prior six months and the number of patients who were asked about smoking in the prior six months. And with that we could get a proportion. And in every case, the self-report Likert question had a higher outcome than the raw data based on the data that was pulled from the EHR. And so, we saw this increase significantly over time, both in the self-report Likert question, but also in the EHR based data. And so, it was a win in two ways. What I think is really interesting though is that at baseline, even though 92% of programs said that they regularly ask about their patient smoking status, 16% of programs could not provide data that would allow calculation of an ask rate. So, they were reporting that they were able to do so but then could not actually do so. So, I think what that means essentially is that there's a disconnect between what programs are doing regularly or they believe that they're doing regularly and what their data actually shows. And it could be an issue with the quality of the data that's going into the EHR, or it could be an issue with pulling the data out of the EHR. And so one of the things that we saw that I think is a second indicator of success of Just Ask is that the quality of the data that programs were inputting into the EHR related to their patients smoking history and smoking status did improve over time, which meant that by the end it really was the case that the vast majority of programs were asking. And not only that, but they were also documenting it in a way to where it could inform patient care. Does that make sense?

Dr. Davide Soldato
Absolutely. And I think that that explanation really is truly important because I think that it also connects a little bit to how the initiative was able also to change things at the structural level, to be sure that there was the best possible way of asking, but also of having that information readily available inside of the EHR. This also connects a little bit to my next question, which was a little bit about organizational structure and also implementation barriers, which you report also as a self-reported information by the specific programs. So, there was a little bit of implementation barriers that was reported by the programs and this was not a specific endpoint of the Just Ask initiative, but you kind of mentioned it a little bit. The difficulties in pulling data from the EHR in understanding whether the information was collected and how it was collected. This might be one of the implementation barrier when we are looking at initiatives like Just Ask. So, I just wanted a little bit of your opinion if you think that these implementational barriers are more on the organizational side or on the provider side. And how can we use these quality improvement programs to really tackle this type of barriers to improve overall the reach and the importance of our action regarding smoking cessation.

Dr. Jessica Burris
The devils in the details, right? So I think it's a "both and" situation and not either or I think for providers, for individual providers, oncologists, nurses, supportive care providers, the issue of feeling like they're not fully trained in tobacco use assessment and treatment, and also feeling because of a lack of training that they don't feel confident or competent or even comfortable having conversations with their patients about their smoking history or being in the position to where they can really help someone who wants to quit in choosing the best path and way forward to do that that really matters. And so organizational readiness, these programs that participated were pretty high even at baseline in terms of the organizational readiness. They understood that it's a problem and they wanted to do something about it. And they were really eager and chomping at the bit to do so. But that has to trickle down to individual providers. And so, I think one of the implementation strategies that was used was staff training and provider education. And a lot of the participating programs chose that strategy. And I think as staff and providers are trained in how to ask and how to do so in a way that is nonjudgmental and that doesn't lean into things like stigma or blame or making patients feel guilty that perhaps their behavior led to their cancer, but really just understanding tobacco history and understanding nicotine dependence and the best strategies that we have to address those things that helped and that made a difference but it also is things at the system level, like having good EHR data, being able to pull those data out at a regular interval every three months or every four months, or even every six months to make sure that you're tracking smoking and also quitting over time. Both of those things need to happen. And I think those were things that we saw change as a result of Just Ask participation.

Dr. Davide Soldato
Relating to this, provider readiness also to counsel patients on how to stop smoking or what is the best strategy. Despite, as you said in the very beginning, this was not the objective of Just Ask because you just wanted to improve the rate of smoking assessment and the quality of reporting of smoking assessment. You still observed higher rates of patients and survivors that were actually referred to some kind of intervention for smoking cessation. So, I was just wondering, why do you think that even though that was not required, you still observe this type of improvement? Like, is it just inherent to the fact that we are improving and we are placing more interest and more attention on the fact that patients should quit smoking, or do you think that it relates to something else completely?

Dr. Jessica Burris
I think there's probably multiple things going on. One is once you're fully aware of the fact of the impact of smoking after a cancer diagnosis, you're going to be compelled to do something, I think. And so just the simple fact of knowing now that the patient sitting in front of you has smoked in the past week or two, they may be under a lot of stress because they're coping with cancer and they're coping with the side effects of their treatment. They may even have increased their smoking since their cancer diagnosis. And now you have this information. I think people who are providing cancer care, they want to improve the health and the life of the person sitting in front of them. And if they understand that smoking is a detriment or a hurdle to their doing so, then they're also more inclined to try and help that person quit smoking. And so, I think the asking and the documenting likely led to an increase in assistance and referrals to tobacco treatment specialists or to a state quit line, which was also common, simply because that's part of providing quality care. I think also there's been a greater emphasis nationally, in part led by the National Cancer Institute and a cancer moonshot initiative that it led, they're really focused on getting more treatment to more patients with smoking and increasing the reach and the effectiveness of the treatments that we provide. And so, I think there has been a shift in oncology care broadly to put more attention on smoking and smoking cessation as part of standard cancer care. And so, I think this kind of shift in the field also informed things as well as, again, thinking about the patient and the individual who's in the room and wanting to do something about the problem that you've just identified.

Dr. Davide Soldato
And one thing that I believe is truly exceptional about the Just Ask initiative is really also the diversity of the type of programs that you involved. Like, you went from community centers to more academic centers. And really, I did not have the impression reading the manuscript that there was any difference in the way this type of quality improvement initiative can really benefit all these programs and all these centers. So, I was just wanting to have your opinion or comment on how do you think this type of initiative could be transferable across the country and across different settings and different types of cancer care?

Dr. Jessica Burris
Yeah, I'm really glad that you brought that up, because I think most of the clinical trials that are done in this area are done at academic medical centers, which are admittedly kind of resource rich places to receive cancer care. And so, what works in academic medical center may not work in a small rural practice in the middle of Kansas, for example, or in Mississippi. And it may not work in other community-based practices, even if they're larger and set in an urban setting. And so, one of the things that frankly I loved about Just Ask is that it was very heterogeneous in terms of the sites and the participating groups. And so not only was it national and by far the largest initiative in this area, again with over 750 different programs, but the programs were diverse. So, we had large community-based programs, integrated networks, smaller community programs. And then the academic centers were actually the smallest. Only like 10 or 12 out of the 750 plus were academic. And so, it was very different than what is the norm in this research area and in this area generally in terms of clinical practice. And we were able to show that the type of program that participated had no bearing on their success. And so, when we think about initiatives that work and interventions that work, we also really have to think about what is scalable and what could be disseminated across different practices. And this is one of those things that can. It worked and it worked across different swaths of group, which was great.

Dr. Davide Soldato
Absolutely. And just one last comment about the intervention, and it's also a point that you raised in the manuscript. This initiative, like many others also at the national levels that have been reported previously, they rarely had really the participation or the perspective of the patients embodied inside of them. So, I was wondering, how do you see the field moving forward. Like you envision something that would implement sort of a co-creation with patients or cancer survivors in order to really create something that is more appealing and takes more into consideration what is the patient perspectives when we are approaching something like smoking cessation, which as you were mentioning before, it can have a lot of stigma or already some negative feelings by the patients and feelings of guilt regarding the fact that they smoked and that might have caused that cancer. So just a little bit of your opinion as to how you see the implementation science in smoking cessation moving forward while integrating also the patient perspectives.

Dr. Jessica Burris
Yeah, that's a great question. So, this is something that I've thought about a lot in my lab and at Market Cancer center, which I'll use as an example. But oftentimes what we see is that even when tobacco treatment is offered as part of standard cancer care, even when we try to remove barriers like the financial cost of treatment at Markey, we embed it within our psych oncology program. And so, all of those services are offered for free. The rate at which patients say, yes, they want to engage in treatment is much, much lower than what we would want. And so that means two things. One, we need to offer help repeatedly to patients and understand that their willingness to quit and their willingness to accept treatment likely would change over time. And so, we need to keep coming back to people. It's not a one and done situation. But then also we need to understand what the barriers are from a patient's perspective. So why are they saying no? That they're either not ready or that they don't want treatment. They want to, quote, unquote, go it alone. And oftentimes what we hear is that patients want to be able to do this by themselves. They want to feel like, I quit smoking and I did it all by myself. And this is this huge thing that I've overcome. Not too different from the perspective that a lot of patients have about fighting cancer. They want to fight this addiction, this dependence that they've had oftentimes for multiple decades. And so, I think one thing that might be beneficial is to think about having peer led tobacco treatment. So have a patient who was able to quit successfully and have them provide counseling alongside a trained provider so that patients see someone like them who's went through it in the context of cancer care and who was able to overcome and to fight and win against tobacco, essentially. I think the other thing is trying to make sure that when we're asking about smoking and when we're offering treatment that we are not accidentally harming patients by bringing up feelings of stigma or guilt or shame. And I think one way to make sure we don't do that is to really lean on clinicians who are trained in addressing social determinants of health and other supportive care. So, our social workers, I think would be great. They're oftentimes embedded within oncology care. They are surely able to be trained as tobacco treatment specialists. They're already working with patients; they're addressing other barriers to care. They're sensitive in how they ask questions oftentimes. And so, they're really an ideal partner for this work. And we have found in a lot of settings that social workers are great in terms of being tobacco treatment specialists, including what we saw in Just Ask.

Dr. Davide Soldato
Thank you very much. That was really very, very interesting. And so, last question, moving forward, we improved the rate of asking patients. We are able to document this addiction more clearly in the EHR. So how do you see the field moving forward? In the manuscript, you speak a little bit about the Beyond Ask initiative. So just a little bit of a background about what is this initiative, what you are planning to do, and what do you think would be the best way to really act on this information that we are starting to collect in a better way and more frequently.

Dr. Jessica Burris
Yeah. So Beyond Ask really took everything that we did in Just Ask and amplified it. So instead of focusing on asking, we really said to make a difference and to improve cancer outcomes, ultimately patients need to be able to quit smoking. It's not enough that we know who is smoking, but that we help that individual or those groups of people quit. And so Beyond Ask had the goal to increase cessation assistance. So, either prescribing medication to help with smoking cessation, referring to a quit line, or another evidence-based program, or personally providing cessation counseling on site at that cancer program and to try and improve again within assistance. It was another one-year study, but we increased the frequency of surveys. I think we ended up with five total surveys. So, we were capturing two to three months at a time instead of a six-month period. And the data that we were capturing was very similar to what we did in Just Ask. And I can say we're still doing the data analysis, but it was another major success. So, with Beyond Ask, we had about 350 participating programs, many of whom not all, but many did participate in Just Ask. So, I think Just Ask kind of energized people around addressing the issue of smoking in their patient population. And again, they were really chomping at the bit to do more. And so, we offered Beyond Ask just after Just Ask. So Just Ask was 2022. Beyond ask was 2023. It ended in the spring of 2024. And again, another success.

Dr. Davide Soldato
Thank you very much. So, we are eager to see the results of this study. So that leads us to the end of this interview. So, thank you again, Dr. Burris for joining us today and speaking about your work.

Dr. Jessica Burris
Thank you.

Dr. Davide Soldato
So we appreciate you sharing more on the JCO article titled Longitudinal Results from the Nationwide Just Ask Initiative to Promote Routine Smoking Assessment in American College of Surgeons Accredited Cancer Program. If you enjoy our show, please leave us a rating and a review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcast.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Come back for the next episode where JCO After Hours host, Dr. Davide Soldato interviews the author of the JCO article discussed, Dr. Jessica Burris.

TRANSCRIPT

Lauren Shih: Hello and welcome to JCO Article Insights. I'm your host Lauren Shih, and today we will be discussing the article, "Longitudinal Results From the Nationwide Just ASK Initiative to Promote Routine Smoking Assessment in American College of Surgeons–Accredited Cancer Programs" by Dr. Jessica Burris and colleagues published in the March issue of JCO. This study reports the finding of the Just ASK Initiative, an effort aimed at improving universal smoking assessment in cancer programs nationwide.

We know that smoking after a cancer diagnosis is associated with numerous negative outcomes including worse survival, increased treatment related complications, poorer quality of life and higher healthcare costs. Patients who smoke are also at increased risk for cancer recurrence and second primary malignancies. Despite these risks, data show that a significant number of patients with newly diagnosed cancer still smoke and around 15% of cancer survivors continue smoking. Recognizing this discrepancy, national oncology organizations strongly recommend routine smoking assessment and cessation support as part of standard cancer care. However, despite these guidelines, smoking assessment and cessation assistance remain inconsistent across oncology practices.

Surveys show that most National Cancer Institute designated cancer centers have insufficient resources to effectively support smoking cessation efforts. To address this gap, several large scale initiatives have been launched, including efforts by the National Cancer Institute, the Canadian Partnership Against Cancer, and the American College of Surgeons. The largest of these initiatives, through the American College of Surgeons, is the subject of our report today.

In 2022, the American College of Surgeons introduced the Just ASK Quality Improvement Program with the goal of increasing routine smoking assessment. As member institutions, accredited programs are required to complete at least one quality improvement program annually. And in 2022, 40% of programs chose to participate in Just ASK. The primary goal of this quality improvement program was to ask at least 90% of newly diagnosed cancer patients about their smoking status. Offering smoking cessation support was encouraged, but not a mandatory component or primary endpoint for the initiative. To implement Just ASK, participating programs used a well-established Plan-Do-Study-Act methodology which is a structured, iterative approach for improving healthcare processes. Programs used local quality improvement teams and resources for implementation and had access to online training, educational webinars, and technical resources to help integrate smoking assessment into routine care.

Programs completed three surveys: a baseline survey reflecting smoking assessment practices in the year before Just ASK; a midpoint survey after six months of participation; and a final survey after one year in the program. The surveys assess program characteristics, barriers to smoking assessment, readiness to change, and the frequency of smoking related clinical practices such as asking about smoking, documenting smoking status, and advising smoking cessation. Programs reported on implementation strategies they adopted to improve smoking assessment. Finally, programs reported the number of newly diagnosed cancer patients they saw, how many were asked about their smoking status and how many were identified as current smokers during each reporting period. Results from 762 participating cancer center programs were analyzed. The programs represented a diverse mix of practice sites with over 50% identified as community based. Retention in the program was high, with nearly 90% of programs completing the final survey. Most programs reported moderate organizational readiness at baseline along with an average of 4.6 implementation barriers to conducting routine smoking assessment. Barriers included factors such as lack of time, competing clinical priorities, and lack of designated tobacco treatment specialists. At baseline, the ask rate was 87.8% and this increased to 91.9% at the final survey, meeting the previously identified goal for the initiative.

Throughout the initiative, programs reported increases over time in assessing smoking status, in advising patients who smoked and quit, and in documenting these assessments and recommendations in the medical record. Importantly, the smoking rate among patients asked ranged from 18.5% to 19.8% across the three surveys, demonstrating a high rate of current smoking among newly diagnosed cancer patients. The most common implementation strategies adopted by programs to promote change included gaining leadership support, improving documentation on the electronic health record, and training staff and providers. There were no major differences in implementation strategies based on program type. Organizational readiness was positively associated with better smoking assessment practices, and implementation barriers had a negative impact, although not always statistically significant. The number of implementation strategies used by programs showed a positive, significant association with smoking assessment practices at the final survey. Exploratory analyses did not suggest that program type or patient volume had a consistent relationship with the outcomes.

Although the primary goal of Just ASK was smoking assessment and not cessation assistance or intervention, programs did report on cessation related practices. For example, programs reported providing education or self-help materials increased from 26% to 48%, referrals to tobacco treatment specialists increased from 25% to 35%, and referrals to quit lines increased from 27% to 45%. Prescribing or recommending FDA approved cessation medications increased from 17% to 21%.

In conclusion, Just ASK is the largest nationwide initiative to standardize and improve smoking assessment in cancer care. It successfully improves smoking assessment across a diverse range of cancer practices, ensuring that hundreds of thousands of newly diagnosed cancer patients were asked about their smoking status. As nearly 20% of the cohort reported smoking, this represents a critical first step in helping patients access smoking cessation resources. Participating programs demonstrated small but sustained practice changes in smoking assessment, meeting the a priori determined goal of a 90% ask rate. However, as a quality improvement initiative, Just ASK was not designed as a clinical trial, so conclusions regarding the efficacy of the program as an intervention are limited. Selection bias may have also played a role in the findings as program participation was voluntary. Additionally, the initiative lasted just one year and while the initial improvements were steady during that time, the long term impacts of Just ASK on smoking assessment remain uncertain.

Looking ahead, the American College of Surgeons recently completed the Beyond ASK initiative. This initiative is designed to go a step further and focuses on improving smoking cessation assistance and we await the results. The Just ASK initiative demonstrates the routine smoking assessment is feasible to complete as routine cancer care. This assessment is essential as identifying patients that smoke is the first and critical step towards offering smoking cessation support, which in turn can improve health outcomes and reduce cancer treatment costs. While Just ASK was a success in increasing assessment, the challenge now is ensuring that smoking cessation support is readily available for all patients who need it.

Thank you for listening to JCO Article Insights. Please give us a rating or review and subscribe so you never miss a JCO episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT 

Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on research that has been published in the Journal of Clinical Oncology. I am your host, Gynecologic Oncologist and Social Media Consultant Editor of the JCO, Shannon Westin. I serve here from the University of Texas MD Anderson Cancer Center. And I am so excited to welcome Dr. Breelyn Wilky. She's an Associate Professor and the Director of Sarcoma Medical Oncology in the Department of Medicine Division of Medical Oncology, and the Cheryl Bennett & McNeilly family endowed chair in Sarcoma Research, the Deputy Associate Director of Clinical research at the University of Colorado Cancer Center.

Welcome.

Dr. Breelyn Wilky: Thank you so much. I'm delighted to be here.

Shannon Westin: And with all those titles, I'm super impressed that she was able to complete the manuscript that we're going to discuss today, which is "Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas." And this was published in the JCO on January 27, 2025.

And please note, our participants do not have any conflicts of interest.

So this is exciting. Let's first level set. Can you review with us just the current state of sarcoma incidents, survival outcomes, that kind of thing so we all know where we're starting?

Dr. Breelyn Wilky: Yes. So, you know, sarcomas are really, I like to call them the black box cancer type. And the big thing is that there's really more than a hundred different kinds of sarcomas, which collectively altogether make up only 1% of adult cancers. And so we talk about these as being bone and soft tissue tumors, but really, the heterogeneity is just incredible. You're talking maybe 10,000 to 12,000 new cases of soft tissue sarcoma per year, which is pretty rare in the grand scheme of things. And the trouble with these is that while you can cure sarcomas if you find them early and they're localized, when they metastasize and spread and are not resectable, we're looking at median overall survivals of really only 12 to 18 months, even, you know, with our best therapies that we have. So, really there's just a dire need for new treatments for this really tough group of diseases.

Shannon Westin: Yeah, I agree. I'm a gynecologic oncologist, and we have our little subset of sarcomas that I know there's a little bit out of every one. So I'm really excited to pull this manuscript as one of our podcasts offerings because I think we're all seeing these patients in the clinic and certainly our listeners that have sarcoma or have family members with sarcoma, this is so good to have a real focus on a rare group of tumors that have been a little bit lumped together.

Now, with that being said, I know this is such a heterogeneous population, but can you briefly overview a little bit around the standard of care for treatment of recurrent sarcomas?

Dr. Breelyn Wilky: We have actually been using the same drugs really since about the 1970s, and up until very recently, nothing had really challenged doxorubicin, the old 'red devil', like we used to call it. And this has been the mainstay of treatment for metastatic sarcomas and really used across the board. In the GYN literature, for uterine leiomyosarcoma, we did see some promising activity with the combination of doxorubicin and trabectedin coming out of the French group. But, except for that study, no combination therapy or new drug has been proven better in terms of overall survival compared to doxorubicin monotherapy, really over 40, 50 years. So it's definitely a tough situation.

Now, we do have other drugs that we use, so most patients will wind up getting doxorubicin-based therapy. There's a couple of other regimens that we'll reach to, like gemcitabine docetaxel. And once you get into the specific subtypes, we have some approvals in liposarcomas and leiomyosarcomas for some other drugs. But really the median progression for survival for most of these regimens is somewhere four to six months. And response rates typically are somewhere like 10%, 15% for most of these. So it's really just a very tough field and a tough group of patients to try to make an impact for.

Shannon Westin: So let's talk a little bit more kind of getting focused on what you've studied here. What's been the role of immunotherapy thus far in the treatment of sarcomas maybe prior to this particular study?

Dr. Breelyn Wilky: Clearly, we all know that immune therapy has just changed cancer care forever over the last few years for so many different types of cancers and diseases like melanoma and renal cell and lung cancer have just been transformed by checkpoint inhibitors specifically directed against PD-1 or CTLA-4 or both. And so, of course, you know, sarcoma docs we're super excited to try to see if these might potentially have activity in our tumors as well. I never had seen myself in my career getting into immunotherapy until I was able to run an investigator-initiated study during my role in Miami, where we combined pembrolizumab, so PD-1 inhibitor, with axitinib which was a pan-VEGF inhibitor. And lo and behold, like I had patients that I was seeing responses when other treatments, all those chemotherapies I was just talking about had failed. And one of my first patients I treated was about a 60-year-old lady with something called cutaneous angiosarcoma. So this is a blood vessel sarcoma all over her face. And we had treated her with 10 different therapies, all the chemotherapy regimens, targeted therapies, clinical trials, and nothing was working. But I put her on a phase 1 trial with a baby dose of CTLA-4 and this woman had a complete response. And so for me, once I saw it work in even just those couple of patients, like that was nothing that we'd ever seen with our chemotherapy regimens. And so that sort of shifted my career towards really focusing on this, and this is about the time where some of the studies started to come out for sarcomas.

And the take home with sarcoma is about 20% of sarcomas have this sort of immune hot physiology. So what that basically means is if you look at gene expression of immune related gene signatures, or you look for infiltrating T-cells, sort of the SWAT team of our immune system, like you can find those in the tumors. And it's sort of evidence that the immune system had some clue for that 20% of patients that this was a foreign tumor and that it should be attacking it and maybe just needed a little help.

But globally, about 80% of sarcomas are these immune cold tumors, which means the immune system has no clue that these things are even a threat. And there's almost no immune activation, very, very few antigens. In other cancer types, high neoantigens or tumor antigens help the immune system work better. And so that basically goes with what we've seen with trials of PD-1 or CTLA-4 blockade. About 20% of sarcomas, with some exceptions, can respond. But really 80% across the board, you're stuck, you just can't get them to be recognized. And so that's where I think this data is so interesting is there's some signals of activity in these immune cold tumors which, at least historically with the trials we've done so far, we really haven't seen that with sort of the traditional checkpoints.

Shannon Westin: So I think now this is a great time to maybe talk about the study design in general, the eligibility and just give us kind of a run through of that.

Dr. Breelyn Wilky: So this trial was a phase 1 trial of a drug called botensilimab, which is a next generation CTLA-4 directed immune modulator. So what makes botensilimab different is that the CTLA-4 end is very similar to other CTLA-4 inhibitors that are out there, but it's been engineered on the back end of the molecule that binds to Fc gamma receptors to basically bind tighter with higher affinity. And what this translates to in laboratory models and increasingly now in patients is it does a better job of priming, of educating our T cells, our, again, these highly intelligent antigen specific cells, but also natural killer cells. It does a better job of sort of educating those. It helps to activate macrophages and other supporting actors in the immune response. And so the idea here is that there's evidence that botensilimab may do a better job at creating new responses in immune cold tumors.

The study combined either botensilimab as monotherapy or in combination with a PD-1 inhibitor called balstilimab. And this was all comers, really a variety of tumor types. And to date I think we're close to about 500 patients with a variety of solid tumors that have been accrued to this study, this C-800-01 phase 1 trial. This paper reports on the sarcoma patients that were enrolled as part of this study. And so, again, given what I've told you about sarcomas being really immune cold, we were just so excited to have the opportunity to enroll on a next generation immune therapy for these tumors that really we were running into roadblocks trying to use immunotherapy previously.

Shannon Westin: It's a very compelling idea and I'm so excited for you to tell people what you found. I think first things first, it was an early phase trial. So why don't we talk a little bit about the safety of the regimen. Was there anything that you didn't expect?

Dr. Breelyn Wilky: Right. So similar to other checkpoint inhibitors, you know, the idea is that these drugs can cause immune mediated toxicities, right? So essentially you're revving up the immune system and it can sometimes get a bit confused and start attacking our normal cells, our normal organs, leading to essentially any number of toxicities of basically head to toe, something can get inflamed and you can develop a toxicity from that. So the key take homes with this particular drug with, botensilimab with balstilimab, we saw colitis was sort of the primary immune mediated toxicity and it was about a third of patients, give or take. It happens and it can be aggressive and needs to be managed aggressively. And you know, one of the things that we learned very quickly taking part in this study is how important it is that as soon as patients start to get diarrhea, immunosuppression gets on board. So steroids, early use of TNF alpha blockade, so infliximab for example, if we jumped on it quickly and we recognized it and we got the patients treated, it would resolve fairly quickly and even some patients could remain on treatment. So I think that was sort of the first take home is "Okay if you get colitis, you treat it fast, you treat it early and you can still have patients not only recover, which essentially everybody recovered from this colitis and then being able to continue on treatment and still have their anti-tumor responses." So that's the first point.

The second thing that was really interesting is part of the engineering of botensilimab on the back end of the molecule, it's been designed to decrease complement binding and it's thought that that triggers some of these other toxicities that we've seen with prior CTLA-4 inhibitors like pneumonitis or hypophysitis. We actually don't see that with botensilimab. So there's sort of this selective toxicity that may reflect the design of the molecule. But overall the treatment was, we didn't see any new safety signals that were outside of what we would expect in class. And colitis was sort of the dominant thing that we had to be ready for and ready to manage.

Shannon Westin: We've been doing it for a while now, so we kind of know what to do and we can act quickly and really try to mitigate and avoid some of the major toxicities. So that's great that that was what was reflected in what you found. And then of course I think: What about the efficacy?" Right. This is what we care about as practitioners, as patients. Does it work and are there any subtypes that seem to benefit the most from this combination?

Dr. Breelyn Wilky: Right. So for the sarcoma patients, we treated 64 patients and 52 of those patients were evaluable for efficacy. So a decent size group of patients in sarcomas, where, you know, typically our trials are pretty small, they're very rare, but we had 52 evaluable with at least one post baseline scan. So that was our criteria. And basically we saw across all of the patients, and keep in mind, these are heavily pre-treated patients, as you mentioned, so a median of 3 prior lines of therapy, so most of these patients had had chemotherapies and then about 20% had also had prior immunotherapy as well. So PD-1 treatments or so on. The overall response rate by RECIST was 19.2% for all of the evaluable patients. And then with iRECIST, which is sort of that immune adapted response criteria that allows for early pseudo progression, we actually had another patient who did have that. And so that response rate was 21.2%. Overall, we were really excited to see this in a heavily pre-treated group of patients.

But what was really exciting to me was when we looked at the subset of patients that had angiosarcoma, that blood vessel tumor I was talking about earlier with my other patient. So angios come in two flavors. One is this sort of cutaneous type, or meaning involving the skin that has a UV signature, a UV damage signature, very similar to melanoma. So these tumors tend to have a high mutation burden. And oftentimes there is a track record that we've seen responses with immunotherapy in cutaneous angiosarcomas. But the other group that we deal with is called visceral angiosarcomas. And so these are totally different biologically. These are often driven by mutations in MYC or KDR amplification, and they arise in organs, so primary breast angiosarcoma, not associated with radiation, or they can arise in the liver or the spleen or an extremity. So these are very, very different tumors, and the visceral ones almost never historically have responded to checkpoint inhibitors. So we had 18 patients with angio split - 9 with cutaneous, 9 with visceral. And we were just blown away because the response rate for that group was 27.8%. And if you looked at the responses between the hot ones and the cold ones, it was almost equal and a little bit better in the visceral. So we had a 33% response rate in visceral angiosarcoma, which is crazy, historically speaking, and about 20% again in the cutaneous angios. So for a disease where visceral angio gets treated with chemotherapy, might respond initially, but then rapidly progresses - like these people go through multiple lines of therapy - to have a third of patients responding, and then some of those responses were durable. Our median duration of response for the study was 21.7 months, which is just nuts for sarcomas where we just don't see those sorts of long term benefits with the drugs that we have. So I think those are kind of the two main things.

There were other subtypes that had clinical benefit and responses as well in d-diff liposarcoma, soft tissue leiomyosarcoma, which are again thought to be fairly cold immune subtypes. So just really exciting to kind of see responses we hadn't expected in a very challenging group of tumors.

Shannon Westin: We see all these patients and we have patients that respond so well to immunotherapy with other histotypes. And so it's so exciting to see an option for these really hard to treat tumors that our patients struggle with. So this is so, so very exciting.

I wanted to make mention, you know, I was really impressed with the amount of translational work you were able to do in this early phase study. So do you want to review just maybe a few of the key findings that you guys discovered?

Dr. Breelyn Wilky: It's always great. I'm a translational researcher at heart and we do a lot of immune correlative work. And I think the reason I got so excited about this field to begin with was trying to learn why it works for some patients and why it doesn't work for other patients. So I'm a huge believer in learning from every patient that we can. So it's such a testament to the company, Agenus, who sponsored this trial to invest their time and resources into correlative studies at this phase. It's huge.

So we learned a couple of things. IL-6 or interleukin 6 is a cytokine that basically has, in other tumor types, been associated with worse outcomes. And what we were interested in this group is we saw the same thing. And again, sarcomas have very, very little correlative biology that's done. We're really in infancy and understanding the microenvironment and how that milieu balances out in our tumors. So we were really excited to see again that lower peripheral interleukin 6 associated with improved overall survival. So again, kind of sorting out a group of patients that might be immunologically favorable when it comes to this type of therapy.

The other thing that's important to know about sarcoma is so the other tumor types are lucky and have PD-L1 expression and the tumor is a biomarker, but we never have PD-L1 expression. We can find it in sarcomas and it can be loosely correlated with a chance of benefit with immunotherapy. But I've had patients respond that were PD-L1 negative, and I've had patients that were loaded with PD-L1 that didn't seem to make a difference. And that's not just in this study.

So we saw in this trial a trend towards improved overall survival with PD-L1 expression that wasn't significant, but there was like this trend. And it's really interesting because, again, this is largely a CTLA-4 directed therapy. And so what we wondered is if PD-L1 expression is an index of sort of this underlying potential immunogenicity. And actually PD-1 works very late in the whole immune process. That's really at the very end where you've got the T cell that's facing the tumor cell and it's just activating that T cell that's already grown up and already educated and ready to go. Whereas CTLA-4 is really educating in early immune responses and expanding the T cells that have potential to kill. So I'm interested to look into this in more depth in the future to see if this is actually the biomarker for CTLA-4 directed therapy that we've been looking for, because we really don't have a great sense about that.

And then the last piece just to note is that in this trial, like most others, very, very few sarcomas had high mutational burden. Everybody was very low, which reflects the population. And it's just really more encouragement than an immune cold tumor with very crappy neoantigens can still respond to immunotherapy if we get them the right agents.

Shannon Westin: Yeah, I mean, I'm taking notes because we have such a struggle with this across the gynecologic tumors. I'm like, "Okay, maybe this is finally it." So hopefully your work will go on to really inspire us across a number of solid tumors that have been traditionally cold. So, so very exciting.

And I would just say for my last question, obviously, congratulations on this successful study. What do you think are the next steps for this combination in sarcomas?

Dr. Breelyn Wilky: So, again, just to your point, this trial enrolled a bunch of different subtypes, and sarcomas are not the only immune cold tumor that this combo has looked really promising for, microsatellite stable colorectal cancer, ovarian cancer that was platinum refractory, non-small cell lungs. So I think the future is really bright for immune cold tumors kind of across the board. So, yes, lots of hope for not just sarcomas but in terms of our patients, I just have to be so grateful to Agenus for their interest in a rare disease. Sometimes it's hard to get that interest for a very challenging group of patients that are all heterogeneous, they are not all the same and our big clinical trials are a few hundred patients. It's just a very different environment. But they have been so supportive and involved in making sure that sarcomas are represented in their priorities. So there are ongoing discussions about what the optimal way to explore this further in sarcomas is going to be and I cannot wait to have the official plans in place. But my hope is this will not be the last that we see of these drugs for our patients.

Shannon Westin: Well, I support that and my vote is on your side.

So, thank you so much again, Dr. Wilky. This time just flew by. This was such a great discussion and I mean, I think it's, again, a testament to your exciting data.

And thank you to all of our listeners. This has been JCO After Hours' discussion of "Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas," published in the JCO on January 27, 2025. So be sure to check out the full manuscript.

And we hope that you enjoyed this podcast. And if you want to hear more about research published in the JCO, check this out on our ASCO JCO website or wherever you get your podcasts.

Have an awesome day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Wilky Disclosures 

Consulting or Advisory Role: SpringWorks Therapeutics, Deciphera, Epizyme, Adcendo, Polaris, Boehringer Ingelheim, AADi, InhibRx

Research Funding: Exelixis

Travel, Accommodations, Expenses: Agenus

TRANSCRIPT

Peter Li: Hello and welcome to the JCO Article Insights. I'm your host Peter Li and today we will be discussing the Journal of Clinical Oncology article, "Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years," by Dr. Jianwei Zhang et al. 

For a reminder to the audience, the FOWARC study is a Chinese-based study that looked into the treatment of locally advanced rectal cancers with neoadjuvant chemotherapy based regimens with or without radiation. This study was first published back in 2019 where the three-year data showed no difference in three-year disease-free survival over survival between the three study arms. As a reminder of what those arms were, there were one historical control and two interventional arms. The control arm used 5-FU with radiation therapy with five cycles of 5-fluorouracil with radiation during cycles two to four followed by surgery and then seven cycles adjuvantly. Their first interventional arm was the same as the control arm with the addition of oxaliplatin on day 1of each cycle. And lastly, the third arm was FOLFOX only for four to six cycles followed by surgery and then six to eight cycles adjuvantly completing about a total of 12 weeks of chemotherapy. 

They recruited about 495 patients with 165 patients randomized to each arm. They were relatively well balanced by age, clinical staging and distance from the anal verge. Median age was about mid-50s with a slight male predominance and patients were primarily stage 3 with 20% to 30% being stage 2. About 30% had clinical T4 disease and about 25% had clinical N2 disease. Median follow up time was 122.5 months or 10 years and their follow up endpoints were disease-free survival, overall survival and local recurrence, and they also performed subgroup analyses based on post surgical pathological staging. Survival was analyzed using Kaplan-Meier method with a significant threshold of p being less than 0.05. About 451 patients actually underwent surgery, which is about 91% of patients. The main reason for not going through surgery was due to refusal but one was due to toxicity and two were due to disease progression in the control arm. Follow up loss rate was about 10% in each group. Now looking at their primary endpoints in their initial study, local recurrence was about 8.8% in the control arm versus 7.9% in the FOLFOX radiation group versus 9.2% in the FOLFOX only group. Distant metastasis was about 30% in each arm and the sites of metastases were primarily in the lung and liver.  

Now, following up with 10 years, there were only three new events in the chemoradiation group with local recurrence happening at 10.8% in the control arm versus 8% in the FOLFOX RT group versus 9.6% in the chemo only group. These findings were not statistically significant. In their subgroup analysis by pathological staging, they found that pathological CR or complete response had a lower rate of local recurrence compared to those with increasing pathological staging coming in at 3% versus 4.3% versus 11.6% versus 15.8% in pCR versus Stage 1, 2, 3 respectively. And they found no difference in each stage with each interventional arm. Looking at long term survival their 10-year disease free survival showed 52.5% in the 5-FU radiation group versus 62.6% in the FOLFOX RT group versus 60.5% in the chemotherapy only group with no statistically significant difference between three groups. By pathological staging, they found improved 10-year disease survival in those who achieved pathological complete response versus those who did not with 84.3% in the pCR group versus 78.7% versus 56.8% versus 27.7% in the stage 1 versus 2 versus 3 group. And again they found no statistical significance difference between each arm.  

Now looking at the 10-year overall survival rates between the three arms, in the control arm the 10-year overall survival was 65.9% versus 72.3% in the FOLFOX RT group versus 73.4% in the chemo only group. By pathological stage, again, they showed a statistically significant difference in those who achieved pCR versus those who had pathological stage 1 to 3 disease with overall survival being 92.4% in those who achieved pCR versus 84.9% versus 68.6% versus 48.8% in stage 1, 2, 3 respectively. Now in the discussion, authors mentioned that with a median follow up of 10 years, FOLFOX alone had similar disease-free survival, local recurrence and distant metastasis and overall survival compared to those who received neoadjuvant chemoradiation, justifying the omission of radiation without compromising results or outcomes for each patient. There were no differences in subgroup analysis for disease free survival local recurrence or overall survival based on pathological staging. There were only three new events compared to the last follow up, with local recurrence happening only in the chemo radiation groups. Local recurrence rates at 10 years was about 10%. Compared to other clinical trials such as CAO, ARO or AIO-94, the rate of local recurrence was similar to those historical trials. 

The authors also compared their findings to the PROSPECT study which looks at the use of total neoadjuvant chemo radiation versus chemotherapy alone, which boasted only about a 2% local recurrence rate. But as a reminder, high risk locally advanced rectal cancers were excluded, mainly those with T4 or N2 disease, which may explain the difference in terms of local recurrence in the PROSPECT versus this study. Another finding is that pathological complete responses are also an important prognostic marker with lower 10-year local recurrence rate, disease-free survival and overall survival with worse outcomes with increased pathological staging. Distant metastasis rates were still at 30%, with the most common site being lung then liver then lymph nodes consistent with other historical studies. Chemotherapy seemed to be better at reducing liver mets than lung metastasis per their findings. In their post hoc analysis of their own study, chemo radiation was also associated with higher incidence of low anterior resection syndrome and persistent ostomy compared to chemotherapy alone, meaning that they had better quality of life with the chemotherapy only approach. 

In conclusion, a chemotherapy only approach can be safe and a feasible treatment for locally advanced rectal cancer without compromising outcomes. Omission of radiation may reduce the risk of overtreatment and improve quality of life for some of these patients. However, this does not necessarily exclude the role of radiation as it may still play a role in a response escalation approach for those who do not respond to chemotherapy alone.  

This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT 

Dr. Shannon Westin: Hello everyone and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, GYN Oncologist by trade and one of the grateful Social Media Editors of the JCO. And I am very excited to welcome a special guest today, Dr. William Aronson. He is professor of Urology in the UCLA Department of Urology, the Chief of Urology at Olive View UCLA Medical Center, and Chief of Urologic Oncology at the Veterans Administration West Los Angeles.

Welcome, Dr. Aronson.

Dr. William Aronson: Thank you, Shannon, and delighted to be here.

Dr. Shannon Westin: We are so excited to have you discussing your manuscript, "High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial," which was published in the Journal of Clinical Oncology on December 13, 2024.

So let's get right to it. First of all, you know we have a very mixed audience, so can you just level set for us and speak about the population you studied in this important trial - that low risk, favorable, intermediate risk prostate cancer. How common is that? How is it defined? That would really help.

Dr. William Aronson: I would say about 50% of the patients that we diagnose with prostate cancer either have low risk disease or what we call favorable intermediate risk disease. So when the pathologists look at the cancer under the microscope, they assign what's called a Gleason grade. Grade 3 is the slower growing type of prostate cancer, grade 5 is the fastest growing type, and grade 4 is somewhere in between. So a low risk group would be only the grade 3, the slower growing type. And the favorable intermediate risk group would actually be the grade 3+4, which means they mostly see the low risk type in there, but they also see the slightly faster growing type, grade 4. So this is what we typically see. We see these patients on a very regular basis when they're newly diagnosed with prostate cancer.

Dr. Shannon Westin: Okay, got it. And then can you walk us through just what the management options are typically for this patient population?

Dr. William Aronson: So typically for what we call the low risk group, the patients with a low PSA and only that grade 3 type, slower growing type of prostate cancer, the standard recommendations are active surveillance. So typically, we'll periodically monitor these patients with PSA blood testing and periodically do prostate biopsies depending upon the patient's other medical problems.

Dr. Shannon Westin: So I think it would also be really helpful just to understand what your typical management options are for this patient population.

Dr. William Aronson: So for patients with low risk prostate cancer, they only have the Gleason Grade 3+3 with a low PSA. The standard practice is observation. And so these men will periodically see them and measure their PSA values. And periodically, they'll undergo prostate biopsy to make sure they're not getting progression of their disease.

For men with favorable intermediate risk prostate cancer, that's a little different. In some practices, the patient and the urologist will decide to do active surveillance. In other scenarios, these patients will definitely elect treatment, either with radical prostatectomy or radiation therapy or other treatments that are available.

Dr. Shannon Westin: So your manuscript notes that there was a high level of interest in dietary supplements and approaches among patients with prostate cancer that do elect for active surveillance. Prior to the results of CAPFISH-3, did we have any data to support those types of recommendations?

Dr. William Aronson: We actually don't have any long term prospective randomized trials that support that recommendation. There have been a number of very interesting epidemiologic studies, for example, suggesting maybe a plant-based diet might be helpful. Or a number of other studies suggesting maybe more tomato-based products like tomato sauces or tomato paste may be helpful. But no prospective longer term randomized trials that were positive.

Dr. Shannon Westin: Okay, that makes sense. So what led you all to explore the high omega-3, low omega-6 fatty acid diet in this trial?

Dr. William Aronson: After our initial omega-6 studies, we subsequently did some studies where we raised the omega-3 from fish oil and lowered the 6, looking at a more favorable ratio of the omega-3 to omega-6. And once again, we found that in our animal models, there was a significant delay in progression of prostate cancer. That then led us to perform a clinical trial. It was a short term trial in men prior to undergoing radical prostatectomy. And in these men, they were randomly assigned to one of two groups, either a western high fat diet or a low fat diet with fish oil. And we found after just four to six weeks, a significant change in the Ki67 level in their radical prostatectomy tissue. And Ki67 is actually a strong indicator of prostate cancer progression, spread, or even death from prostate cancer.

Dr. Shannon Westin: Well, and I think that leads us really nicely into the design of the current study. So why don't you walk us through how CAPFISH-3 was designed. And you've already spoken a little bit about your primary endpoint.

Dr. William Aronson: Based on the results of what we saw in the lab and what we saw in our short term clinical trial, we decided to perform a one year trial, a longer term trial in men on active surveillance. And these men were randomly assigned to either a diet with slight reduction in dietary fat, specifically reduction in the omega-6 intake as well as increase in foods with omega-3 and fish oil capsules. The other group, we asked the men to just not take fish oil capsules, but they could eat whatever else they wanted during the course of the study. Men in the diet where we lowered the omega-6 and raised the omega-3, they were seen by a dietitian once a month to really ensure that they were compliant with that intervention, which they were. The other intriguing part of our study, which I think is super important, is the precision that was used when these men underwent prostate biopsy. So, at baseline and at one year, when these men underwent prostate biopsy, they had the same site within the prostate biopsied. That's important because it's not so easy to find the same site within the prostate because of heterogeneity throughout the prostate. And so we were able to obtain that high level of precision as they were in an active surveillance program at UCLA with Dr. Leonard Marks.

Dr. Shannon Westin: So we spoke a little bit about what's important about the Ki67 index as your primary endpoint. Can you talk a little bit about what the study found with your intervention?

Dr. William Aronson: So we found that the Ki67 index increased by 24% in the control group and decreased by 15% in the low omega-6, high omega-3 group with fish oil capsules. So that ended up resulting in a statistically significant change between the groups favoring the low omega-6, high omega-3 group.

Dr. Shannon Westin: And then what were the secondary endpoints that CAPFISH-3 explored? Anything of note that you want to review for the listeners?

Dr. William Aronson: So a number of positive secondary endpoints from the trial. Firstly, we saw that the triglyceride levels were lower, which is what can typically be seen with omega-3 intake. We also saw reduced levels of a cytokine, a circulating factor in the bloodstream called 'macrophage colony stimulating factor'. And that's particularly interesting because there's a certain type of macrophage which is well known to be involved in prostate cancer progression in men with more advanced prostate cancer, and we've been able to inhibit that in our animal models and in our tissue culture studies. And it was especially interesting to see that we did have an effect on this particular cytokine in this prospective randomized trial. We did not see changes in a number of other measures, including Gleason grade or PSA. These are measures that we use in clinical practice. To see an effect on those would have required a longer term and larger study to be performed.

Dr. Shannon Westin: That makes sense. I think it's always great to try to get as much of these types of translational data as we can. But sometimes you just have to do what is reasonable and you get what you get.

It looks to me like this regimen was fairly well tolerated. Did you obtain any patient reported outcomes or feedback on the trial?

Dr. William Aronson: So, there were four patients in the fish oil group that did have some side effects, and we withdrew them from the study. They did have some effects on their upset stomach, and a number of men also had some diarrhea as well. And so for those four patients, we did withdraw them from the study.

Dr. Shannon Westin: And then I guess the last question I have is really, what's next for this intervention? Are we ready to move this to the clinic or what do you see as next steps?

Dr. William Aronson: Well, this next step that we're working on right now is to better understand exactly what happened in these patients. So we have blood, we have tissue, we're doing genetic studies on these patients. So that's really the first step, in our mind, to better understand what happened before moving to the next step. I'm particularly intrigued about trying this intervention in men with more advanced prostate cancer, specifically because of what we see, this particular diet and how it's affecting the patient's immune system and how that may favorably affect their course of their prostate cancer.

Dr. Shannon Westin: Well, great. Well, thank you so much for taking the time to chat with us about such an important clinical trial, and I really appreciate all the work you're doing and hope to get to see you soon.

Dr. William Aronson: Well, thanks for having me, Shannon. It's really an exciting finding and I think it's something that clinicians and patients are going to be super interested in.

Dr. Shannon Westin: We love straightforward interventions that actually make a difference, so you guys are to be congratulated for that.

And I just want to thank all of you for listening. Thanks again, and I hope you enjoyed this episode of JCO After Hours. Be sure to check out our other podcast offerings wherever you get your podcasts. Have an awesome day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Aronson Disclosures:

Stock and Other Ownership Interests Johnson and Johnson

Speakers' Bureau Company name: Janssen Oncology, Bayer, Blue Earth Diagnostics, AstraZeneca, Pfizer/Astellas

Research Funding: Lantheus Medical Imaging

UCLA Health Article Video

TRANSCRIPT

Ece Cali: Hello and welcome to the JCO Article Insights. I'm your host Ece Cali and today we will be discussing the Journal of Clinical Oncology article the "Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study." 

Despite significant advances in non-small cell lung cancer treatment over the past decades, second line treatment options for non-small cell lung cancer without actionable genomic alterations have remained largely unchanged since 2000. Many clinical trials failed to demonstrate improved overall survival compared to docetaxel based regimens. TROPION-Lung01 is a global open label randomized phase 3 trial comparing the efficacy and safety of Dato-DXd to docetaxel in patients with previously treated advanced or metastatic non-small cell lung cancer. Dato-DXd is an antibody drug conjugate targeting TROP2 and delivering deruxtecan, a DNA topoisomerase 1 inhibitor, as its payload. The trial is designed with dual primary endpoints of progression free survival, as assessed by blinded independent central review, and overall survival. The initial PFS results were presented at ESMO in 2023 and this article reports more detailed data and overall survival analysis of the trial.  

In the TROPION-Lung01, 299 patients were randomly assigned to receive Dato-DXd and 305 patients to receive docetaxel. Patients were stratified by the presence of actionable genomic alterations, histology, treatment with PD-1/PD-L1 immunotherapy as the last line of therapy, and geographical region. The baseline characteristics of the patient population were overall balanced between the treatment arms. I'd like to highlight a couple of key points here. The median age was 63 years in the Dato-DXd and 64 years in the docetaxel arm. Similar to the many clinical trials in the thoracic oncology field, this is younger than the median age of lung cancer diagnosis in the US, which is around 70. African American and Hispanic patients were underrepresented in this trial with 41% of patients identifying themselves as white and 39% as Asian. The D\docetaxel arm had a slightly higher percentage of male patients, 69% versus 61%. The majority of the trial population, 73%, had adenocarcinoma. Patients with actionable genomic alterations were included in this trial if they received one or more targeted therapy and platinum based chemotherapy prior to the enrollment. 17% of the trial population had an actionable genomic alteration in this trial. 

When it comes to the efficacy results in the full analysis set, the PFS improvement was statistically significant. The median PFS was reported as 4.4 months for the Dato-DXd, and 3.7 months for the docetaxel arm with the hazard ratio of 0.75 and a P value of 0.004. However, after a median follow up of 23 months, the trial did not meet its primary endpoint of overall survival. The median overall survival was 12.9 months for patients treated with Dato-DXd and 11.8 months for patients treated with docetaxel with the hazard ratio of 0.94 and a P value of 0.53. Objective response was a secondary endpoint and the confirmed objective response rate was 26% with Dato-DXd, and 13% with docetaxel. 

Now let's take a closer look at some of the subgroup analyses. Exploratory analyses of key subgroups in TROPION-Lung01 demonstrated differences in efficacy based on histology. In the nonsquamous subgroup, Dato-DXd showed a longer progression free survival of 5.5 months compared to 3.6 months with docetaxel with a hazard ratio of 0.84. However, in the squamous subgroup, Dato-DXd performed worse with a progression free survival of 2.8 months compared to 3.9 months with docetaxel corresponding to a hazard ratio of 1.32. A similar trend was observed in the overall survival analyses, though confidence intervals crossed 1 in both histology subsets, in this case, the differences observed were not statistically significant. In the nonsquamous subset, the median overall survival was 14.6 months with Dato-DXd and 12.3 months with docetaxel with a hazard ratio of 0.84. In the squamous subset, both arms had shorter survival compared to the nonsquamous subset. The median overall survival with Dato-DXd was almost two months shorter, so 7.6 months, compared to 9.6 months with docetaxel corresponding to a hazard ratio of 1.32. While these analyses suggest the potential survival benefit for Dato-DXd in nonsquamous subset, this trial was not powered to test this hypothesis hence these analyses remain exploratory. Another subgroup analysis of note was the group with actionable genomic alterations. Patients with actionable genomic alterations achieved a median PFS of 5.7 months with Dato-DXD and 2.6 months with docetaxel corresponding to a hazard ratio of 0.35. Similarly, the median overall survival was longer in patients with actionable genomic alterations by almost six months, with a median overall survival of 15.6 months with Dato-DXd and 9.8 months with docetaxel corresponding to a hazard ratio of 0.65. 

Now, let's talk about safety. Grade 3 or higher treatment related adverse events occurred in 26% of patients with Dato-DXd and 42% with docetaxel. The most common adverse event of any grade seen in the Dato-DXd arm were stomatitis seen in 47% of patients, nausea in 34%, and alopecia in 32%. Treatment related interstitial lung disease occurred in 8.8% of patients on Dato-DXd and 4.1% of patients on docetaxel. Of note, grade 5 drug related ILD was more frequent with Dato-DXd. Seven patients on Dato-DXd and one patient on docetaxel died secondary to drug related ILD in this trial. 

In summary, TROPION-Lung01 aims to address an unmet need for patients with previously treated non-small cell lung cancer. For this population, the treatment options remain limited with poor survival outcomes. TROPION-Lung01 is a positive trial by design due to clinically modest improvement in PFS. However, the lack of overall survival improvement is disappointing. Exploratory subgroup analyses suggest Dato-DXd may offer survival advantage in specific subsets such as nonsquamous non-small cell lung cancer and patients with actionable genomic alterations. However, these findings require further validation in a prospective trial since TROPION-Lung01 was not designed to address these questions. The data from this trial alone is not sufficient to argue for a change in clinical practice. However, it informs how the future trials using this drug should be tailored. This highlights the importance of studying potential predictive biomarkers earlier in the drug development and incorporating these biomarkers prospectively into the clinical trial designs. 

Due to the lack of overall survival benefit in this trial, the biologic license application for accelerated approval of Dato-DXd for patients with previously treated nonsquamous non-small cell lung cancer was voluntarily withdrawn. New BLA was submitted for Dato-DXd for patients with previously treated advanced EGFR positive non-small cell lung cancer. This BLA is based on data from TROPION-Lung05, TROPION-Lung01 and TROPION-PanTumor01. Of note, the results of TROPION-Lung05 trial have been just published in JCO.  

This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

The guests on this podcast episode have no disclosures to declare.

 Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. 

Today, we are joined by JCO authors Dr. Anna Wu and Dr. Alexander White. Dr. Wu is a professor of Population and Public Health Sciences at the Keck School of Medicine of UCS, while Dr. White is an investigator in the Epidemiology branch of the Environment and Cancer Epidemiology Group at the National Institute of Health. 

Today, we will be discussing the article titled, "Air Pollution and Breast Cancer Incidence in the Multiethnic Cohort Study," and the accompanying editorial. 

So, thank you for speaking with us, Dr. Wu, Dr. White.

Dr. Anna Wu: Thank you for having us.

Dr. Alexandra White: Yes, thank you so much for the invitation to be here.

Dr. Davide Soldato: So before going in depth about the results of the study that was published in the JCO, I was wondering if you could give us like a brief introduction and a little bit of background about what was known about air pollution as a risk factor for breast cancer and what was the evidence before this study was conducted.

Dr. Alexandra White: Okay. I can start with that question. So, there's been research for decades looking at the relationship between air pollution and breast cancer. And it's been a really challenging question to address for a number of reasons. One being that it can be really difficult to assess exposure to air pollution and many previous studies have had really limited information on people's residences over time. But in general, what we thought leading up to this study was that evidence was most consistent that exposure to traffic related pollutants such as nitrogen dioxide was more consistently related to a higher risk of breast cancer. The evidence for fine particulate matter or PM2.5 was less consistent. More recently, there have been a few large, well conducted studies that have supported a positive association. This new study in the multiethnic cohort led by Dr. Wu is really important because it really demonstrated that, in this large study of over 50,000 women in California, that they also do see an association with PM2.5. 

Dr. Davide Soldato: Thank you very much for the introduction. So, Dr. Wu, we just want to hear a little bit more about the results. So, what was the association that was observed for PM2.5? And specifically, the study that you ran was focused on a very diverse population, a multiethnic cohort, and so I was wondering if you observed any type of differences when you consider the different populations that were included in your study. And if you could also give us a little bit of what was the composition of the women that were enrolled in this cohort.

Dr. Anna Wu: Thank you for the question. So, the multiethnic cohort study is a cohort of over 200,000 individuals who were enrolled when they lived in Hawaii or California. For the air pollution studies that we've been conducting, we have focused on primarily the California participants. And in this instance for the breast cancer study, it was based on roughly 56,000 individuals out of- there were about 100,000 because half of them were men and they were not included. Of the California participants, 75% of them were African Americans or Latinos and they were self-identified as these racial ethnic groups when they enrolled in the study. And this was a particularly important consideration for us because in most of the studies that have been published so far on-air pollution and breast cancer, as well as other cancer sites, most of those studies were conducted among whites in the US or whites in Europe. And even if they included non-white populations, the numbers tend to be small so that they were not able to conduct racial ethnic specific analysis. So, we were particularly interested in examining these other racial ethnic groups because we know from other studies that racial ethnic minority groups tend to live in communities of low socioeconomic status and those communities also tend to have higher levels of various types of environmental pollutants. And so, it was important for us to actually try to tease apart these various interrelated factors. 

So, what we found was that per 10 micrograms per cubic meter, we had a 28% increased risk overall in all participants combined that meet across the racial ethnic groups. We actually did not see any differences or significant differences in the hazard ratios by race ethnicity and they were in general quite compatible with each other. But we did see a stronger finding among the white participants in our study.

Dr. Davide Soldato: Thank you, a lot, Dr. Wu. So, I think it's very interesting the fact that in the end you observed that air pollution is a significant risk factor across all the ethnicities that were included in the study. But I think that one very strong point of the manuscript and one very strong point of the analysis was that in the end you also corrected for a series of different factors because we know that the incidence of breast cancer can be modified, for example, by familial history or BMI or smoking habits or also alcohol consumption. And a lot of these risk factors were included in your analysis. And so, I was wondering if you could tell us a little bit whether you observed any significant differences when you observed or included also these risk factors in your analysis, or whether the association for air pollution as a risk factor stands even when we consider all of these other elements.

Dr. Anna Wu: Yes. So, we considered all the well-established breast cancer risk factors. And in this situation, we were particularly interested in considering smoking, alcohol intake, use of menopausal hormones, history of diabetes, body mass index, family history, as well as physical activity, because many of these risk factors, such as, for example, diabetes and body mass index, they are risk factors for breast cancer, and air pollution, have also been found to increase risk of these factors. 

So, in our analysis, we first adjusted for all of these potential confounders in a mutually adjusted manner, so all of them were considered. In addition, we also conducted stratify analysis. So as an example, we stratified the analysis to examine whether the hazard ratio associated with PM2.5 provided comparable risk estimate or hazard ratio estimates for never smokers, former smokers, and current smokers. Although we did not see significant heterogeneity by these various subgroups, we did see a significantly stronger effect of PM2.5 among individuals who did not have a family history of breast cancer. 

Interestingly, our finding was also stronger among individuals who were never smokers and light alcohol drinkers, even though the results were not significantly different. So, we surmised that maybe individuals who already had a high risk because of other established risk factors for breast cancer, we were less likely to be able to observe the effect of air pollution. But it's important to note that other studies, such as the ones that Dr. White has conducted, have also looked at various subgroups, and I think part of the limitation that all of us have is that once you subdivide the study population, even if you start out with a large sample size, often the sample size gets cut in half or a third. And so, we still lack the statistical power to be able to observe significant differences. But I think it is important to note that, in fact, the hazard ratio estimates are actually quite comparable, but we did see a hint of stronger effects among never smokers, and people who were light alcohol drinkers. So, I think this is an area that we certainly need to continue to investigate since there are other subgroups, such as menopausal status, such as hormone receptor status of breast cancer, that we need to consider in future studies. There's still a lot of work we need to do to sort this out, to actually figure out who are the women who are the most susceptible to the exposures.

Dr. Davide Soldato: Dr. White, I would really love a comment from you on this specific area and specifically on what still needs to be done. And related to this, a question actually, for both of you, because I think that from a methodological point of view, there is a lot of work that goes into deciding how we are going to assess the exposure to air pollution. So which type of data are we going to use? Which type of data are we currently using in the epidemiological studies that have been conducted and in the one that we are discussing right now in JCO? And what are the caveats for this data that we are using? Meaning, I think that we use mostly residential addresses, which means that we are looking at the exposure where people actually live, which might not be the place where they spend most of their time. For example, if someone is working, maybe they could be more exposed and have higher exposure when they are at work compared to when they are at home. So, I was wondering if you could give us a little bit of an overview as to what is the methodological standard of care right now in terms of this analysis and what can we do better to refine and understand this specific factor as Dr. Wu was mentioning?

Dr. Alexandra White: Yeah, so I'm happy to take a first stab at that question. So, I think it's important to note just how far we've come. I think even a few years ago, air pollution was really not considered a risk factor for breast cancer. And a lot of the work that we've been doing and others have really moved this forward in terms of understanding this as a risk factor. And as I mentioned earlier, there have been a lot of challenges in exposure assessment. And to get to your question, I think that our studies in general are doing better at looking at exposure over more years, residences, more time. We know that cancer takes time to develop, and we can't rely on just a single snapshot of exposure. But as you mentioned, almost all of the studies published have really exclusively focused on residential estimates of exposure. And so, there's a real need to understand the exposures that people are experiencing in other aspects of their life, from their commute to their jobs, to really capture that totality of exposure. 

And then I think one of the points that Dr. Wu was alluding to as well as we know that breast cancer is a very heterogeneous disease, so risk factors for breast cancer vary by tumor subtypes, by menopausal status at diagnosis. And a lot of studies have really focused on considering breast cancer as a combined outcome, and that might be missing some really important signals where we might have a stronger effect for certain subtypes due to the fact that there's different biologic pathways that are underlying these subtypes or by menopausal status. And so having large study populations where, as we discussed earlier, would really give us the power to look among these smaller groups of women who might be more susceptible and those with younger women, we know that incidence of cancer is rising in young people, and we need to understand the risk factors for that. And most of our studies are really focused on older individuals, so I think that's one important gap, as well as having the power to really look at different differences by tumor subtypes.

Dr. Davide Soldato: I think it's very interesting, and I think one point both of you made in the original article and in the accompanying editorial is also the fact that we tend to look at these risk factors in people who are actually aged, while we maybe should be looking at this in an earlier phase of development and potentially during puberty. Do you think that we should design studies that are more focused on this population even though I think that they will take a lot of time to produce significant results? 

Dr. Alexandra White: Yeah. I think that it is really important to consider how exposure during early life is related to breast cancer risk. We know that exposures during pregnancy or even as early as during puberty might be particularly relevant for breast cancer. And I think a lot of our studies have really been up against the challenge of the fact that exposure monitoring for air pollution really didn't start until the 1990s. And so, it's challenging, especially for these older cohorts, to get back at that time period that might be relevant. But I think that's something that definitely newer cohorts are going to be able to address, and I think it's going to be really important, and also will give us some clues to better understand the important windows of exposure, but also that might provide clues for the biologic pathways as well that are relevant.

Dr. Davide Soldato: And just a related question, because I'm not aware of this, but are there right now cohorts that are specifically looking at this in the US or in other parts of the world? If you are aware of that, of course. 

Dr. Alexandra White: There have been some cohorts that have focused on exposure during these hypothesized windows of susceptibility, but I don't think they've been able to follow those women long enough to develop breast cancer. One of the things that we're working on in the sister study is trying to expand our assessment of air pollution exposure back in time to try to get at these earlier windows of exposure. So, I'm hoping that it's something we'll be able to comment on and at least for some of the women in our cohort who are younger. But I don't know, Dr. Wu, if you're familiar with any other populations that are doing this now? 

Dr. Anna Wu: Well, NCI funded several new cohorts in the last couple years that are really focused on trying to get a much more refined exposure assessment. So, I know colleagues at University of Michigan that are peers and also Dr. Wei Zheng at Vanderbilt, they are putting together newer cohorts that are younger and also trying to include a range of exposure, not just air pollution, but really environmental exposures. Those cohorts I think have the potential in the future to try to address some of these questions, but again, it will take at least another number of years before there are a sufficient number of endpoints so that they can actually do these types of studies. 

Another possibility is that there are a number of big cohort studies in Asia. The age of diagnosis tends to be earlier in Asia. I know that investigators in China are very interested and concerned with the air pollution effects in China. I think there are potentials that in other countries where the age of breast cancer diagnosis is actually younger than in the US and if they establish in a manner that allows them to assess air pollution that they may have opportunities. 

And I think the other way to try to address this question, whether there are studies where you can actually tap into either biomarkers or pathology samples so you won't be actually studying air pollution in a large population, but you're actually narrowing it down to try to see if you see any signals in a way that would give you some additional clues and insights as to the mechanism. So I think we're going to have to piece together various types of study to try to answer the questions because one type of study like these observational air pollution studies, will allow us to address one slice of the questions that we have and then we need to put together other studies so that we can address other aspects that we're interested in to put it together.

Dr. Davide Soldato: Thank you very much both of you. That was very interesting. 

Coming back to the results of the manuscript, we really focused up until now on PM2.5. But it's true that inside of the study you evaluated different pollutants. So, I was wondering whether you saw a similar association for other pollutants that were included in the study or whether the association for higher risk was observed only for PM2.5.

Dr. Anna Wu: The results for NO2, NOx, PM10, and carbon monoxide were actually very compatible with the risk estimates that other studies have published as well as from the meta-analysis. So, I would say that our results from the other pollutants are actually very consistent with other results. I think one difference is that our PM2.5 estimates were based on the satellite-based PM2.5 estimates, whereas all the other pollutants were based on monitoring station estimates from EPA sponsored air monitoring stations. So, they are not measured in the same way. And I think different studies over time have used either monitoring station type measures for other pollutants. And I think we were particularly interested in PM2.5 because the measurement of PM2.5 in the monitoring world didn't start until around 2000. So, studies up until that time were less able to actually provide the assessment of PM2.5 as good as we can for air pollution. There's always misclassification. So, I think it's a matter of how much misclassification in the assessment. But, again, we are really limited in really just having exposure over one part of adult life. 

Dr. Davide Soldato: Thank you very much. And one potentially related question. We are speaking in general about air pollution, but I think that since we are considering residential addresses, probably we are capturing more either traffic pollution or pollution that comes from probably industries or stuff like that, which is mostly related to residential areas or the place where people live. But I think that in the end we also think about air pollution as something that can come from different forms. And one very interesting point, Dr. White, that you made in your editorial is also that there is a global change also in the way we are faced with air pollution. For example, you made the example of wildfires in your editorial and how this might potentially change exposure to air pollution, maybe for limited times, but with concentrations that are fairly higher compared to what we generally observed. So, I was wondering if you could comment a little bit on that and also, if there is potentially a way to also consider this in future epidemiological studies.

Dr. Alexandra White: Yeah, so when we talk about exposure to fine particulate matter, PM2.5, we're assessing exposure to particles that are based on the size of the particle, and we're really not evaluating the types of particles that people are experiencing exposure to. And we know that, in general, that PM2.5 composition really varies geographically due to differing sources of exposure. So, like you were saying, there might be a stronger contribution to industry or from agriculture or from traffic. And so that could really change the PM2.5 exposure profile that individuals experience. And so it could be that this is another really important area that this research needs to consider, which could really help us identify what sources of exposure are most relevant.  

Wildfires are a really important growing concern. We know that wildfires are increasing in both intensity and duration and frequency, and we really don't understand the long-term health impacts of wildfires. But we know that wildfire associated PM2.5 might be one of the most dominant contributors to PM2.5 moving forward. And although we've seen historic declines in PM2.5 in the US after the Clean Air Act, those declines have really stalled. PM2.5 itself is projected to increase over the next few decades, so understanding different PM2.5 composition profiles and the sources that drive them can really help us identify the most important targets for any potential interventions. And wildfire PM2.5 in particular may be of concern because it's a combustion byproduct, and so it's thought to have more of the components that might, we hypothesize, are most relevant for breast cancer, such as PAHs or polycyclic aromatic hydrocarbons or metals. And so, these components are thought to act as endocrine disruptors, which may be particularly relevant for breast cancer. So, I think understanding this changing landscape of PM2.5 moving forward is going to be really important in understanding how PM2.5 contributes to cancers beyond just breast, but as well as other female hormone driven cancers and all of the cancers really. 

Dr. Davide Soldato: Thank you very much. So, one closing remark, because I think that in general, we have been really in a field of primary prevention for breast cancer where we were focusing on individual behaviors, for example, smoking cessation, reduction in alcohol intake, reduction of BMI, increase of physical activity. But I think that the evidence that is accumulating in the last three years or so is telling us more and more that we also need to shift the perspective on prevention going not only on individuals, but also as including environmental risk. So, I was wondering, how can we include this new evidence in the policies that we implement and how policymakers should act on the data that we have available right now?

Dr. Anna Wu: I think it's really important that this new information is communicated to all the stakeholders, including our policymakers, so that they are, first of all, really aware that any changes and not actually adhering to current guidelines can have long lasting consequences, deleterious consequences. And I think it's important to also note that over 90% of the world actually live in areas where PM2.5 exceeds the limit. We have observed increases in breast cancer in many middle- and low-income countries, so I think it's particularly important to emphasize that this is really not just a western country issue, it is really a global issue.

Dr. Alexandra White: I agree. And I would just add to that that air pollution is not something that an individual can really change on their own. There are things you can do, you can monitor air quality, you can try to live in a home that's far away from traffic. But really these are large scale problems that really require large scale solutions. And we know that policy changes can be effective here and that this is something that, in my opinion, is not something that we leave to the individual to change. This is something that we as a society should encourage change for the health of everyone.

Dr. Davide Soldato: So, thank you very much again, Dr. Wu, Dr. White, for joining us today on the podcast.

Dr. Anna Wu: Thank you.

Dr. Alexandra White: Thank you so much for having us. 

Dr. Davide Soldato: So we appreciate you sharing more on your JCO article and accompanying editorial titled, "Air Pollution and Breast Cancer Incidents in the Multiethnic Cohort Study." 

If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

Giselle Carvalho: Hello and welcome to JCO Article Insights episode for the December issue of the Journal of Clinical Oncology. I'm your host Giselle Carvalho, Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers and one of the ASCO Editorial Fellows at JCO this year. Today, I will be discussing two articles. The first one is "Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies," and the second one is the "US FDA Approval Summary on Capivasertib with Fulvestrant  for HR-positive HER2-negative Locally Advanced or Metastatic Breast Cancer with PIK3CA/AKT1/PTEN Alteration." 

As we know, 65% to 70% of all breast cancers are HR-positive HER2-negative and this is also the most common subtype of metastatic breast cancer. The current standard of care for frontline therapy of patients with luminal metastatic disease is a CDK4/6 inhibitor in combination with endocrine therapy. However, as new endocrine and targeted therapies gain approval, choosing the best systemic therapy upon disease progression after frontline therapy is a topic of ongoing debate. Nearly 40 to 50% of HR-positive breast cancers have actionable genomic alterations and molecular testing should be a routine recommendation for patients with metastatic HR-positive HER2-negative disease. This can be performed repeating tissue biopsy at the time of progression or from archival tissue. Treatment options after progression on CDK4/6 inhibitors include alpelisib in combination with fulvestrant in patients with PIK3CA mutant tumors as seen in the SOLAR-1 trial, or capivasertib with fulvestrant in patients with a tumor mutation in (PI3K)–AKT–PTEN pathway as seen in the CAPItello-291 study, which will be discussed further. 

In approximately 30% of patients, progression on frontline endocrine plus CDK4/6 inhibitor treatment is caused by endocrine resistance, frequently involving activating mutations in ESR1. For those tumors, elacestrant, an oral SERD is an option as demonstrated in the EMERALD trial. For patients with a BRCA mutation, PARP inhibitors represent another option. If no mutations are detected, everolimus, an mTOR inhibitor, can be used based on the BOLERO-2 results. The phase 2 MAINTAIN and PACE trials, along with the phase 3 postMONARCH trial support changing the endocrine therapy backbone with or without switching the CDK4/6 inhibitor. In less resourced areas, fulvestrant monotherapy is still an option to delay cytotoxic chemotherapy, though its efficacy is limited when used as a single agent. Finally, after progression on at least one line of chemotherapy, antibody drug conjugates including sacituzumab govitecan or trastuzumab deruxtecan may be an option. 

Now focusing on the PI3K AKT PTEN signaling pathway, activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN occur in approximately half of luminal breast cancers. In June 2023, the CAPItello-291 trial was published and treatment with fulvestrant plus capivasertib, a PTEN AKT inhibitor, demonstrated a 3.6 month PFS benefit compared to fulvestrant alone, regardless of the presence of AKT pathway alterations. However, for those with tumors without AKT pathway alteration, an exploratory analysis showed that although there was a numerical improvement in PFS, it did not meet statistical significance, indicating that the biomarker positive population primarily drove the positive results noted in the overall population. Therefore, capivasertib plus fulvestrant was approved by the US FDA in November 2023 exclusively for patients with PI3K/AKT1/PTEN tumor alterations after progression on an aromatized inhibitor with or without a CDK4/6 inhibitor. The approved schedule of capivasertib is slightly different from that of other agents used in breast cancer. It is 400 milligrams taken orally twice a day for four days per week every week in a 28-day cycle in combination with fulvestrant. Diarrhea, rash and hyperglycemia were the most commonly reported grade three or four adverse events in the interventional group. I would like to highlight that even though the CAPItello trial excluded patients with glycosylated hemoglobin levels higher than 8% or those diagnosed with diabetes who required insulin, hyperglycemia occurred in 19% of biomarker positive patients treated with capivasertib, with nearly 2% of this population experiencing grade 3 or 4 hyperglycemia and some patients experiencing life threatening outcomes such as diabetic ketoacidosis. 

By way of comparison, hyperglycemia of any grade was three times higher with alpelisib therapy in the SOLAR-1 trial, occurring in 64% of the patients and grade three or higher hyperglycemia was seen in 37% of the patients. Diarrhea was the most common treatment related adverse event experienced by 77% of the biomarker positive population. Prompt use of the antidiarrheal drugs when needed, such as loperamide must be encouraged as untreated diarrhea can lead to dehydration and renal injury. Cutaneous rash occurred in 56% of the biomarker positive population in the interventional group and 15% experienced a grade 3 or 4 rash. Nearly half of the patients with cutaneous adverse reactions required treatment and this was the leading reason for dose reduction of capivasertib. 

In the biomarker positive population, the improvement in medium PFS were 4.3 months by investigator assessment. Overall survival data from the CAPItello-291 trial is still immature, but quality of life data was recently published in September this year and was assessed by the 30 item QLQ C30 questionnaire and the QLQ BR23, the breast module. According to Oliveira et al, global health status and quality of life were maintained for a longer period with capivasertib fulvestrant than with placebo fulvestrant except for symptoms of diarrhea which were significantly worse in the capivasertib group. The median time of deterioration of global health status and quality of life was twice as long in the capivasertib group being almost 25 months versus 12 months in the placebo fulvestrant group. These data reinforced the use of capivasertib in combination with fulvestrant for the treatment of HR-positive HER2-negative advanced breast cancer patients with PIK3CA/AKT1/PTEN tumor alterations who have progressed after an aromatase inhibitor-based therapy with or without a CDK4/6 inhibitor. 

Thank you for listening to JCO Article Insights. This is Giselle Carvalho. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. See you next time.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT TO COME

Dr. Davide Soldato: Hello and welcome to JCO's After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy.

Today, we are joined by JCO authors Liz Salmi, Researcher and Patient Advocate, and by Dr. Suzanne George, who works as a Medical Oncologist at the Dana-Farber Cancer Institute where she acts as the Chief of the Division of Sarcoma. She is also Associate Professor of Medicine at Harvard Medical School. Today, we are going to discuss with Suzanne and with Liz the article titled, "Overcoming Systemic Barriers to Make Patient-Partnered Research a Reality."

So thank you for speaking with us, Suzanne, Liz.

Liz Salmi: Thanks for having us.

Dr. Suzanne George: Yes, thanks.

Dr. Davide Soldato: I just want to make a brief introduction because I think that the concept of patient partner research is very wide and I'm not sure that all of the readers of JCO really have a deep understanding because I imagine that there are a lot of ways we can involve patient and patient advocates in the research process. And so I was wondering if you could give us a little bit of an introduction about the concept.

Dr. Suzanne George: Sure. I think the point that you raise is really important because there are many terms that are used, patient-partnered research, patient advocacy, but I don't think that there's a single definition as to what that actually means. In the context of our work, we've sort of summarized our experience through something called the PE-CGS or the Participant Engagement and Cancer Genome Sequencing network. And in that project, which is a Moonshot funded network, the intention is to have participants in research be true partners working with traditional academic research teams in order to develop networks specifically focused on cancer genomics. So what we've done, every center is a little bit different in the network, but we're really having research participants not just act, but really work on the research team from the beginning of the project inception all the way through the research project.

Liz Salmi: What brings me to the PE-CGS network is my 17 years experience as a person living with a low grade glioma, brain tumor or brain cancer and involving patients in the co-design of research is super critical because patients bring unique lived experiences that can shape research questions, study designs and outcome measures in ways researchers might not anticipate. And we're finding this through our network. So through my work, including my patient experience and brain tumor focused study designs, I've seen firsthand that patient insights can drive more practical implementations that ultimately benefit both patients and the researchers. And so the particular project I work on in the network, we've got like five different arms and different groups of cancer types that are being represented, so I'm basically focusing on the OPTIMUM study around how brain tumor patients can help in this study design. So in this project I serve as not just a participant in the research, but also as a patient co-investigator.

Dr. Davide Soldato: That is very interesting. And I think that we really captured the essence of patient-partnered research by having both of you here talking with us about the PE-CGS. And the second question that I wanted to ask is: I really think that the network focuses on something that is quite important right now and currently in medical oncology - so cancer genome sequencing, access to novel therapies - and I think that it's really challenging to imagine a way in which we can really get our patient and get patient advocates to help us designing new trials who are looking into this. And I just wanted to know, do you think that there is something that is particularly challenging when we are speaking specifically about cancer genomics and access to this type of drugs that are targeting specific molecular alteration? Because I think that in general it might be a little bit easier, maybe I'm biased on this, so you can also tell me if I'm wrong, but I think that it's a little bit easier when we are trying to design, for example, behavioral intervention or things that are more commonly found in oncology and a little bit more complicated when we are speaking about genomics.

Dr. Suzanne George: So I think that's part of what this network is trying to address, which is really what are the barriers and the opportunities around cancer genomics from the patient perspective and how do we make sure that that perspective is included as we're thinking about study design and inclusion? As Liz mentioned, this network has five different networks within the network, five different centers, and each center is slightly different with the population that it engages with. And so there's diversity there in terms of reaching out to different patient communities and partner communities around potential barriers for genomics research. I think one of the things though that we're finding across the network is that people want to be part of this work. People that have a lived experience of cancer want to help move the field forward. And what we ended up writing about was some of the barriers that get in the way of that. It's awesome to have people like Liz that are like all in and then there's people who are on the other end of the spectrum that want to share their information to help move the field forward around genomics, but then there's all these barriers at the systems level that get in the way of that. So I think that that's one of the challenges we're trying to overcome and learn about across the network.

Liz Salmi: Yeah, I think I bring this really interesting, I can't say I'm really interesting, but I think I bring this really niche perspective. Not only am I a person living with a brain tumor and I'm a co-investigator but also like a participant in this study. I also, in my day job, I'm an investigator as part of the director of communications and patient initiatives on the OpenNotes lab at Beth Israel Deaconess Medical Center. And our lab really focuses on how open, transparent communication between doctors and patients improves care. And that's been going on for longer than I've been around on our team. But what I bring to that lab is I focus on engaging both patients and clinicians in spreading the awareness about the power of how easy access and transparent communication, access to information across healthcare settings helps patients feel more involved and informed in their care.

And I work specifically, it's a really niche area. I work on projects that aim to expand access to notes and test results in diverse care settings, really helping tailoring initiatives so that various patient communities can understand how they can be involved in these types of research projects. Ultimately that's what brought me into this space. I might be one of the first generation of patients that actually starts helping co-design studies on things like this. And I think that across a lot of healthcare settings cancer is really what we're focused on. But patients are now increasingly being involved as research collaborators. And there's many different funding institutions such as the NCI but also PCORI they now mandate that funders reflect a shift towards more patient centered research frameworks. So it's like the PE-CGS network isn't the only group that's being funded to do research in this way. And I think other investigators, even outside of the cancer space, but specifically in cancer, need to learn how to do research in this way.

Dr. Suzanne George: Yeah, I agree. And I think the other thing that we need to do is if people want to participate and that participation in many of these networks has to do with record sharing and data sharing, the system needs to accommodate that. If people want to share their information in order to allow research to be performed, then we need to make sure that that can happen, and that it's not that the institution systems don't connect with someone else's systems or that you to pay X, Y and Z dollars for the data to go A, B and C, or that some places are on this EHR and some places are on that EHR and so, sure, you can share it, but you have to go through all of these hurdles in order to make it happen. When a patient signs a consent form that says, "I want my data to be used," we as an investigator community, we owe it to that patient to make sure that their information is being part of the data set that will be used for learnings. And that's part of what we wrote about, is the lots of behind the scenes things that just get in the way and that we need to work towards improving.

Liz Salmi: Both Suzanne and I are really passionate about this stuff. And as a person living with a brain tumor for the last 17 years, I'm a chronic research participant. I always, always, am really curious. I'm like, "Yes, let me contribute my data. Whether that's electronic health record data or maybe I'm being interviewed about certain aspects of the cancer care experience." And the one thing that bummed me out for like the first 10 years of being this chronic research participant is I would enroll in things, I'd be interviewed for things, I'd fill out these surveys and then I never heard anything about what happened with that information and that time I spent. And people would send me like a $10 gift card to Amazon, like, "Thanks for participating," but really what I wanted to know is like, did you do anything with that? How did that inform things? So that really annoyed me to the point where I was like, I'm just going to be part of the research process and really figure out how we share that information back to everybody who had spent so much time. And so my participation in this space is like, "Let's change it. Let's give people information back." And now I know it takes a really long time to have a finding that could be published somewhere that we then get it back. But closing the loop on the communications gap is something I'm really passionate about.

Dr. Davide Soldato: Do you think that we are changing a little bit this perspective? I feel like we are getting a little bit better in creating patient communities of patients who are included in specific clinical trials. And then we do the effort of creating a community, of keeping people really involved with the research that they are participating in. I think that we are not quite there yet, but I think that we are making some kind of steps in that direction. For example, trying also to inform patients to participate in the study when the publication that is related to that specific study comes out. What is the benefit? What have we discovered? I think that we are not quite there yet. There is a lot of room for improvement, particularly in the way I think we communicate these to patients who participated in research. But I have the impression that we are making some steps forward. So I don't know. Do you share the same thoughts?

Liz Salmi: So Dr. George talked about the PE-CGS network and then there's five different cancer types being studied. So the thing I can reflect on is what we've done in the, this is a really long acronym but, Optimizing Molecular Characterization of Low Grade Glioma. Say that 10 times fast. So our particular group is people who donate tissues about their brain tumors. We're really collecting data from people with multiple brain surgeries over time, which is really complicated and to make that process easier. And then once those tissue samples are stored somewhere, studying that information about what changes in the brain tumors over time and then also giving those results back to people so they can take that research level data and bring it back to their neuro oncology team and say, "Hey. Here's what I found out, "and having a conversation.

So, this is a long multi touch point study and in order to do that, to even make that possible is the individual patients need to understand what's in it for them. They're donating precious tissue in order to make the research process work. And so in order to do that, it's not just the investigators saying, "Hey. Give us your brain tissue, peace out." It is we have a whole research advisory council of people living with these particular tumor types who help us co-design how do we do that outreach, how do we explain why this is important, or how do we message the importance of this work so they understand,"Oh, this is what's in it for me and this is what's in it for other people like me." And from there then with that process, which again I mentioned, all of these multi-step processes, once we're able to understand how patients want to hear that information, what's in it for them, then we bring it back to like those bench scientists, investigators going, "Okay. And here's how this workflow should work for the patients," and design everything around the patient experience before we even care about what's happening from the scientist researcher perspective.

Dr. Suzanne George: I agree. I think to your point, I think the fact that we're all here today talking about this is just like you said, is that we are making progress, right? Like we're even here having this conversation. Just like you said, I think there's opportunities to improve and further refine the communication and the involvement back in the patient community. When I think- if I put on my clinical investigator hat, I'm very involved in PE-CGS, but my primary research interest historically has been clinical trials and drug development. And I think that our approach in communicating results back has just not been consistent. But I do think that there's opportunities, just like you said, to provide summaries of information to loop back. I don't think that we've completely solved: What do we do? How do we provide information back to loved ones of patients that may no longer be alive that participated? How do we provide information to people who maybe we don't have their contact information? What if we lose track of them? How do we also make sure that we give people the choice to know? Do you want to know about this or would you rather just participate and then give space to that research? Because maybe that's how people's best for them. So I think that you're right, we're making progress, but I think that there's also a lot more that we can do. So I'm glad we're talking about it.

Dr. Davide Soldato: How much do you think that directly involving patients in this process, like asking them directly and co-designing the trial from the very beginning and understanding the level of information? This might also be another question inside of the question. So first, how much co-designing this type of research helps, and then do we also need to further refine at that level of communication, different communication depending on the level of information that different people want to have? Because I think that that's another level of complexity that we need to work towards at a certain point. We need to work on that first level of giving back the information. But then I think that there is also the other point of providing the information and information that should also be probably adapted to the cultural belief of different patients, to the ethnicity or to whatever cultural background or social background or whatever they may place their most interest in.

Dr. Suzanne George: So I think that you're 100% right on all of those points. I think those are all topics that need to be considered. We may be able to get to a certain degree of granularity around those communication points, but on the other hand, we also want to be able to communicate broadly and accessibly as possible.

One of the interesting things about PE-CGS, as Liz was mentioning, is each of the five centers has a slightly different focus. For example, one of the centers is focused on American Indians and Tribal Nations, and the communication practices coming out of that center are really unique and really very special and something that's been really, I think for me, very fascinating to hear about. Because to your point, like, just the strategy and what's considered appropriate is just different. I think if we hope to build a research world where our research participants and research data come from a broad swath of the population that really represents the population, the only way that we're going to be able to do that is find ways that bring meaning across the population as well. And that may be different based on where people are coming from and where people are at in their own journeys and in their own lives. But it's on us to be open to that and like to hear that, so we can do the right thing.

Dr. Davide Soldato: And I think that this is one of the objectives of the PE-CGS, really trying to bring this type of research participation to really diverse and underrepresented populations, not only in terms of cultural background, but I also think about different types of tumors. Like Liz was referring about brain cancer or low grade glioma, which is a very niche population. And I also think about sarcomas, for example, the degree of variability that we have in that specific type of disease is such that we really need to probably find different ways to communicate also inside of this diversity in terms of single patient and experiences, but also in terms of single diseases.

You were speaking a little bit before about the fact that the manuscript is really on the barriers that we would need to identify and then to change to make this system a reality. We were talking a little bit about consenting information and consenting the sharing of information, and I think that you make a very interesting point about the consent process when we are designing research. Could you give a little bit of your impressions about giving informed consent? What we need to change, how can we improve?

Dr. Suzanne George: The bottom line is the consent process needs to be simple, clear, and transparent. And sometimes I feel, because the traditional way that we've always gone about consent is frequently consent is as it should be in many ways. These consent forms are developed from a regulatory framework. What are we required to do to consent and how do we meet those requirements? Sometimes that becomes directly at odds with how do we do this simply, clearly and transparently? And I think as a research community, we have to be able to find a common ground there. That has to include regulatory requirements, that has to include IRBs. When we think about consents and work with our patient communities on this, everybody agrees the consents need to be more simple, except the IRB or maybe the IRB agrees, but it's this tension between how do we make it simple, clear and transparent and not get so bogged down in the regulatory that we lose that intent.

Liz Salmi: It's complicated. As a person, I mentioned, I'm a chronic research participant living with a brain tumor for 17 years. I remember enrolling in studies and seeing things that are just so complicated. I'm like, "Well, I'm just going to sign off." I imagine somewhere somebody who knew more than me said, "I should just fill out this thing." And then as I switched to the research world, I spent more time digging into, "Wow, this is a really complicated consent," versus, "This is a really streamlined consent and I love this."

And throughout my work with Dr. George and others on the PE-CGS network, an example of a good consent that's easy for people to understand is what the NIH All Of Us research project did, where they're trying to get a million people, more than that, signed up to be in this longitudinal study. And their consent is to go to their website and they have a whole bunch of short YouTube videos. There's a kind of like a quiz involved and they're animated, they have multiple languages involved. And I signed up for that study and I was like, "This is a beautiful consent." And it's a very plain language. And more consents like that. If you're looking for a good example, go there. I have not been paid by them in any way. I'm a participant in their study.

I'm not sure if you guys and your listeners are aware, but there was I think, October 19th of this year or 2024, there was a special communication published in JAMA on an update on the Helsinki Principles for Medical Research involving human participants. And what they're saying is an ethical update is patient engagement in research, which emphasizes the need for continuous, meaningful engagement with research participants and their communities throughout the research life cycle, before, during and after studies. And so this is what we're talking about here. And it's now been embedded in these updated principles.

Dr. Suzanne George: That's really great and I agree with you. I think the All Of Us consent process is very accessible. It feels like you can understand it. But the other thing is that, again, I also am not directly involved with All Of Us, but the other thing about it is that they also have a high-touch way to consent where they have navigators and people that will go into communities in a very resource intensive way. So there's all different ways to go about it. We need to find a way that we can balance the complexity around regulatory and the simplicity and transparency that we need in cancer research.

Dr. Davide Soldato: Do you think that in terms of patient engagement we are doing better in academic sponsored research compared to sponsored research? A little bit of a provocative question maybe.

Dr. Suzanne George: I think that's a really interesting question. I think this idea of participant engagement and involvement is being infused across the research community. And in part, the FDA has prioritized it as well. I think the industry sees the FDA prioritizing this as well. And I think that there are many companies that are involving participant and advocacy communities in different ways in the study design, in the study process early on. So I think it's happening.

Liz Salmi: I'll be spicy. I've been a participant, I've been an investigator, co-investigator on studies and I have been reached out to often by pharma of, "Hey Liz, brain tumor patient advocate, would you be kind of like the poster child of our study or be involved in that way?" And I personally want to have no work in that space. I have no interest. However, I am approached, and other people living with cancer have been approached, by industry about lending their likeness or being commercials. And I don't think there's enough education to patient advocates of what that necessarily means, pros and cons. But I also can't speak on behalf of all of the patient advocates who might want to see that's a way that they could lend their voice and advance research. I personally think that there needs to be more involvement from the academic side of creating spaces where patients can be involved in the co-design of research and they also get compensated for their time fairly at the same level or some version of it in a way so they don't just jump to the pharma side of things. But that's an opinion that I have. Opinions.

Dr. Suzanne George: I think it's really interesting the point that you make about providing more awareness or information about what it even means to do these things from a patient side. I certainly don't know that side as well, but I do see, often, the term patient advocate used very frequently in many different contexts that mean many different things. And I think that there's an opportunity there for understanding more about what that really means and what it can mean.

Liz Salmi: Yeah. We want to involve patients, we want to do patient engagement. The BMJ or the British Medical Journal, have this new policy in place for patients as reviewers of research. And what I find interesting with the BMJ is they also ask patients to declare their conflicts of interest. So this is kind of a new space. If you're involved in patient research or perhaps working with pharma, patients, if you're involved at that level, should also be declaring their conflicts of interest if they're getting paid by a pharma. Or do I have a conflict now that I'm doing this cool ASCO podcast? Maybe. But do we want to overburden patients with tracking all this information? So it's a new world. The more we have access to information, the more we share information, the more we can read studies and we co-design, there's a new space I think over the next 5 to 10 years where how do we define this in a transparent way.

Dr. Suzanne George: Yeah, I think you're right. I know that we're getting long, but I just want to say one other thing about that, which is that you're right. If we're bringing patients in to be partners, then we have to treat each other that way. We have to acknowledge- I think this issue that you raise about compensation and about paying people for their time or acknowledging people for their time, I think that's really important and very under-discussed. Liz and I were at the annual meeting for the PE-CGS and someone was there giving a talk about- this was a guest speaker that was giving a talk about a very large high impact grant and that included a patient advocacy kind of module, let's say. And they put in a specific funding and budget for that component that included compensation for the people- from the people in the advocacy community that were spending their time. And the PI of this project, again, not to get into the details of it, but they were sharing that they got a fair bit of pushback on that. But the PI pushed back and said, "Listen, we're compensating other people for their time. These guys, we want them to be partners, we need to treat them as such." And I think that also again, kind of we're in a new space, but if we're going to do it right, then we have to acknowledge that we're partners.

Dr. Davide Soldato: But I think that maybe an experience like the PE-CGS probably can be also a network for expanding awareness for patient advocates and also for creating sort of a new culture about what does that mean and how can we also improve on that part. Because in the end, if we want to engage, we also need to provide patients with the instruments to engage in a way that we think it's both useful for them, that can make research better, but can also make them at the exact same level as everyone who is participating in that research, which I think it's the bottom line of all the concepts that we are discussing right now.

Liz Salmi: Yep.

Dr. Suzanne George: Yes, I agree.

Dr. Davide Soldato: So I think we have covered a lot of things. Just wanted to make one last reference to a point that Suzanne mentioned earlier, which is the interoperability of systems. And I think that when we come to the cancer genome, that is very important, being able to share information, especially for those diverse and less common cancer types that we were discussing earlier. There is a lot of work in gaining all that information and we need to be able to gather all of that information in the same place to advance research. You were mentioning before that the process is actually very complicated and I was wondering if in the network you are already working on some potential ways to address this type of issue.

Dr. Suzanne George: I think our first step is really just calling it out, acknowledging how hard this is and what the barriers are. Oftentimes I think in research, we don't talk enough about what our methodologic barriers are. We talk more about what our results are, but not like how hard it is. But like in our projects, the Count Me In project, my network that I'm involved with, we're doing rare tumors. We can only do the United States and Canada because of privacy issues. And we're doing a completely web based platform. So we have the technology. But the privacy laws are impeding our ability to involve other parts of the world. And even within the United States, it's not as easy as we would like to get records. For example, despite the fact that people are saying, "Yes, use my records." But then it's like, "Okay. Well, that's not that easy. How are we going to get them?" We had to hire a third party vendor in order to get the records, in order to manage all the different consents and releases that were needed across all these different hospital systems. So I think the first question is just calling it out and then from there working together as a community to try to see what the solutions can be, because we need to come up with those solutions.

Liz Salmi: Yeah, we're in the same camp as Dr. George and the fact that of the five partners, we're not associated with one particular institution. So we can reach out around the country and get access to those records. And we need them at multiple points in time, over time and it takes a lot of effort and work. And it's not like you could just, say, call hospital A and they have all the information. It's like all of the calls to all of the other sites. And it's not just from one surgery, it's from two or more surgeries. But also the way that people stay involved, and, by people, I mean patients and family members, there's this promise that at some point you're going to get some sort of information in response. Like, it's the "what's in it for me?" aspect of it. We do interviews with those who've been enrolled in the study, those who could be potential enrollees in the future because they've only had one surgery. And what we're learning overall is there's this altruistic nature that people have of- they want to participate in the research because they're like, "Here's my horrible cancer experience. I know other people are going to go through this as well." There's this guiding light of "I want to do something, and I'm not going to be the person that creates the cure, discovers the genome or whatever for this particular cancer type. But my little bit of participation in this multiplied by 20, 30, 100, 1000 people, is what is going to lead us to the next phase in development and is going to move the needle for this particular tumor type or other cancer types." And so what I think the impact in this space and participant engagement isn't just something we figure out, like a little research method and a little finding for one small tumor type, it's like the methods to do that is the big impact. The method around participant engagement can impact even beyond the cancer community.

Dr. Davide Soldato: Yeah. As Suzanne was saying, we need to be in a system that really helps us and allows us to do that. So I think that you really have a lot of things to work on inside of the network.

Dr. Suzanne George: I think one thing that I would say is I think that this issue of interoperability is acknowledged as a challenge. We refer to several different initiatives across the US where this is supposed to ideally change over time. I think people want it to change over time. I think investigators at the ERTC want it to change over time. I think different countries are working on this. And I think, again, the first step is getting us at the table talking about it, and then figuring out ways to move it forward. And I think it's there. I think that there is the will. We just have to figure out the how and continue to work on that together, because there's just a tremendous opportunity. I live in the rare tumor space, and between the FDA and the EMA and the regulatory, the national and the international research groups, the patient communities, people want this to be solved and I do hope that we will be able to get there.

Dr. Davide Soldato: So I would like to thank Liz and Suzanne for joining us today.

Dr. Suzanne George: Thanks for having us.

Liz Salmi: Thank you.

Dr. Davide Soldato: Suzanne, Liz, we appreciate you sharing more on your JCO article titled, "Overcoming Systemic Barriers to Make Patient-Partnered Research a Reality."

If you enjoy our show, please leave us a rating and a review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

DISCLOSURES

Dr. Suzanne George

Honoraria
CStone Pharmaceuticals

Consulting or Advisory Role
Blueprint Medicines, deciphera, Bayer,  Lilly, UpToDate, Research to Practice, MORE Health, Daiichi, Kayothera, Immunicum, BioAtla
 
Research Funding
Blueprint Medicines, Deciphera, Daiichi Sankyo RD Novare, Merck, Eisai, SpringWorks Therapeutics, TRACON Pharma, Theseus Pharmaceuticals, BioAtla, IDRx, NewBay Pharma, Acrivon Therapeutics
 
Patents, Royalties, Other Intellectual Property
Company name: UptoDate

Stock and Other Ownership Interests
Abbott Laboratories and Pfizer
Recipient: An Immediate Family Member

TRANSCRIPT

Rohit Singh: Hello and welcome to JCO Article Insights. I'm your host Rohit Singh, Assistant Professor at the University of Vermont Cancer Center and today we'll be discussing the article "First-Line Nivolumab Plus Relatlimab Versus Nivolumab Plus Ipilimumab in Advanced Melanoma: An Indirect Treatment Comparison Using RELATIVITY-047 and CheckMate 067 Trials," authored by Dr. Georgina Long from the Melanoma Institute of Australia and her colleagues. 

So as we know, nivolumab plus relatlimab and nivo plus ipi, I'm going to refer to as ipi-nivo moving forward, are dual immune checkpoint inhibitors regimens that are approved for treating patients with advanced melanoma based on the phase 2 and 3 RELATIVITY-047 and phase 3 CheckMate 067 trials respectively. Nivo plus relatlimab is the only dual PD-1 and LAG-3 inhibitor regimen approved for treating patients with advanced melanoma and relatlimab is the first in class human IgG4 LAG-3 blocking antibody. Ipi plus nivo is a dual PD-1 and CTLA-4 inhibitor regimen. 

So this paper basically is an indirect treatment comparison using a patient level database from these trials and this pretty much was conducted because of the absence of head to head trials looking at different regimens in advanced melanoma in first line setting. In this trial, the authors tried to compare these two trials. However, it's always hard to compare two different trials and we usually don't do cross trial comparisons. The problem is that the groups might be different to begin with. For example, one group might have younger patients, healthier patients, while the other might have older or sicker. These differences can make it hard to tell if the treatment caused improvement or if the groups were different to begin with. In this trial, researchers use inverse probability of treatment weighting to adjust the baseline differences between the two patient groups or between these two trials. Inverse probability of treatment weighting is a method used in research to help make a fair comparison between two groups when studying how a treatment intervention works. Basically, IPTW helps level the playing field between the two groups or like two trials for this paper. So, it calculates the likelihood of receiving a treatment. For each person, for each patient, researchers estimate the chance they would have gotten the treatment based on their characteristics like age, health, condition, their baseline staging, and based on that they create weights. People who are less likely to get the treatment but did are given more weight, and those who are very likely to get the treatment are given less weight. The same is done for the group that didn't get the treatment, and then they rebalance the groups. By applying these weights the group becomes more similar in their characteristics as if everyone had an equal chance of getting the treatment. This way, IPTW helps researchers focus on the effect of treatment itself and other differences between the groups. It's like adjusting the scales to make sure you are comparing apples to apples. 

The key outcomes the authors are looking at in this one was progression free survivals, overall survival, confirmed objective response rate, melanoma specific survival, and treatment related adverse events. Looking at the results of this cross comparison trial, first looking at the PFS or progression free survival, both regimens ipi plus nivo and nivo plus relatlimab, showed similar PFS. At 36 months, PFS was 36% in nivo-relatlimab versus 39% in the ipi-nivo regimen with a hazard ratio of 1.08 indicating no significant differences. Looking at the overall survival at 36 months, overall survival was 57% in both the treatment regimens with a hazard ratio of 0.14, again, indicating no significant differences. Now looking at another confirmed objective response rate, confirmed objective rates were similar between both treatment regimens after weighting, 48% versus 50% with an odds ratio of 0.91 suggesting comparable response rates between the two regimens. Looking at melanoma specific survival at 36 months it was 65% versus 62%. Both treatments had similar melanoma specific survival with a hazard ratio 0.86. 

An interesting thing in these results was subgroup analysis. Subgroups showed larger numerical differences in efficacy which favored ipi-nivo over nivo-relatlimab that included acral melanoma with a hazard ratio of 1.42 and OS with a hazard ratio of 1.72 in favor of ipi-nivo. Similarly for BRAF mutant melanoma, it showed a confirmed objective response rate with odds ratio 1.54 and same applied to mucosal melanoma with odds ratio of 1.59 and patients who have high LDH more than two times upper level limit. Looking at the safety and adverse side effects, nivolumab plus relatlimab had fewer grade 3 or 4 treatment related adverse effect which is 23% versus 61% and fewer any grade treatment related adverse events leading to discontinuation which was 17% versus 41%, which means 41% of the patients in the ipi-nivo arm lead to discontinuation. However, I would like to add to that that ipi-nivo was conducted much earlier and at that time we were still kind of assessing and trying to understand the immunity adverse effects, how to manage them, which probably could have made discontinuation more common compared to a nivo-relatlimab trial. By that time we definitely had much more experience dealing with immunity adverse effects.A couple of things mentionable in this, notable rates of hepatic and GI grade 3 or 4 treatment adverse events were lower in nivo plus relatlimab than with ipi-nivo, although the onset of any grade endocrine GI hepatic or skin related treatment related adverse events occurred most frequently in both treatment arms and in less than three months from randomization. 

So looking at all this data and looking at all this, it definitely seems like both the trials are very comparable in terms of efficacy, though nivo plus relatlimab seems to have a better safety profile. This trial does have some strengths. It does use the patient level data from two large well conducted trials allowing for a robust comparison and inverse weighting which would definitely better help balance baseline characteristics, enhancing the reliability of the results, and it does lead to comprehensive assessment of both efficacy and safety outcomes, and provides a holistic view of the treatments. Given all this, definitely the fact that it's a cross comparison trial which leads to a big limitation, as I already mentioned, like definitely two trials, it's hard to compare two trials which can have its own inherited biases. So it has some differences in trial design, conduct and follow up times. Small size subgroup analysis definitely limits the ability to draw definite conclusions from those groups. There's definitely some inherent uncertainty with direct head to head cross comparison trials. 

Looking at the future direction I would take from this trial, if we can have a direct head to head trial because both of the treatments are proven first line setting, it will be comparing these two regimen that can definitely provide more definite evidence and further research is needed to explore the efficacy of these regimens in specific subgroups. As I mentioned in this, some subgroups showed increased benefit in the ipi-nivo regimen, however, they were very small sample size so we need more research exploring those subgroups. One other part in both these trials, patients with active brain mets were excluded. However, there's a phase 2 trial looking at ipi-nivo in active brain mets patients. So I think assessing patients with active brain mets moving forward is also a crucial part looking at, because often, patients with advanced melanoma develop brain mets. It does lead to some unanswered questions like long term survival and quality of life. How do these regimens compare in terms of long term survival and quality of life? While the study provides data on PFS and OS, long term survival and quality of life metrics are essential for understanding the full impact of these treatments. Optimal sequencing strategies: what are the optimal sequence strategies for these patients who progress on one regimen? There is data suggesting that patients may respond to alternative regimens after progression, but more research is needed to establish the best treatment sequence. And real world performance: how do these treatments perform in real world settings outside of clinical trials? Real world data can provide insight into the effectiveness and safety of these regimens in a broader patient population. 

So, in summary, nivo plus relatlimab offers similar efficacy to nivolumab plus ipilimumab but a significantly improved safety profile, making it the potentially preferable option for patients with untreated advanced melanoma. However, results should be interpreted with caution due to limitations of cross trial analysis for certain subgroups like acral melanoma, mucosal melanoma, BRAF mutant melanoma, and patients with high LDH more than two times off upper normal limit. The trial showed that there's a trend definitely with ipi-nivo may be more beneficial. Also, today data on the use of nivolumab plus relatlimab in active brain mets has not been reported. Based on these existing data, ipi-nivo remains a standard immunotherapy for patients with active brain mets. Further research, including direct head to head trials is needed to confirm these findings and explore optimal treatment strategies. 

Thank you for tuning into today's episode. We hope this detailed summary of the study comparing Nivolumab Plus Relatlimab and Nivolumab Plus Ipilimumab in advanced melanoma has been informative. This is Rohit Singh. Thank you again for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Hospital San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Aaron Mitchell. Dr. Mitchell is a medical oncologist working at Memorial Sloan Kettering Cancer Center where he is also part of the Department of Epidemiology and Biostatistics. Dr. Mitchell specializes in treating genitourinary malignancy and has a research focus on improving how the healthcare system helps people with these and other cancers. So today, Dr. Mitchell will be discussing the article titled, "Quality of Treatment Selection for Medicare Beneficiaries with Cancer."

Thank you for speaking with us, Dr. Mitchell.

Dr. Aaron Mitchell: Well, thank you for inviting me. I'm very glad to be here.

Dr. Davide Soldato: So I just wanted to introduce the topic by asking a couple of questions, very general, about the background of the article. So basically you reported the data using the SEER-Medicare to assist to assess the determinants of optimal systemic therapies delivery and selection. So, in particular, you focused on individuals that were diagnosed with cancer who were Medicare beneficiaries and in particular were part of the low income subsidy, which is also known as LIS. So I just wanted to ask you if you could briefly explain to our listeners how this program works, and what was the rationale of the study, and if there is any element of novelty in your study compared to what was done before the study was published.

Dr. Aaron Mitchell: Yeah. So that's a lot to cover, but yeah, a lot of opportunity to introduce the low income subsidy program which is a very important part of the Medicare program for prescription drugs, but often one that flies under the radar a little bit in the policy discussion. So this subsidy was created synchronously back with the Medicare Part D Program, which was created in 2006. There was some anticipation that for some high cost drugs, not all patients would be able to afford them even with the Part D program insurance as it was being created. And so they created a pathway to give an additional subsidy to some patients who had low income, who were anticipated to being at need and needing that assistance to afford high cost drugs. As the number of high cost drugs has really risen since 2006, this program has played an important role in helping patients afford drugs, especially those who need very expensive cancer drugs. 

And what this program does is, once you meet the eligibility requirements, which require patients to have both quite a low income. So if you're single, that is at 135% of the federal poverty limit or below, and it also places some restrictions on assets. You also have to have low assets, so low income and low assets in order to qualify for the subsidy. But then once you do, the subsidy is really quite large. Patients who qualify for the LIS at the full subsidy level will pay about $10 per month per drug, even for specialty cancer drugs. So if you think about drugs such as those that we use to treat prostate cancer, my specialty, drugs like enzalutamide or XTANDI that run $15,000 to $20,000 per month, the out of pocket cost for a low income subsidy beneficiary is $10. So that is a huge discount. $10 isn't nothing, but even for someone with a low income, if they've got one or two cancer drugs that are at this rate, it's something that they can often afford. 

This program applies to Part D cancer drugs that are prescription drugs basically. By and large, these are oral pills that patients are taking on a daily basis at home. These are the drugs that the low income subsidy program applies to. So if a patient needs a drug like that to treat their cancer, then they are able to receive it at very low cost. And what you'll see is a patient- in the studies that have been done, when a patient has low income, low enough for them to be able to qualify for this program, they then have better access to these drugs. You see increased adherence rates, you see increased prescription fill rates. And then when someone, when their income is just high enough to no longer qualify for this program, and they go back to regular Medicare Part D coverage, that's when the problems arise. So it's like as your income moves up the scale, you actually get more problems affording your cancer drugs. So that's the state of the literature so far. 

And what we realize though, is that all these studies that have looked at the low income subsidy have really focused on just the Part D drugs themselves, the oral drugs. And that's certainly not all of cancer care. There is a growing number of oral drugs, but for many cancers, especially when you're talking about immunotherapy drugs or new systemic radioligand therapies, these are not Part D drugs, these are Part B drugs. And so even if you are low income and you're qualifying for this subsidy, it's not going to help you if you need a Part B drug. Yes, there are certainly a whole host of other programs and different avenues that we can get patients assistance, but some percentage of them, even though they're low income and high need, would not have assistance with a Part B drug. 

So now, in coming back, the long answer to your question, our rationale was, let's look at these Part D low income subsidy patients and let's see what their access looks like, not just to the oral drugs, but to cancer care writ large. And can we study where they're fitting into the system, not only when they need oral drugs, but when they need any kind of cancer care across the board?

Dr. Davide Soldato: So basically, just to summarize, it was an extension of previous literature, but specifically evaluating whether novel regimens that use, for example intravenous drugs, they were covered at the same level and whether there were any inequities in access to cancer treatment under this specific program, which is the LIS.

Dr. Aaron Mitchell: Yes, I'd say that's a fair summary.

Dr. Davide Soldato: Okay. So more or less, you included 9,000 patients inside of the study and 25% of them were beneficiaries of the LIS program. And you specifically looked at factors that could be associated with not receiving therapies at all, and also whether the quality of care that these patients were receiving were any different compared to those who were not part of the LIS program. So I just wanted to see if you could guide us a little bit in the results, whether you see any kind of differences when we look at access to any type of systemic therapies and whether being a part of the LIS program modified access to the drugs.

Dr. Aaron Mitchell: Let me take this opportunity also to highlight a feature of our study that differentiates us a little bit from previous work that's been done. And this is around the specific definition of quality that we use. I know quality is in the title of the manuscript, but I think it's important to emphasize exactly what we mean in this study when we say quality, and it's something very specific. So our measure of quality references back to the NCCN guidelines, which I don't think our audience needs much of an introduction to that. It's the most worldwide recognized standard of care guidelines for oncology practice. And we specifically looked not only at the NCCN guidelines, but at their evidence block scoring system. So what we did was we looked not only at one set of guidelines, but we looked at guidelines across time. We looked at guidelines across our full study period, which was, give or take, 2015-2018, depending on the cancer. And we looked at each point in time to see what was the treatment regimen that was recommended by the NCCN guidelines as being preferred. Some of them make that designation, some of them don't. If there was not a designation of preferred, then we turned to the evidence blocks. And the evidence blocks, we then apply several different measures to kind of rank treatments from those that get high scores for efficacy and safety to those that get low scores for efficacy, safety and the quality of evidence. So we basically come up with a kind of a rank list of the recommended treatments at each point in time. And then we look at the ones that are the highest, we say which are the most highly recommended treatments at any given point in time. That then becomes our definition of quality treatment. And I'm saying this with air quotes, we use the term "optimal treatment" in the study. Did they get that treatment? If there were ties, you could have gotten either of the two treatments that got the equally good score, did you get that treatment versus did you get anything else? 

So then getting back to our analysis, what we really did was kind of a two-stage study. First, we put all of our patients into our pool, into one big analytic model. And we looked to see what are the factors that predict or are associated with a patient either getting no systemic therapy or any systemic therapy. And then as a second question, we look at the patients who got some form of systemic therapy, and then we ask, again, what percentage of those got the optimal treatment or high quality treatment as opposed to one of the more lowly recommended treatment regimens? So that's how we asked it. We found that patients who were low income subsidy recipients, the low income ones, they were both less likely to receive any systemic therapy. And then even the ones that receive systemic therapy, the ones who made it in the door to see their doctor or their part of the system, they still were less likely to get the optimal treatment that was recommended for their cancer type at the time that they were diagnosed.

Dr. Davide Soldato: So basically, even when you are a part of this subsidiary program, you still have a lower access to any type of treatment. And even if you get treatment, you kind of get the ones that were not the preferred according to the NCCN guidelines, or at least they were not scoring as well as those specific regimens. But I think that what our audience might be wondering about is that frequently there are also some other types of characteristics, for example, age or number of comorbidities, which can be associated with having a low socioeconomic status. So I was wondering whether in the analysis you kind of looked specifically also at patient factors, for example, income rather than age or comorbidities, and whether you found any significant association with those and whether it was something that you planned to do in your study.

Dr. Aaron Mitchell: Yes. So we looked at many patient factors and those included age and they included the degree of comorbidity. And what we saw with respect to those characteristics was not too surprising. We saw that patients who were older were less likely to receive systemic therapy. We saw that patients who had more comorbidities were also less likely to get systemic therapy. And then across our different designations of treatments, we saw that those patients were also less likely to get the optimal treatment for their cancer. This result though, we would say it certainly needs more study in the future, but it's not immediately concerning. And that is because for patients who have more age, more comorbidity, those often correlate with frailty. And so it could be that these patients aren't getting optimally treated or it could be that their oncologists are just making clinically appropriate decisions about patient selection. 

We saw as we were doing this work that the treatment regimens that are often getting the highest recommendations from the NCCN, hence, it would become our definition of high quality optimal treatment, are often ones that are aggressive. They're often ones that are multi-drug combinations. They're often ones that it's not just your old antineoplastics, it's the antineoplastics plus an additional immunotherapy or plus a targeted drug. So it's the ones that are more aggressive by and large, and that might be in some cases more than a patient who is older, more frail, could be able to tolerate. And so the oncologist might be making inappropriate judgment to say I'm going to do something a little bit less aggressive here and make an appropriate trade off between anti cancer efficacy and safety. 

I think we've got kind of a bookmark there and we can look at those trends in the future. So we saw that kind of as expected, and then we turned and looked towards the low income subsidy. And our premise there is, well, your income shouldn't predict what you're getting clinically. In an ideal world, you'd be able to get the appropriate treatment for a patient, and not depend on whether their income is above or below 135% of the poverty limit. So that one seems more like on its face an immediate concern.

Dr. Davide Soldato: Thank you very much for the explanation. I was just wondering, did you make some kind of selection when you were analyzing specific diseases or settings where you included just metastatic patients or you also included patients with early stage neoadjuvant treatments? Because I think that it is also very interesting from the perspective of the objectives that we have as oncologists when we are administering systemic treatments.

Dr. Aaron Mitchell: Yeah, thank you for bringing that up. That was also one of the goals of our study was to be broad. And we wanted to look for factors, whether it be low income subsidy, whether it be age, socioeconomic background, etc., things that would be broad predictors of outcomes, and by which I mean care delivery outcomes across the board. So not just for, let's say, metastatic breast cancer, but also across any cancer that a patient might walk in the door with, what are the systemic predictors. And so when you mentioned before that our overall cohort is approximately 9,000 patients, that's 9,000 patients split over a variety of what we call clinical scenarios or clinical indications. And that includes multiple solid tumor as well as liquid tumor malignancies. It includes both patients who are initiating systemic therapy with palliative intent for metastatic disease. It also includes several groups of patients who are getting adjuvant therapy. So we want it to be as broad as possible. Our selection of those scenarios was really done with the goal of being as broad as possible and really bringing in everything that we could within the constraints of our data source. And that was really the only limitation that we applied in concept was tumor types that are common enough to have a meaningful sample of patients to analyze. So, one, are there enough patients? And then two, are you able to identify this specific group of patients within SEER-Medicare data? Because when the NCCN divides groups of patients by biomarkers that are not available in SEER-Medicare, we can't really say, "Oh, we're going to study this group of patients." That would then be one that we have to leave on the side and not include. But everything else where one of those things didn't apply, we tried to include it as best we could.

Dr. Davide Soldato: Thank you very much for the explanation. And among the scenarios that you included in the study, were there any striking differences in terms of access to treatment and access to quality treatment the way you define the study?

Dr. Aaron Mitchell: Yes, there were differences between these different cancer types, these different cancer indications, but they're not differences that I want to over interpret or read too much into. Certainly, every cancer indication is going to be different, but when we start getting into the individual cancer types, the sample size does get smaller. And we've not done formal tests of comparison or heterogeneity among cancer types. So I don't want to say that the differences which we certainly do see, like numerically, there are differences in the proportion of patients who are getting optimal treatment versus no treatment. I don't want to say that it's because the low income subsidy status or patient age has a bigger impact, let's say for lung cancer than breast cancer. I want to say that is heterogeneity for potential future study when we are able to do a similar follow up analysis with say a larger sample size. I don't want to over interpret those differences at the moment.

Dr. Davide Soldato: I was just wondering in case there was anything in particular that you wanted to highlight. But in the end, I think that we also have to acknowledge that the data are based on claims data, observational data. So maybe you're right when you say we should not over interpret this type of difference. 

And this is just to speculate a little bit, do you think that if you would look at this same specific question in a more contemporary diagnosis frame, like for example, you refer to the fact that most of the diagnoses were between 2016 and 2018. Now that we have more and more of these drugs that would qualify as Part B in the adjuvant or new adjuvant setting, do you think that you would see more differences compared to what you observed in the current study or do you think that it would be more or less the same? Of course this was not part of the analysis that you did, but it's just to have your opinion on the topic in general.

Dr. Aaron Mitchell: My expectation would be that since not much has changed with respect to the low income subsidy program from the time period of our study until now, my baseline expectation would be that those results would hold. On the other hand, it is the case that there have been improvements to the standard Medicare Part D benefit since the time of our study. So the low income subsidy patients would be paying the same low out of pocket costs that I mentioned before, about $10 a month give or take, for a specialty cancer drug. But what has started to happen is that for everyone else, their coverage has improved. Because in the US we're in the process of closing, or I think now we finally finished, but you know, a few years lag in claims data, we've closed what used to be called the donut hole, where there was this big coverage gap where patients had to pay a large amount out of pocket for drugs. So there might therefore be a narrowing of the difference, let's say between our low income subsidy participants, the lowest income patients, and then everyone else. But not so much because the low income subsidy status improved or changed, but just because the baseline level of coverage for everyone else may have improved, narrowing that gap. So I'd say that would be very possible. 

And if your question is more geared towards not so much policy changes, but treatment landscape changes, I would say the big thing that I would maybe guess, and again, this is very much speculation, but you introduce the speculation in TBD on follow up. I think the big change in the landscape has been the broadening indication and uptake of immunotherapy drugs, our PD-1, PD-L1 inhibitors, for a variety of cancer types. And I think the way that that would manifest in our data, were we to repeat it in a more contemporary data set, would be, I think that the access for, let's say, that any systemic therapy among older patients might change. And that is because rather than just having your cytotoxics in hand, the clinical oncologists now know that for many cases there's if not first line therapy, then second line therapy for patients who don't qualify, you can go straight to it, to someone who's not a chemo candidate, you've got a much more tolerable treatment in your back pocket. And so I think that for patients who are more old or more comorbid, we might start to see that a greater proportion of them receive some systemic therapy, it just might not be the cytotoxic agent that is still most highly recommended. It might be, say a single agent, PD-L1 inhibitor, because their oncologist wants to be able to give them something. So I wouldn't be surprised if that gap starts to narrow as well if you're measuring no systemic therapy versus any systemic therapy.

Dr. Davide Soldato: And going back to the policy part of the study that you did, do you think that the results of the study that you published in the JCO can better inform policy makers on how to make these treatments more available and be sure that the largest possible proportion of patients gets a systemic treatment and gets the optimal systemic treatment?

Dr. Aaron Mitchell: Yes, I do think that this study has some direct and indirect policy implications. I think that our finding is one to highlight the low income subsidy program and maybe help it not to fly under the radar so much anymore. I think all the work that has been done on how much it has helped patients who need oral cancer medications is great, and it shows how beneficial this program can be. We're now shining the light kind of everywhere else and saying, "Okay. That's great. Here's how well it can work when it covers an oral drug, but we've got this group of low income patients who are still at need and they're still very clearly not able to access everything else. When it's not axitinib that they need, it's a pembrolizumab, they're still very much behind the curve and they need some help." So I think that's one thing just to call attention to this as an ongoing problem. Low income patients, it's not a solved problem yet. It's something that needs further attention. 

And then for direct policy implications that are on the table, I think we're about to see the Medicare program be able to start negotiating not just Part D drugs, but also in future years, Part B covered drugs and try to lower the price for everyone, both for insurance, both for Medicare itself. And then to the extent that that boils over to the patient's out of pocket responsibility, it'll start to reduce the patient out of pocket costs as well. So I think we can look forward to hopefully an aggressive negotiation program by Medicare to start to directly lower the prices of Part B cancer drugs that these patients are unable to afford.

Dr. Davide Soldato: Thank you very much. You did the research you published in the JCO, but you really seem very passionate about the topic of care delivery and quality of care and policy. So I just wanted to ask on a personal note, how did you come to this area of research which is frequently not one that is very cared for by oncologists? It's more frequently something that biostatisticians or public health scientists put their attention to. I just had this curiosity and I wanted to ask you if you could explain a little bit how you came to this area of research.

Dr. Aaron Mitchell: Thank you for asking. That's a great question. I'll tell my favorite story about my journey there. I entered medical school planning to be a clinical investigator or maybe even a basic science researcher, and I had some background in that. I went to medical school at NYU where the teaching hospital is Bellevue, which is a large, well known public hospital within New York City. And my eyes started to open regarding the inequities in the system. You always hear about it, you read about the problems in the US healthcare system, but then when you see it on a day to day basis and you can walk four blocks from a private, very well resourced hospital to see a patient with a similar condition four blocks down the road at a under resourced public hospital getting very different treatments and receiving very different outcomes, the injustice in the system really hits you on a visceral level. And it was really, I would say, as soon as I started my clinical rotations in medical school that I realized maybe that's where I can make the most impact with my career and just really fell into it. By the time I was done with medical school, I then knew that I wanted to do something that was in the health policy space. And then by the time I was done with residency, I was like, "Oh, someone had mentioned the words health services research" and the light went on. It's like, "Oh, that's me. That's what I want to do."

Dr. Davide Soldato: Thank you very much. That was a nice story. And I really think that we should all work towards trying to make sure that the inequities inside of the system are eliminated as much as possible. 

So I think that this concludes our interview for today. So thank you again, Dr. Mitchell, for joining us.

Dr. Aaron Mitchell: You're very welcome and thank you so much for your interest.

Dr. Davide Soldato: We appreciate you sharing more on your JCO article titled, "Quality of Treatment Selection for Medicare Beneficiaries with Cancer." 

If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinion, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing an original report published in the October 1st issue of JCO titled, "Post-Transplant Cyclophosphamide–Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors," by Shaffer et al.

The CIBMTR registry study set out to compare outcomes of patients undergoing allogeneic stem cell transplantation hematologic malignancies by HLA antigen matching status as well as by the type of GVHD prophylaxis regimen received either calcineurin inhibitor-based prophylaxis or post-transplant cyclophosphamide or PTCy. This study included patients reported to CIBMTR from January 2017 to June 2021 with AML, ALL or MDS, and required that they have undergone allotransplant with either a calcineurin inhibitor based so tacro or cyclosporine, GVHD prophylaxis, or PTCy, which included a calcineurin inhibitor or sirolimus with or without MMF and ATG. Matched unrelated donors were defined as an 8 out of 8 HLA match. And mismatched unrelated donors were defined as HLA mismatched at any single locus or 7 out of 8. The primary objective of the study aimed to compare overall survival or OS and GVHD and relapse-free survival (GRFS) within and between matched unrelated donors versus mismatched unrelated donors separated by calcineurin inhibitor versus PTCy based GVHD prophylaxis.

GRFS was defined as survival without grade 3 to 4 acute GVHD, moderate to severe chronic GVHD requiring systemic therapy or relapse. 10,025 patients were included from 153 centers, with a median follow up of over 36 months. Mismatched unrelated donor recipients were made up of 22% minority ancestry patients as compared to just 8% of patients receiving a matched unrelated donor allo transplant, showing an enrichment for patients of minority ancestry in the mismatched unrelated donor group. Just under 10% of patients were of minority ancestry in the study overall, reflective of challenges in transplant care for these patients, which may include inferior access to care, fewer available and suitably matched donors, among other factors. 54% of all patients were transplanted for AML and 29% for MDS. 45% of patients received myeloablative conditioning, 25% received regimens containing ATG, and 23% overall received PTCy with either a calcineurin inhibitor or sirolimus as well as MMF.

Among patients receiving PTCy, the authors did not find differences in overall survival by degree of HLA matching, whereas among patients receiving calcineurin inhibitor-based prophylaxis, there remained survival differences by HLA matching status. When comparing matched unrelated donor calcineurin inhibitor patients with PTCy matched unrelated donor patients, the PTCy arm had better OS, and the mismatched unrelated donor group who received PTCy had similar OS as well. For GRFS, matched unrelated donor and mismatched unrelated donor PTCy patients had no difference in GRFS, similar to the trend the authors see with overall survival. But these patients also had better GRFS than matched unrelated donor patients receiving calcineurin inhibitor-based prophylaxis. Within each prophylaxis arm, there was no difference in GRFS by HLA matching status. HLA mismatched patients receiving PTCy were less likely to experience GRFS than HLA mismatched patients receiving calcineurin inhibitor-based prophylaxis.

The authors saw similar differences in comparative trends when subgrouping patients based on conditioning intensity and additionally did not find differences in GRFS and OS by ATG exposure. When looking at patients with minority ancestry, those patients who received a match unrelated donor or mismatched unrelated donor with PTCy had comparable outcomes to non-Hispanic white patients. Additionally, among minority ancestry patients, there was a significant benefit in both GRFS and OS in the PTCy groups as compared to calcineurin inhibitor-based prophylaxis. When examining other specific toxicities included in the composite GRFS endpoint, such as GVHD rates among PTCy patients, the authors note that patients receiving a matched unrelated donor had similar rates of grade 3 to 4 acute GVHD but lower rates of moderate to severe chronic GVHD requiring systemic therapy. There appears to be signal that among PTCy patients, HLA matching reduced rates of moderate to severe chronic GVHD compared to mismatched unrelated donor patients receiving PTCy. These same trends also held when the authors looked at non relapse mortality with no significant differences within the PTCy groups by HLA matching status but reduced non relapse mortality compared to both calcineur and inhibitor-based groups.

However, notably, there was a greater risk of relapse among matched unrelated donor PTCy patients than matched unrelated donor calcineurin inhibitor patients, although this risk was comparable between mismatched unrelated donor patients by type of prophylaxis. The authors note that this has also been observed in other retrospective cohorts and may be confounded by differences in conditioning intensity between these cohorts of matched unrelated donor patients, affecting the risk of relapse. Finally, the authors also evaluate whether expansion of donor search criteria to mismatch donors from full HLA matching would increase availability of young donors from minority ancestry patients, and the study noted striking increases for all subgroups examined.

This study fits nicely with the BMT CTN 1703 trial published in the recent past, which has showed the superiority of PTCy with the calcineurin inhibitor and MMF when compared with conventional calcineurin inhibitor based immune prophylaxis for reduced intensity matched related donor and matched unrelated donor allotransplant. Of note, very few patients with one HLA antigen mismatch were enrolled on that study. However, others have shown the feasibility of PTCy in the mismatched unrelated donor setting, which has led to its adoption in practice. Although less than a quarter of patients included in this current study received PTCy overall, the findings clearly are aligned with the BMT CTN 1703 study, which is likely to change clinical practice in the longer term in this field.

As the accompanying editorial in JCO, written by Dr. Chakravarty nicely lays out, the differences between this study and the EBMT registry study, also published in this issue of JCO are subtle but worthy of note. While both studies show that mismatched unrelated donor patients had worse OS and GRFS than those receiving matched unrelated donor transplants, and then among matched unrelated donor patients the addition of PTCy improved GRFS and OS, there is discordance between the studies whether the addition of PTCy abrogates the effect of HLA mismatching on GRFS and OS. As this editorial points out, there are strikingly different rates of T cell depletion with ATG between the US and Europe, which may account for differences in comparator arms that lead to this discordance. There are several very exciting clinical trials ongoing that will aim to answer some of these outstanding questions regarding comparisons of PTCy and T cell depletion, which the field eagerly looks forward to reviewing.

In summary, this registry study of patients receiving allo transplant with matched unrelated donor or mismatched unrelated donor and calcineurin inhibitor or PTCy based GVHD prophylaxis, most notably shows that for patients who may not have a matched unrelated donor available, the addition of PTCy to a mismatched unrelated donor allo transplant allows for improved outcomes after transplant in toxicities and survival. This is most significant for patients of minority ancestries who usually have fewer matched unrelated donors available in registry searches. Improving the transplant options available to these groups of patients is of critical importance in improving equitable access to care for all of our patients. And this study, although retrospective in nature, provides an important understanding of our progress to date and suggests directions for future investigation may indeed be very feasible to continue to close these gaps in care for patients in need of an allo transplant for hematologic malignancies.

This is Alexandra Rojek. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

The guest's disclosures can be found in the transcript. 

Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts and literature published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, gynecologic oncologist and JCO Social Media Editor by trade. I am thrilled because we are going to be talking about gynecologic cancer today. So, this is my jam. And specifically, we're going to be talking about a manuscript that's a simultaneous publication in the Journal of Clinical Oncology and presented at the Annual Meeting of the International Gynecologic Cancer Society on October 16, 2024. And this is "Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer: Results in Mismatch Repair Deficient Tumors." This is affectionately the KEYNOTE-B21 trial, also known as the GOG-3053 trial and the ENGOT-en11 trial.

And we are joined today by the primary author in this manuscript, Dr. Brian Slomovitz, who is the Director of Gynecologic Oncology at Mount Sinai Medical Center in Miami Beach, Florida, and the clinical trial advisor in uterine cancer for the Gynecologic Oncology Group foundation.

Welcome, Brian.

Dr. Brian Slomovitz: Hey, thanks, Shannon, so much. It's a pleasure to be here. And thanks for giving us the opportunity to discuss this trial.

Dr. Shannon Westin: Yes, it's a great trial and I'm so excited to talk about it. And I think we'll start just because this is a broad group that listens to this podcast, they're not all GYN oncologists, experts like yourself, so can you just level set a little bit and speak a bit about the incidence and mortality of endometrial cancer overall and the recent trends in this disease?

Dr. Brian Slomovitz: Yeah, sure. So, and it is nice to speak about gynecologic cancers, as we know, endometrial cancer was and still is the most common of all gynecologic cancers. The numbers are going up. Right now, there's about 65,000 to 70,000 cases each year in the US diagnosed with endometrial cancer. The numbers are going up. A lot of its obesity related, some other factors, but as the population gets less healthy, those are some of the risk factors for the disease. The thing that, however, is quite surprising is that we're seeing the deaths due to endometrial cancer going up as well, while for other diseases, we're making slow, steady steps to try to decrease the mortality we're actually seeing an increase in mortality. And the most discouraging point, Shannon, as you know is the number of deaths from endometrial cancer is going to outnumber the number of deaths from ovarian cancer if it hasn't done it already. I mean, now's the time. So, we really need to come up with better treatment strategies to everything to decrease the incidence of disease, to help with prevention, but for those poor women who are diagnosed, to come up with better treatment options so we don't have to keep this increasing trend in mortality.

Dr. Shannon Westin: Absolutely. And I think some of that is related and we don't need to get on a soapbox here, but the amount of funding that goes towards research in endometrial cancer, and of course you, you have been leading the way and really trying to get a ton of trials in this space and getting our industry partners and our government partners to really support this. So really just commending you on how much you've worked on, on this area. And to that end, we've had a huge renaissance with immunotherapy and endometrial cancer, a lot of really big trials. Why don't you give the audience a rundown of where, so far, this seems to be best utilized for people with endometrial cancer?

Dr. Brian Slomovitz: Thanks for that. And as you sort of alluded to, it's been a revolution, really, with immunotherapy. We started off at immunotherapy looking at microsatellite instability or the dMMR patients. What we found is similar to other disease sites in the second and third line setting that we saw good activity with the single agent checkpoints, pembrolizumab dostarlimab, that's based on the earlier KEYNOTE data and the GARNET trial. Really, a landmark study in the second line was Vicki Makker and her colleagues put pembrolizumab and lenvatinib combination for those patients with the cold tumors. Not the dMMRs or MSI Highs, but the proficient mismatch repair. And that study in a second line setting found that it was better than chemotherapy for an overall survival advantage. So right there, we know that it works in the second line setting in the dMMR population, and we got an indication in the PMR population saying that immunotherapy works in all women with endometrial cancer at some point, then we really had the groundbreaking trials. And Shannon, thank you. You are the leader on one of the four trials that happened, to DUO-E, AtTEnd, GY018 and RUBY trial, all very similar studies showing that the combination of immunotherapy with chemotherapy in the first line, metastatic or recurrent setting had a better outcome for patients than if given chemotherapy alone.

That actually led to amazing things. We had three of those drugs have FDA approvals, pembrolizumab for all comers, dMMR and PMMR in the first line metastatic setting with chemotherapy; Dostarlimab, PMR, dMMR in the first line or metastatic with chemotherapy. And Shannon, in your study, I think we still have to learn a lot from your study. DUO-E, chemotherapy plus minus dostarlimab. And you also added a PARP inhib, and those patients with a PARP did better. So I'm really looking forward to your data, to the subgroup analysis to figure out which of those patients, depending on the biomarker, do better with PARP therapy. And right now, you have a dMMR FDA indication. But who knows? The future is really exciting to see- to be splitters, not lumpers. And I really want to see how that data pans out. And so that's how it came into the first and second line setting and that led us really to come up with the idea for this trial to put it into the adjuvant setting.

Dr. Shannon Westin: Right. And so, I think this would be really important because we're so ingrained in this. We see this on the day to day. Can you kind of tease out a little bit what's different about those patients that would be treated in that advanced recurrent setting versus the patients that would be potentially treated in this B21 study?

Dr. Brian Slomovitz: Yeah, so the first step, we demonstrated the efficacy in patients that really the treatment options were an unmet need. In the second line setting, we didn't have good treatment options. Those are the patients with measurable disease, with symptomatic disease giving immunotherapy. And not only did we see the efficacy, which was better, but we also were able to give it with limiting the side effects as seen with chemotherapy, which is nice. And then we know that the first line therapy, traditionally for endometrial cancer with carboplatin paclitaxel, response rates about 50%, progression free survival about a year, really something that we needed to improve upon. So, adding immunotherapy to the platinum backbone therapy really demonstrated an advantage. But now what we want to do is we want to see if we could prevent, in the high-risk patients, those without disease, what can we do to help prevent the disease from recurring and help patients live longer without really the need for really lifesaving types of treatments? We want to prevent it from recurring.

Dr. Shannon Westin: Yeah, I think that's essential. We know that if we can sit on that prevention side and kind of invest all the time and effort that we need to upfront, that really does yield the longer survival. So why don't you just walk through the overall design of this trial, please?

Dr. Brian Slomovitz: Yeah. So, this was an all-comers trial, meaning in individuals that had high risk endometrial cancer, high risk for recurrence, that included, in endometrial cancer, we have aggressive histologic subtypes, serous histologies, clear cell histologies, any stage, as long as there was some myometrial invasion. We also, for the first time, included patients looking at the molecular subclassifications. So, if there was a P53 mutation and they were stage 1 with myometrial invasion, they were included. And then in all comers, any patients with stage 3 or up to 4a disease, as long as the surgery was for a curative intent, and they had no residual disease after surgery, then they were allowed to enroll into this trial.

One of the things is that this is the first time we've done an adjuvant trial this large. I think one of the reasons that helped us succeed in doing a trial like this is that we left radiation as investigator's choice, because a lot of times going into a trial like this, people feel strongly, we know our radiation oncology colleagues, rightfully so, feel that radiation could help prevent disease from coming back. And we also have the camp that says they don't need radiation. We took that question out of this study. We let investigators decide whether or not they're going to get radiation. It was for patients to get chemotherapy, who are going to normally get chemotherapy for their high-risk disease and randomize them to chemotherapy plus placebo or chemotherapy plus pembrolizumab, a PD-1 inhibitor, in order to see if we could prevent the disease from coming back.

Dr. Shannon Westin: And the primary results of this study were just presented at ESMO and published in the Annals of Oncology. Can you give us just a quick overview of what that was, what they found?

Dr. Brian Slomovitz: Yep. So, we enrolled 1100 patients. The primary objective of the study was to look at the ITT population, progression free survival and overall survival. And the overall study was negative. Okay, so the hazard ratio in the ITT population was 1.02, not demonstrating a benefit of adding pembrolizumab in this population. I would say disappointing, but at the same point, something that we could really learn a lot from and somewhere that we know that in the whole population, we need to come up with better strategies to help prevent recurrence of disease, better adjuvant treatment strategies. But there's also information that we learned from this trial and that we're reporting on that we're actually super excited about and we feel may be game changing.

Dr. Shannon Westin: Yeah. So, let's go to that. This is the good news. Your manuscript in the JCO, thank goodness you published it here, was focused on that subset of mismatch repair deficient. So, tell us what you found.

Dr. Brian Slomovitz: So, in this study, we found that the first stratification factor was dMMR versus pMMR. Now, in the pMMR group, those patients had further stratification factors, but dMMR by itself was a stratification factor. Amongst those patients that had dMMR tumors, we found the hazard ratio to be 0.31 benefiting those patients who received pembrolizumab in the adjuvant setting. Really something that when we look at the treatment studies, the GY018s, the RUBYs, the atTEnds, the DUO-Es, in a dMMR setting, we see a similar hazard ratio of 0.3, 0.4. But to get that hazard ratio, which was statistically significant, obviously, is something that we were quite pleased with and something that we felt was worthy of reporting further. I will say it was a pre-specified endpoint. We didn't allocate alpha to it. So, at the beginning, it was a pre-specified endpoint, but at the same time even though we didn't specify alpha towards that outcome, it still, we feel is clinically meaningful and can definitely add to affect the standard of care and the management of these patients.

Dr. Shannon Westin: Yeah. I'm very intrigued to see what kind of people do with this. It makes sense, mechanistically, it makes sense if there was a population that was going to benefit, if not everybody does, this is the group that will. I mean, do you feel like there's enough data? What are you going to do? FDA approval aside, obviously, those kinds of things. But how do you feel about this? Is this something you're going to offer to your patients?

Dr. Brian Slomovitz: The first answer is yes. I think it's something that I would like to offer my patients. As you know, we need one of two things: we either need an FDA approval or for a lot of our payers required to be in the NCCN listings. I don't serve on the committee. I have no influence on NCCN. I'm excited to see how they'll respond to not only the Annals article, but obviously in today's release of the JCO article, I hope that they'll look upon it favorably. It's a drug that we're used to giving. Pembrolizumab, we have a lot of experience with it. It's interesting. We didn't see any new safety signals, Shannon.

Dr. Shannon Westin: Yeah, I was going to ask - that's great.

Dr. Brian Slomovitz: There was nothing, nothing additional that we found in this trial. So, I feel that it can definitely improve the outcome of those patients, in my view, with high risk for recurrence, treating pembrolizumab in this setting.

Dr. Shannon Westin: Yeah, I think it's important, of course, to look at the safety. What about quality of life? Any new findings there?

Dr. Brian Slomovitz: Yeah, we did that quality of life as part of the phase 3 trial. No difference between the two arms. No difference between the two arms. When we looked at a couple of the other analyses, we found that the benefit is the same on stage 3, 4 tumors. We saw that the benefit was there as well. So, there were less patients in the stage 1, 2 group. But I think really, for all comers, for the patient population, I would definitely consider giving pembrolizumab, again, for those patients with a deficient mismatch repair.

Dr. Shannon Westin: It's really exciting, and I think you mentioned some of the statistical limitations. Anything else that gives you pause about the study or things you wish you did better? I know we always like to armchair quarterback ourselves after we do these kinds of studies.

Dr. Brian Slomovitz: Yeah, it's interesting. When we designed the study years ago, we used the best information we had at that time to come up with the study design, and we're happy with it, and we really don't think that we could have done it much better. I should say, this was a great partnership that we had here between the GOG, ENGOT and with sponsor Merck, Toon Van Gorp was the lead PI of the global trial. When he gave me the good opportunity to present it at the IGCS and to be the lead author on this, it was really a great partnership. And when we came up with a trial years ago, it was the best trial that we thought at that time. And based on the information now, I think it's really something that we're excited about these results, even though the overall trial was negative.

Dr. Shannon Westin: Yeah, I agree with you. I think it's interesting, it's informative to think about, "Well, what would we do now or then if we knew what we knew now?" But still, you design the trial the best way you can. I think the results are super intriguing. I'm hopeful at the way they'll be reviewed. I agree I don't have any inside information about the NCCN committee, but I do hope that they'll consider the overarching data to support immunotherapy and mismatch repair deficiency and the findings of this study.

And then I guess the last question I would just ask, as you're an expert here, what are you looking forward to seeing coming next in this space? What's the stuff you're intrigued about in endometrial cancer?

Dr. Brian Slomovitz: I think, Shannon, you and I have talked about this for a while. I think we're getting really close to eliminating chemotherapy for some of the patients who suffer from this disease. So, I'm not sure if we'll do a follow up to this trial, but I think a logical type of follow up would be to see: what if we just took away chemotherapy altogether and we did pembro in the adjuvant setting, pembrolizumab versus chemotherapy? We don't have that trial in the adjuvant setting, but actually, we completed accrual of that trial in the recurrent setting and we're anxiously awaiting those results. That's KEYNOTE-C93, where in the dMMR population we studied pembrolizumab versus carboplatin paclitaxel. How those results may translate into this setting, I'm not sure. Right now, it's exciting what we have, but yeah. And I think future is bright for this. Just to highlight, in the two arms, there's 140 patients approximately in each arm; there were 25 recurrences in those patients who received placebo. Only eight recurrences in those that received pembrolizumab. Really, when we talk about numbers, it's really remarkable and it shows you the benefit it really had on the patients.

Dr. Shannon Westin: Well, this was great. It flew by, as it always does when I'm having conversations with you. I just really want to thank you again for taking the time to share your knowledge with our listeners.

Dr. Brian Slomovitz: Thanks, Shannon.

Dr. Shannon Westin: And listeners. Thank you all for taking the time to hear about endometrial cancer. Again, this was "Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer Results in Mismatch Repair Deficient Tumors."

And this was the JCO After Hours. If you loved what you heard, please check out wherever you get your podcast to see what else we have to offer. Have an awesome day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

Subodh Selukar: Welcome to this episode of JCO Article Insights. This is Subodh Selukar, JCO's editorial fellow. Today, I am interviewing Dr. Robert Maki on his recent editorial, "Combining Response and Toxicity Data to Implement Project Optimus."

At the time of this recording, our guest has disclosures that are available in the manuscript and will be linked in the transcript.

Dr. Maki, welcome to our podcast.

Dr. Robert Maki: Hi, Subodh. It's a pleasure to be able to take part.

Subodh Selukar: Yeah, thank you.

So, to start us off, would you give an overview of your article?

Dr. Robert Maki: Yes. Well, it's not my article, but it's just an editorial which is a commentary on an article by authors Cheng and Associates. It's called, "Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs." That's a very technical title and so forth, and yet it's a JCO article because we think that it makes an important point that in oncological trials, we talk a lot about primary endpoints, oftentimes of overall survival or progression free survival, sometimes even just response rates, but most of the time, we don't take into account the toxicity of an agent. So, you can imagine that if a drug is relatively nontoxic, then what you see is what you get. Progression free survival could be associated with what is called some sort of so-called clinical benefit. However, if a drug is really toxic and you're just laid up on the couch all day or bed bound, or need transfusions three days a week, where is that really beneficial for the patient? But, by the same token, there's no quality of life without life itself. You have to have some sort of evidence that someone is going to be around for a longer period of time as an indication of benefit. So, these are ideas that have been played out to some degree for the better part of a quarter of a century.

There's a biostatistician at MD Anderson named Peter Thall, who's one of the first people to think about this idea of combining toxicity data and response data as some sort of a combination primary endpoint for a trial. And where this comes into play for Project Optimus, this FDA initiative to come up with not just necessarily one dose or one dose and schedule, but rather a range or multiple doses and schedules for a drug based on the toxicity that's seen, is that this new paper by Dr. Cheng and colleagues provides one mechanism for doing this, for combining not just traditional clinical outcomes data, but also toxicity data.

Subodh Selukar: So, you mentioned Project Optimus is an important component of all of this. So, can you tell a little bit about what Project Optimus is and maybe a little bit potentially about how Project Optimus has affected you so far?

Dr. Robert Maki: I'd say it's having an effect mostly in the earlier phases of drug development. I'm not certain, but I think it was an outgrowth of some of the toxicity that was seen in some of the studies that were done over the course of the last 10 to 15 years with kinase-targeted drugs. The overall goal from the FDA Project Optimus was to work with companies, with academia, groups like ASCO and regulatory authorities, as well as patients to try and come up with dosing for everyone basically based on patient characteristics that they're focusing not just on those outcomes, such as progression, pre survival, overall survival, but also looking for quality of life and adding that into the mix in terms of how you choose a dose. So that's an effort that's been going on for the last several years now. There's been some nice articles on that from FDA on that and perhaps we could provide some links to those as well for people who are interested in some of the more introductory core information about Project Optimus.

Subodh Selukar: Yeah, for sure. And so, I mean you're on the editorial board at JCO and you've written this editorial, but has Project Optimus affected your clinical research yet?

Dr. Robert Maki: It's just beginning to. So, in phase 1 and 2 clinical trials, especially in phase 1, the goal is not necessarily to look for activity, but just to come up with a recommended phase 2 dose and schedule of a drug. Well, Project Optimus says, "Okay. Well, maybe there's more than one dose and schedule that should arise." And as I was alluding to earlier, this may have arisen out of what was seen previously where a number of the multi targeted tyrosine kinase inhibitors were developed. But when you got to the phase 3 trial, it was necessary to have dose reductions in 30%, 40%, 50%, 60%, even 70% of patients in some situations. So that to me represents a drug or a development pathway for that drug that was in essence incorrect. Yes, we talk about in traditional chemotherapy of trying to get the maximum dose we can, but is that always the best thing for the patient? And we recognize that there really is a plateau usually for systemic therapies we give, that there is a limit to dose escalation even within an individual patient to try and achieve that same benefit. At some point you're just going to add toxicity. The idea is to bring some element of toxicity into the decision making for a recommended phase 2 dose and schedule or schedules in that case.

Subodh Selukar: And so, building on that, so I think one advantage of these different approaches is that they might identify a single optimal dose, or maybe they'll recommend this range of doses that maximize some maybe clinical utility score combining these different aspects. In the current paradigm, it seems like probably response and toxicity are just these separate concepts that aren't typically linked together. But we typically do have a single recommended dose. But like you said, they might in subsequent trials have a lot of dose reductions and stuff like that.

So how do you think about the process now where this is a single recommended dose of, but there are deviations from that recommended dose in the research process. Like you said, in subsequent trials or within a trial, maybe patients are needing their own dose reductions as well. And then separately once a product is approved, what do you think about deviating from the recommended dose for your standard clinical practice?

Dr. Robert Maki: Oftentimes a work in progress. So even after phase 1, maybe having only treated 30 to 50 patients, they may be relatively homogeneous and that they have to be healthier to qualify for phase 1 trial. Once the drug is released to the whole wide world, then it becomes a different scenario, and you may have patients with poor performance status to start with. Can they still get the same benefit as the patients who got the medication in the context of a clinical trial? And it may not be the case.

And I think this is where Project Optimus and the idea of giving more than one dose or schedule may be useful and say, "Okay. Well, you can give 20% less," and what's the trade off? Maybe the drug doesn't work as well, but it is less toxic. On average, do you really lose a whole lot as a matter of a few weeks of median progression free survival? Or does the response rate really drop off as you decrease the dose intensity of your drug? One concern about having more than one dose and schedule is could you potentially be underdosing patients by the same token? Since we usually have some amount of time, at least a few weeks, to work out what's tolerable for our patient, at least the parameters of having more than one dose and schedule to choose from can be useful.

Subodh Selukar: So then thinking about potentially maybe we would have a range of doses to recommend, what do you think are going to be challenges once that starts to be incorporated into clinical practice? What kind of complications do you think might happen explaining this to a patient?

Dr. Robert Maki: That's a really, really good question and something that we- I think, just have a difficult time with just the regular consent form. It used to be that maybe you had a couple of information sheets on a standard drug, or if it's a clinical trial, then you'll have a relatively modest consent form that's supposed to be at, whatever, 7th, 8th, 9th grade reading level. But now you start adding this form with complex text to a consent form for a clinical trial. What are people really signing up for? They get a 40-page document, and I don't think they really understand that.

So, the idea that you're trying to relate to them, pushing as hard as you can, but by the same token watching out for that toxicity, I think really does speak to those endpoints of the program, that it really can be a patient-friendly idea. Are we going to necessarily get it right every time? No. As I was mentioning previously there, if you're only treating 30 to 50 patients, you may only have partial information and you come up with some sense of dose and schedule to give. And then you move that into phase 2 and phase 3, and you may have to, you see that maybe one dose and schedule is a lot more effective as you get into a randomized portion of a phase 2 trial before you move to phase 3, for example, or you see that the toxicity is much greater with no better evidence of progression free survival. So those two scenarios could certainly rise. You can't predict them in the early phases of development of a drug, but you have to be able to react or be able to react with a solid clinical trial design that allows you to have that flexibility to make those decisions later. This is where discussion with the regulators, obviously is very important to make sure that what you're doing really still fits these guardrails, as it were, of traditional clinical trial design, or these ideas of adding in the toxicity-based information from Project Optimus.

Subodh Selukar: One of the challenges in early phase trials is, like you said, we might have 30 to 50 patients at the end of the study. I think in the editorial, you mentioned that some of these newer metrics might require more and more patients. Maybe we need 30 to 50 patients on a single dose in order to have reliable understanding of these clinical utility scores. Whereas right now a sample size at a single dose might be six patients, it might even be fewer. What are your thoughts on that aspect of it?

Dr. Robert Maki: That's an important point, too. When you're doing, let's say, a quick and dirty, as you might say, 3+3 design, which has very large error bars in terms of the confidence intervals around a dose and schedule compared to some of the newer Bayesian-based designs, yes, you can get a phase 1 trial quote done, especially if it's a 'me too' sort of drug, so say, another checkpoint inhibitor, you kind of know the characteristics of those over another inhibitor of a specific kinase, you know the toxicities to expect when you block, let's say, EGF receptor. So, if you have some idea, and therefore you're able to more rapidly get to that recommended phase 2 dose from a phase 1 trial, if it ends up being a new drug, then maybe 30 to 50 patients isn't enough. And you really do need to continue that assessment of both response and toxicity as the trials move forward into phase 2 and phase 3.

So, it's kind of one of those ideas of continuous process improvement that if we are going to do this, we really do need to include it, not just in early phase trials, but especially for agents that are acting through a new mechanism of action, that we look at that holistically across the drug development spectrum. And now that trials are kind of being smashed together, phase 1 and 2, now phase 2 and 3, that really increases our need to also add in the assessment of toxicity, and maybe not just on the basis of our own evaluations or lab evaluations of toxicity, but patient reported outcomes, which is something that wasn't addressed in the Cheng article and really hasn't been well addressed in clinical trials in general, I would offer.

There are precious few trials that incorporate patient reported outcome data as a means to determine what's too toxic for a patient, for example. So how do we do that? As you know, we do have patient reported CTCAE clinical toxicity criteria that are based on patient reported outcomes. And wouldn't it be interesting, at the very least, as an academic project, but even more importantly, later on, to use those as the key means to determine whether a dose is too toxic or not in the development of the drug. That, to me, would be really, really interesting and kind of turns the idea of some of the data that we collect on its head. I guess, yes, we do need to collect things like liver function tests and so forth. It is one metric of toxicity of a drug. But patients have a lot of fatigue, we really do a poor job of documenting that as clinicians, and not to mention the elements that go into what that fatigue is. To be able to capture that through PROs would be another noble effort that I think has been underutilized and underappreciated in oncology clinical trials overall.

Subodh Selukar: And so, what do you think are barriers to doing it now?

Dr. Robert Maki: We tend to, for lack of a better term, cut and paste from what we've done before, to develop new, let's say, by patient reported outcome score or metric or worksheet for a given diagnosis. That can be hard, that takes a lot in and of itself, and perhaps has been one of the barriers that we don't have enough disease specific PROs, at least for some diagnoses. For others we do. And the fact that we do have PRO-scored CTCAE sorts of score tables, now, certainly makes it easier to validate and use these tools in clinical trials. So, I would love to see more of that, even if it ends up being secondary tertiary endpoints on phase 1, 2, and 3 trials. It's a pretty easy thing to add, even if you're doing that for the first time. Get some experience with it, and it can only help patients get through a trial or even just assessing it as part of a standard of care that will help our patients in the longer run.

Subodh Selukar: Yeah. And so, thinking about other metrics of success, you mentioned a couple in your article. These aren't necessarily patient reported outcome ones, but like RECIST and RANO. I was curious. I think the Cheng article, maybe I would think about it as a general framework for combining response and toxicity together, whereas some of these other metrics are a lot more disease specific, potentially, or agent and disease specific, maybe even. Do you think that clinical research will end up settling on these metrics that are kind of increasingly specific, or do you think that there's a possibility for general frameworks?

Dr. Robert Maki: Yeah, that's a tough question. I'm just trying to think of some of those patients reported outcomes. They've got kind of the general assessment ones, and then you do have ones that are more disease specific, just like we do have response criteria that are different for, let's say, lymphoma versus brain tumors versus colorectal cancer. We do have different ways of measuring those outcomes, and we all complain that those are imperfect measures. You can always find circumstances where that patient was responding, but it was called progression or vice versa. So even from these more objective tools like RECIST and the like, it's a challenging field, that's for sure.

We keep going around and trying to find ways of improving those sorts of systems. But let's say, for example, you used - this is part of the reason we moved from two dimensional measurements in WHO criteria versus one dimensional RECIST - if you have two dimensions, well, you have that much more variability in the measurements of the lesion. So, it turned out that we just didn't gain anything by having those bidimensional measurements. Now, since we have the ability to measure tumors better in three dimensions, should we be using volumetric assessments? Part of it depends on the size of the tumor. If you're dealing with a tumor that's 1 cm versus 8 cm, well, then the volumetric changes, you have a lot more variability, the small ones, than the big ones. Not to mention the fact that you have shapes that are not just an ovoid mass in a lot of cancers. There's just so many pitfalls in these sorts of data. What really matters at the end of the day, one thing that's underappreciated, and again is underscored by Project Optimus, is getting back to the patient.

Subodh Selukar: Your editorial made me have this one thought, and so bear with me, it's like a multi-part question. One of the reasons that we're becoming more and more interested in these alternative approaches, these clinical utility scores and everything, is that these new agents are being proposed, where there's a hypothesis that there's more complicated relationships between dose, response and toxicity. And so, 50 years ago, researchers probably didn't hypothesize that these complicated relationships were happening. They probably thought that they were more straightforward. What do you think would have happened if we had had these conversations that we're having today if we'd had them 50 years ago, what do you think would be different? Do you think that maybe we would have different therapies that kind of ended up becoming standard today? Maybe would we interpret or run studies differently today?

Dr. Robert Maki: I like that question as well. Now, if we go back to the Charles Moertel studies back from the 1970s, the whole reason that we have tumor measurements as a criterion are really based on his work, where he got a series of clinicians together and he put these masses underneath a piece of rubber sheeting, and they tried to determine how well they could determine the difference between a mass that they could palpate. And this is when we came up with the idea that a partial response was a 50% decrease in the cross-sectional area of a mass. That came from that very crude but important work from about 50 years ago. And of course, that was also a time when there really wasn't any imaging. Maybe the best you would have would be x-ray tomography to look at a lung nodule or something like that. It was a little bit of a different era. We didn't know how our drugs worked very well. We had at least some biochemical reason to use chemotherapy, and we tried to leverage that. But it was always the idea of more is better, finally disproved later on, in let's say the era of breast cancer, looking at the AC combination or doxorubicin as part of a treatment for breast cancer, that there was a ceiling to the benefit of doxorubicin in the adjuvant setting. Even then, it was clear that we needed to think about dose and schedule. We also didn't have the variety of drugs that we have now, or the different metrics that we have, circulating tumor DNA or something along those lines. Those sorts of things just never existed then either. So, we need metrics that are appropriate for their time, and we have more tools to work with.

I suspect that we'll have more specialization in oncology along disease lines, or even molecularly characterized subsets of diagnoses as well. All the detailed classification that we now need for a lymphoma, for example, or different flavors of triple negative breast cancer, all of those things are impacting how we even put a person on a trial. Similarly, since these patients are also going to get different classes of drugs that are relatively unique to them, there are a lot of drugs now that are available that really are only approved for one diagnosis. Then you really have to drill down pretty deeply in order to be able to focus on that clinical scenario. But I think we have the means to do so. Nonetheless, the general idea of these frameworks, again, the idea of combining response and toxicity data that can apply across essentially any cancer or neoplasm that we want to study.

Subodh Selukar: Okay. So, I want to move a little bit to aspirational, like where we want to move forward now. And so I think you've talked a little bit about this so far already, but would you tell me a little bit about when you're seeing a patient, interpreting results that have been given in clinical trials, are there results, metrics, summaries of trials that you wish you could communicate to them, metrics that actually already exist but don't really get implemented? You already mentioned quality of life is something that doesn't seem to be there but are there other things that maybe quality of life might not just be collected enough yet. But are there metrics on data that we have and we just don't really report them at all?

Dr. Robert Maki: That may be the case, or maybe the data end up in a secondary and tertiary publication, so they don't really become part of the lingua franca of the oncologist. I think it really speaks to just having the experience as an oncologist that you try the FDA-approved dose for medication for somebody and you run into trouble if they're, let's say, in their 80s, whereas the study population was in their 40s and their 50s with better bone marrows or better renal function on average, and things like that. So, another untested waters are geriatric oncology. What are the maximum tolerated doses when they're 80 versus when they're 40 or 50? It's a real challenge. Probably they had the most experience of that with things like prostate cancer, where we do treat largely an older population of men compared to other diagnoses, potentially.

I suspect we're going to see just more specialization, just like we do with the medications. We do need more specialized assessments for those adverse events and or quality of life that will be diagnosis specific. If you have GI cancer, abdominal pain is going to be a bigger issue or obstruction sorts of questions. And the symptoms that you may have from having a tumor within the abdomen versus, let's say, another diagnosis, which may tend to give you more, let's say, lung metastases. So those little subtleties can't come out. And the toxicities of the drugs that we use in those diagnoses are also going to differ as well. So those should be kept in mind as we come up with, let's say, disease specific toxicity metrics that we want to combine with those outcome data. So, I think we're going to see more and more specialization of that over time.

You have to create the tool and you've got to validate it. So, all these things will take some time. But again, people have been interested in this for a long, long time. There are any number of careers that are built around quality of life and cancer, or for example, long term survivorship in pediatric cancer patients. And all of these things can be very useful and just require our attention, both as clinical investigators as well as clinicians, when we face our patient's day to day.

Subodh Selukar: And so just one last question before we close. Is there anything that we haven't had a chance to talk about that you like to share with our listeners?

Dr. Robert Maki: If it's anything it's that I'm really heartened as I get older with this very large influx of new clinicians and new investigators. Oncology continues to get more interesting and more sophisticated. We need more people- we still don't have enough oncologists, even for our population here in the United States. We'll have plenty to do for a very, very long time. So, I'm excited to see a new generation of young oncologists such as yourself and the trainees that I see here, the new fellows, junior faculty who are all beginning to answer these questions, thinking about them. And as me and some of my more senior friends can help promote this kind of idea and help together to answer some of these questions. We're still trying to figure it out and there are just so many variables and clinical scenarios that we need to chase down in terms of clinical research. It is going to be an ongoing discussion and hopefully this article is just one example towards the goal again of finding the right dose for our given patient.

Subodh Selukar: Thank you so much for sharing and yeah, I'm very excited to be a part of this as well.

This has been Subodh Selukar interviewing Dr. Robert Maki on his recent editorial, "Combining Response and Toxicity Data to Implement Project Optimus." Thank you for listening and stay tuned for the next episode of JCO Article Insights.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

 Dr. Robert Maki Disclosures:

Consulting or Advisory Role: Deciphera, PEEL Therapeutics, Eisai, GlaxoSmithKline, Medtronic, Boehringer Ingelheim

Speakers' Bureau: MJH Life Sciences 

Research Funding: Amgen, Astex Pharmaceuticals, Boehringer Ingelheim, BioAtla, C4 Therapeutics, InhibRx, Regeneron, SARC: Sarcoma Alliance for Research though Collaboration, TRACON Pharma

Patents, Royalties, Other Intellectual Property, Uptodate

Travel, Accommodations, Expenses Company name: Stand up to Cancer, Fondazione Enrico Pallazzo

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato. I am a Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today we are joined by JCO author Dr. Sheila Garland. She's a Professor of Psychology and Oncology at Memorial University, and she's the director at the Sleep, Health, and Wellness Lab and Senior Scientist at the Beatrice Hunter Cancer Research Institute. Dr. Garland will be discussing the article titled, "Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors." Thank you for speaking with us, Dr. Garland. 

Dr. Sheila Garland: Thank you so much for having me.

Dr. Davide Soldato: So, Dr. Garland, you designed a study that relied on cognitive behavioral therapy to treat insomnia, and then you assessed whether improvement in insomnia would be associated with an improvement in cancer related cognitive impairment. So I wanted to ask if you could give us a little bit of context and explain the rationale between these studies. So how common are these symptoms among cancer survivors, and why do we think that improving insomnia would also improve cognitive function? 

Dr. Sheila Garland: Yeah, thank you very much. That's a really, really good question. And so cognitive behavior therapy for insomnia has been used to successfully treat insomnia in cancer survivors for quite some time. I think JCO was one of the first publishers to really demonstrate the potency of this intervention to improve insomnia. But as we know, patients will often present not just with insomnia, but insomnia comorbid with pain, fatigue, and very commonly cognitive impairment. If we take a look at the experimental research in sleep, we know that sleep quality and quantity is associated with very important cognitive functions. And so we've had clear sleep deprivation studies where if you're not able to successfully get sufficient quality or quantity of sleep, you're going to have impairments in attention and concentration and memory. So it really makes sense that if we're able to improve sleep in cancer survivors, that we're also able to address maybe some of the other concerns that they would have related to sleep. So this is an important clinical question for the patient's quality of life, but I also think it has important system implications where if we're looking at like resources and efficiency of allocating those resources, if we have an intervention that can treat multiple problems, that means that we can more effectively address lots of symptoms and use fewer resources in doing so. So that was the thought in designing this trial.

Dr. Davide Soldato: Thank you very much. That was very, very clear. So you spoke about the intervention that you implemented in the clinical trial. So I was wondering if you could give us a little bit of context. How long was the intervention? What were the main points addressed? Because you said that, in the end, we already have some data regarding cognitive behavioral therapy for treating insomnia. So I was wondering, did you personalize in any way, the program or the intervention to fit more to the cancer survivors population? 

Dr. Sheila Garland: Yeah. So it is based on a protocol that has been well researched and has a great deal of evidence of efficacy. But we delivered this intervention over a course of seven weeks. So individuals had individual sessions with a trained therapist, and those sessions lasted about an hour and were over roughly about two months or so. Seven sessions over two months. And because they were delivered individually, there was some adaptation based on the clients' presenting problems. So while there's sort of a standard protocol, if the client is also presented with levels of fatigue or pain or anxiety or depression, the therapist was able to integrate those concepts into the therapy as well. There was nothing for cognitive impairment. So there was no additional intervention for cognitive impairment at all. We weren't doing any memory training or anything like that. So it was strictly the sleep and other symptoms looking at the impact of improving that on not only your perception of your cognitive abilities, but also on performance on a number of neuropsychological test measures.

Dr. Davide Soldato: So thank you very much for the detail. And I think that it's very interesting what you said, that the personalization of the intervention would also allow to treat some other symptoms that are distressing for cancer survivors. Like, for example, you mentioned fatigue or anxiety or depression. And I think that this goes back to the first point that you made about the intervention. So being able to treat different symptoms all at one in one single intervention, I think that that is a very intelligent use of resources and also to promote and implement, potentially some interventions that are beneficial for survivors of cancer on different domains and potentially different symptoms. So, going to the results a little bit, what did you observe regarding specifically insomnia with the intervention that you delivered?

Dr. Sheila Garland: Yeah, so, of course, we wanted to make sure that we were effective in targeting the primary outcome of what the trial was supposed to do, which was we were supposed to treat effectively, treat insomnia, and then determine whether treating that insomnia was related to improvements in cognition. So we were expecting that the intervention itself was going to be successful at improving insomnia, and we were. So we were able to not only demonstrate a statistically, but also a clinically meaningful improvement in insomnia severity. Usually that's measured by a change of about 8.4 on a measure called the insomnia severity index. And the change that we were able to produce was over 11 points. So it was clearly over the clinically meaningful change threshold.

Dr. Davide Soldato: Going back a little bit to the design of the study, this was a randomized clinical trial. And how did you allocate the participants of the study into which arms? And can you guide us a little bit in the study design? 

Dr. Sheila Garland: Yes. A lot of thought went into the study design. We ultimately decided on having a waitlist randomized controlled trial, and this was because there is no other intervention for insomnia that has comparable efficacy. And we felt it would be unethical to not give people the standard treatment that we know works to treat insomnia. So that's where having them wait for a period of time and then receive the treatment was ultimately what we decided on. Overall, we were able to recruit 132 participants, and those were randomized into either receiving treatment immediately or receiving treatment after a two month waiting period.

Dr. Davide Soldato: So you mentioned that the intervention was actually very effective for treating insomnia. You reported an improvement in the insomnia severity index of almost 11 points. And as you mentioned, this is both clinically meaningful and it was also statistically significant. Did you see any improvement also on cognitive function, and how did you measure this outcome? Was it self reported, or did you also have some objective measure to see, for example, working memory or some other type of cognitive function?

Dr. Sheila Garland: Yeah. Also, a lot of thought went into choosing the primary outcome for this. And there's people who have argued compellingly that self reported cognitive function should be the primary target because we know, based on past research, that objective and subjective ratings of cognitive performance do not always correlate well with each other. And taking a very patient oriented approach, we wanted to make sure that we prioritized the patient's perception of their own function. We used one of the subscales of the functional assessment of cancer treatment cognition scale. So it was the Perceived Cognitive Impairment subscale that was what we used as our primary, but we also reported the two other subscales, which was the Perceived Cognitive Abilities and the Impact of Cognition on Quality of Life. We were able to not only discover that there were clinically significant improvements on all three of those subscales, but actually translated into, again, the clinically meaningful change threshold that's been established for the perceived cognitive impairment subscale is, I think it's around, like 5.9 points. So, using that cutoff, 75% of the participants in the trial reported clinically meaningful improvements in their perceived cognitive impairments, compared to just 43% of those participants in the wait list group. And we looked not only at the immediate intervention effects, but also on whether they were durable. So we had follow up assessments of both three months and six months after completing treatment, and the effects on insomnia, as well as the cognitive dimensions, they were maintained. 

Dr. Davide Soldato: Thank you very much for this last remark, because I think that one of the worries I would say that we have when implementing this type of behavioral intervention is that in the end, the change that we produce and the behavioral change that we produce might be effective in the immediate time after completing the intervention. But frequently we sort of see the loss of this benefit that we produce with the intervention at later time points. And I think that this is very important that you also looked at the benefit that was maintained over time for the three and six months after the end of the intervention. And it's true that before we add some data regarding other types of behavioral intervention, for example, for weight loss or some other symptoms and other toxicity that we frequently target with this type of intervention, I was wondering, do you think that it's something specific to cognitive behavioral therapy and the specific symptoms that you were treating, so insomnia, that in the end, produced a durable and meaningful benefit over time? 

Dr. Sheila Garland: So I do think that there's something really specific about this type of intervention. With insomnia, you're really changing the person's fear of not sleeping, and you're giving them tools to be able to both prevent the reocurrence of insomnia and also if the reocurrence should happen, they know what to do then to address it themselves. I was very curious about the impact that it might have long term. I actually wasn't sure whether it would have an effect immediately, considering that people do accumulate kind of a sleep debt after having insufficient sleep for a period of time. So I didn't know whether we would see anything immediately. I thought maybe we would need the long term follow ups to see some of the effect. But I guess maybe not surprisingly, at the end of the trial, thinking about when somebody has a good night's sleep, they're feeling the effects even the next day.

Dr. Davide Soldato: Thank you. That was very insightful. Regarding the duration of the intervention, because in the end, this was very short, because it was just seven sessions weekly, and usually also when we design or implement this kind of behavioral intervention, we frequently go for a longer period of time where the patient is subjected to this type of behavioral intervention. Frequently, we see around three, six months of intervention. And so I think it's really amazing the effect that you had on this specific symptom with such a short intervention. So I think that that is also something that speaks to the possibility of further implementing this type of intervention and this type of program for symptom control.  

And going back a little bit to what was one of the main questions of the trial that you designed and the results of the article that you published, did you observe a mediating effect of the improvement of insomnia on the cognitive function? So, you said that insomnia improved, and so improved also your primary outcome, which was the scale of the FACT-Cog questionnaire. But did you see whether this improvement in cognitive function was really related and associated to the improvement that you observed in insomnia?

Dr. Sheila Garland: Yeah. So that was a very, very important question. We needed to first demonstrate that there was a relationship between the intervention and insomnia, and then there was a relationship between insomnia and cognition. And then we did some mediation analyses subsequent to determining both of those, and we found that the change in insomnia was a full mediator of the change in cognition. So we were able to say that it's not just time or it wasn't related to something else, that improving sleep did have this direct effect on the improvement that patients reported in their cognitive impairment. 

Dr. Davide Soldato: We spoke a lot about the subjective improvement in cognitive performance. But you said that you also evaluated some specific and objective scale with, for example, I imagine some neuropsychological tests. Did you also observe some improvement for those specific tests, and did you observe the same amount of benefit or the same improvement, we could say, between the subjective and the objective weight of measuring cognitive function? 

Dr. Sheila Garland: I think that's where the outcomes become a little less clear. So, we did measure performance based cognition at all of the time points, and we were very careful in selecting these measures. So we followed the guidance provided by the International Task Force on Cognition and Cancer. They had some very specific recommendations about how and what measures we use. So we made sure to use measures that were able to be repeated, so that had multiple forms, that had very identifiable ways to indicate improvements. So we used the Hopkins Verbal Learning Test to measure word recall, both immediately and delayed. We used measures to look at verbal fluency and working memory. Overall, we had six different specific aspects of cognition that we were looking at, immediate word recall, delayed word recall, word retention, verbal fluency, word recognition, and working memory. Some of those presented with a different pattern of change overall. So a little bit trickier to interpret than the person's perception of their own cognition.

Dr. Davide Soldato: That's very interesting because it's important to have this kind of objective assessment. But in the end, what we are really trying to target is a symptom that is distressing for cancer survivors. I'm not even sure that sometimes we need all of this detail, or at least that even if these outcomes that are more objectively measured, we do not observe the same amount of benefits. Still, if we are able to produce an improvement in the symptoms and the perception that the survivor or the individual or the patient, whoever we are trying to help in that specific moment and for those specific symptoms, reports an improvement, I think that is already very important. And I totally share the patient oriented approach that you followed in the study. 

Going back a little bit to the population, because I think that this speaks a little bit also to potential avenues for further research. You included a population of cancer survivors who completed treatment at least six months before being enrolled in the trial. And relating to the population, I had two questions. So the first one is, do you think that you would have the same kind of results, so the same benefit, also among a population of patients who's in active treatment? And then the second one is a little bit more speculation, but do you think that we will arrive, or do you envision research where we kind of deliver this type of intervention in sort of a preventative way? So if we would be able to identify those patients who might later develop these types of symptoms, could we use this type of intervention sooner? So can we prevent these symptoms even before they appear? And could this be potentially associated also in a less symptoms developed over time and less need to treat these symptoms when they become more severe? 

Dr. Sheila Garland: Those are two very, very good questions. The first one is regarding the population. You're right. These people were at least six months out of treatment, and we wanted to make sure that if there was any temporary disruption, that would have maybe been stabilized over that. But most of the people in this trial, and I will mention that we didn't focus on any specific cancer type or site. So this was really a heterogeneous group of cancer survivors, both male and female. The most prevalent diagnosis that we had was breast. But some of these people who were enrolled in the trial had advanced cancer, and as long as their cancer treatment, their regimen was stable, they were eligible to participate in the trial. So I think that's a very important point. If somebody is on a very intensive round of chemotherapy, it can be tricky to implement some of the more aggressive behavioral changes that can come with some of these insomnia treatments, because their level of wellness just isn't there. So during active treatment it can be challenging, but it is definitely not impossible. We would just tweak things a little bit to accommodate their physical well being at that time. 

To your next question, though, this is where I think we really need to be going. Just like they've done in the area of, like, physical activity, trying to really strengthen people prior to treatment is the way to go. Because some of my other research looked at symptoms prospectively from the time of diagnosis over the first year, and it's roughly about half of people, at least, this was in my work with women with breast cancer, about half of women with breast cancer come into treatment with clinically significant sleep problems. So, a proportion of those people just continue to have sleep problems or even get worse after it. So there's definitely a role for that, sort of like rehabilitation, not only for maybe physical fitness to try and ward off fatigue, but also getting their sleep on track. I think people are really focused, especially in that early time, about like, "I want to eat right, I want to exercise," but I say it as many times as I possibly can, that you're not going to make healthy food choices, and you're not going to be getting out there and working out if you're not getting sufficient sleep. So we really need to have sleep there as the foundation and what supports all of those other healthy lifestyle behaviors that people are trying to change.

Dr. Davide Soldato: So sort of comprehensive intervention for people undergoing treatment where we kind of identify symptoms that are already there at the beginning, and we deliver some sort of intervention that can target a lot of those symptoms, maybe not all of them, but maybe improving also the way that treatment is perceived or the toxicity that they might develop over treatment.

Dr. Sheila Garland: And that's what I think. I think that if you're taking people who are already coming into treatment, that are looking after their health in ways that they can, they may be able to tolerate more aggressive treatments, they might be able to complete more rounds of chemotherapy, just getting them strong, going into treatment that way. 

Dr. Davide Soldato: Also still focusing on that very patient oriented perspective that I think it's very important in general for oncologists and also for patients. I think that you were very wise in choosing an intervention that could be also delivered virtually, and this was one of the bases of the intervention. And regarding also the way the intervention was delivered, I had a question regarding the fact that this was actually an intervention that was delivered by professionals. But we also have some, maybe initial evidence, that suggests that some of this cognitive behavioral therapy can also be experienced, or at least the benefits can be obtained by the patients, even when it's self directed. So programs where patients are not actually interacting with a professional, but they are just following these types of programs. So do you think that there is room for both of those? And maybe should we suggest this type of self directed programs for all patients or all survivors and then just refer only those with a more significant or important symptom severity for the intervention with professionals? And this, I think, also goes to the discussion that we had at the very beginning about allocation of resources and ability also to tailor these types of interventions to the needs of different individuals.

Dr. Sheila Garland: I think that's really important to consider when looking at what's available for patients. They did a survey in the US of NCI Cancer Centers where they looked at the availability of CBT-I, and it was very low. I think around 20% or so of NCI Comprehensive Cancer Centers had the ability to refer to in-house CBT-I. If we had sort of a stepped care model like you're talking about, we may be able to more appropriately allocate people to the level of care that they need. A line of my research now is going into a specific app delivered cognitive behavior therapy for insomnia tailored to cancer survivors. And so looking at that very point, not everybody needs a provider, but I think that a self help manual or an app is also not going to work for everybody. So you're not going to completely take out the person. And depending on the complexity of the situation that the patient finds themselves in, they may really need that provider to consider all of the other factors. They might need it to encourage adherence or address maybe some of the barriers that would be getting in the way. So having different levels of care and being able to match people not only to the level of care, but also maybe by their preference. So, "I'd like to use an app." Great, we've got an app for you. Or "I'd like to see somebody." And I think matching it to people's preferences automatically encourages or enhances their engagement and their motivation to complete because they're getting what their preference would be.

Dr. Davide Soldato: And I think that at least if we could use a little bit more of these types of apps or tools or whatever we have out there, maybe we could increase at least that 20%. For example, if only 20% of NCI Cancer Centers, which are already places where care is delivered, probably with a higher attention to these types of symptoms for survivors compared, for example, to community hospitals or to smaller private clinics. So if we could at least have sort of a base and then refer only those that maybe have a higher need for a provider directed therapy or intervention, that maybe would also improve outcomes for a larger part of the population of survivors.  

And one other thing that I wanted to ask you is, do you think, in your experience, because this was not really in the trial that you designed, but do you think that we also need cultural adaptation of these types of programs? Meaning, do we need to diversify based, for example, on ethnicity or level of education or, I don't know, just the background that the patient is experiencing?

Dr. Sheila Garland: Yeah, very, very good points. There are some studies currently being conducted out of the United States that have looked at cultural adaptations of CBT-I specifically. So there was a trial looking at CBT-I for African American women survivors of breast cancer, and also the Latinx population as well. From the results of those trials, it didn't necessarily improve the effects of intervention, but it improved the engagement, so people were less likely to drop out. So it wasn't always the content. It was how the content was presented. So people were able to visually see themselves more, they were able to relate more to the content in just the way it was presented, which made them go, "Oh, okay. This is why I should be here." And I think that that's part of the argument that I used for sort of adapting the cognitive behavior therapy for insomnia treatment that's being used in the general population, specifically to people who have had cancer, because people want to know, "All right. You know what? Is this safe for me to do? Will this work for me to do? How do I also do this when I have cancer related fatigue, or how do I do this when I also have pain?" So they want to know that, "Alright. This is right for me." That's probably, again, relating more to getting people and keeping people engaged with the treatment, maybe even convincing them to do it to begin with, talking about getting buy-in from important leaders in their community to say, "This is something that I would recommend or I would endorse." And those sort of community level endorsements maybe are just breaking down barriers to get people willing to engage with an evidence based treatment. 

Dr. Davide Soldato: And I think especially with cognitive behavioral therapy, because I think that when we propose drugs for treating symptoms or, I don't know, intervention for losing weight or to be more physically engaged, well, the latter that I mentioned might be also a little bit more complicated, depending on the cultural context. But drugs are very easy to accept for the patients in most cases. But I think that cognitive behavioral therapy also has some type of cultural resistance, maybe among some of our patients and cancer survivors. 

Dr. Sheila Garland: And I would also include oncologists in there as well. So, some of the treatment providers are not even exactly sure why would talking about this help. So I think separating it out, it's not just I'm going to talk about my sleep, it's that I'm going to engage with my sleep differently and breaking down maybe some of the stigma that, just because we're referring you to cognitive behavior therapy doesn't mean your problems are all in your head, but it means that there's ways that you can think about your sleep and ways that you can behave differently, which will reduce the things that are getting in the way of your sleep functioning the way that it should normally. I think when I talk to patients, and also when I do training with providers, I talk about how we can condition our bed to be associated with things other than sleep. So if we repeatedly snack in front of the tv, even though we've just had supper maybe a half an hour before, if we go and sit down in that chair that we always snack in, we're not hungry, but we find ourselves reaching for something to eat. The same thing can happen at night, where if you repeatedly pair your bed with things other than sleep, if you're thinking in bed, if you're planning, if you're worrying, if you're ruminating, if you know you're doing anything, if you're on your screen or you're watching tv or you're doing anything that's arousal producing, people can find that they're so tired, they're nodding off on the couch. They go up to bed, and all of a sudden, bang, they're wide awake and their mind is turning and they're thinking and they're like, "Why is this happening to me? I was just tired. I was so tired." People with insomnia can relate to that very easily. That, "Oh, okay. So there's this conditioned association between my bed and wakefulness. How do I get rid of that?" That's where what we think and what we do around our sleep, we can change to be able to make our bed someplace that is strongly associated with sleep and not all of those other activities. 

Dr. Davide Soldato: Thank you for the remarks on oncologists and sometimes our resistance to accept this type of intervention. I think that this also speaks to the merit of the Journal of Clinical Oncology, which publishes high level evidence also on symptom management, and these types of interventions that are, in the end, effective for our patients. 

So I think that this concludes our interview for today. Thank you again, Dr. Garland for joining us. 

Dr. Sheila Garland: Thank you Dr. Soldato.

Dr. Davide Soldato: Dr. Garland, we appreciate you sharing more on your JCO article titled, "Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors."

If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcast.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

TRANSCRIPT

Giselle Carvalho: Welcome to the JCO Article Insights episode for the August issue of the Journal of Clinical Oncology. This is Giselle Carvalho, your host. I'm a Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers, and one of the ASCO editorial fellows at JCO this year. Today, I will have the opportunity to interview Dr. Hatem Azim and Dr. Ann Partridge, two of the authors of the POSITIVE trial. We will be discussing their trial on "Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy," which was published in May this year. 

Hello, Dr. Azim and Dr. Partridge. Welcome to our podcast.

Dr. Ann Partridge: Hi. Thanks.

Dr. Hatem Azim: Hello.

Giselle Carvalho: So, beginning with our interview for breast cancer survivors, in addition to the treatment itself, aging is one of the major contributors to infertility. The optimal duration of adjuvant endocrine therapy in patients with hormone positive early breast cancer ranges from five to ten years, depending on patient and tumor characteristics. This time interval can be critical for women who wish to attempt pregnancy. One of the main concerns in daily breast cancer oncology practice is whether breast cancer recurrence rates are increased either by temporary interruption of endocrine therapy for pregnancy or by the use of assisted reproductive technologies.

Dr. Azim, what about assisted reproductive technology is worrisome regarding breast cancer outcomes? And how do the POSITIVE study results address the concern about worsening breast cancer outcomes either with assisted reproductive technology or endocrine therapy interruption?

Dr. Hatem Azim: So, in the primary analysis of the POSITIVE trial, we tried to address one of these questions, whether temporary interruption with endocrine therapy affects breast cancer outcome. And what we found was that interruption did not appear to have a detrimental impact at the median follow up of 41 months. So in the current manuscript, we addressed the second question, whether assisted production of fertility preservation has an impact as well on breast cancer outcome. And we did not find any worsening of outcomes in patients who underwent these procedures compared to those who had a spontaneous pregnancy. Of course, we have relatively short follow up, but at least the outcomes at the median follow up of around 3 to 4 years appears to be reassuring.

Giselle Carvalho: I see. Thank you. These are really important outcomes regarding premenopausal patients.

So, moving on, results from your study show that after 24 months, 80% of women under 35 years old had at least one successful pregnancy, while the same was true for 50% of women aged 40 to 42. These results are particularly impressive considering that over 60% of women over 35 had undergone chemotherapy. 

Dr. Partridge, other than age, what factors did you find were associated with a successful pregnancy? 

Dr. Ann Partridge: Yeah. The biggest factor, other than age, that was associated with successful live birth pregnancy was use of assisted reproductive technologies. So either having gone through IVF prior to diagnosis and banking eggs or embryos prior to diagnosis and then using them during the study, for undergoing stimulation of the ovaries during the study and then using it during the study. And that's what we also looked at in this most recent analysis of the initial POSITIVE data. 

Giselle Carvalho: I see. Thank you. The group of patients who underwent embryo oocyte cryopreservation at diagnosis were more likely to be nulliparous and treated with chemotherapy. Presumably these represent the patient group most afraid they will be infertile, as they would be receiving chemotherapy, and most desirous of pregnancy, as they had not yet had any children. Fertility preservation techniques are expensive and not easily available for all patients, particularly in less wealthy countries. Is there any group of your breast cancer patients with a high enough likelihood of pregnancy without assisted reproductive technology that you would not recommend this? 

Dr. Ann Partridge: Sure. So we are so glad to have assisted reproductive technologies available in many places, but as you know, they're not available everywhere. And even where they're available for some people, it's either inaccessible for a number of reasons or it doesn't feel right emotionally or ethically. And then finally, sometimes people need fairly quick treatment and they just don't have the time, even though we don't think there are long delays. And so we do and are able to know who can get pregnant after standard chemotherapy. Not perfectly, but we can give estimates. And the gestalt is, the younger a woman is, the less likely she is to become amenorrheic and the associated infertile, although it's not a perfect match in terms of amenorrhea being a surrogate. And then there are particular chemotherapy regimens that are more gonadotoxic than others. The more cyclophosphamide, for example, or alkylating agent, the more anthracycline, the higher the likelihood generally of causing at least amenorrhea and likely infertility. The huge caveat there is that for some of our newer therapies, we have no good information about how they might impact on menstrual status, let alone the actual rates of fertility. So we need to collect those data. But certainly, if someone's very young, they're going to get four cycles of TC or they have inflammatory breast cancer, we often take kind of a let the chips fall where they may approach, because they just aren't able to access it and we'll often do something like ovarian suppression through the chemotherapy to help support them and hope that it improves their menstrual functioning in the long run and/or fertility.

Giselle Carvalho: Thank you for your insight. So you found that pregnancy incidence over time differed by age group, although incidence of menstrual recovery over time was similar across all age groups, which I conclude that menstrual recovery does not translate into fertility. The addition of gonadotropin releasing hormone analogs to chemotherapy was not associated with time to pregnancy. However, of course, such use was not randomized. 

Dr. Azim, if assisted reproductive technology is not available to patients for reasons such as socioeconomic factors, would you recommend using GnRH analogs with chemotherapy for the purpose of fertility preservation? 

Dr. Hatem Azim: Yes. The short answer is yes. Of course, POSITIVE study was not designed to address the question around GnRH analogs, but we do have several randomized studies and meta analyses that have shown clearly that the use of GnRH analogs with chemotherapy reduce the risk of premature ovarian insufficiency. And subgroup analysis of some of these studies have shown a trend towards higher pregnancy rates as well. So, of course, if a patient does not have access to assist reproductive technology, GnRH analogs in combination with chemotherapy represent a very good alternative. 

Giselle Carvalho: I see. Thank you. Thank you for your response. At enrollment, 93.2% of women on POSITIVE trial had stage 1 or 2 disease and 66% had no negative disease. Therefore, one possible bias is that investigators might have been more comfortable with temporarily interrupting endocrine therapy if the risk of relapse was low.

Dr. Partridge, what recommendations would you have for women with stage three hormone receptor positive breast cancer who desire to attempt pregnancy?

Dr. Ann Partridge: Yeah, thank you. That's a really good question. It comes up in our tumor boards and discussions about patient care all the time, and I think, as you know, only a small proportion, about 6%, had stage 3 disease. Those patients are at higher risk of recurrence by nature of their stage. Not that all stage 3 are created equal, because, of course, if someone had a complete pathologic response to preoperative therapy and their stage 3 disease at diagnosis went to a PCR, then that person may have even better outcomes in the long run than someone who had postoperative treatment, and we don't know their likelihood even with stage 1 or 2 disease. But someone that you're concerned about their risk of recurrence, they still remain at risk of recurrence. And while we do not think, based on the POSITIVE data and all the data that we've had from retrospective studies and other data sets collected for other reasons, that a pregnancy would worsen their outcome, we certainly don't believe that a pregnancy at this point in time will dramatically improve their outcome or as a treatment for breast cancer. That's when I have a heart to heart conversation with the patient, really acknowledging they still remain at high risk. And most of my colleagues tend to want the patient to get more endocrine therapy into their system before they take a break. We've kind of discussed this, and we want someone to get more like at least three to five years. That may be a little bit paternalistic, because, as we know, taking the break for people with a little lower risk didn't seem to worsen outcomes. Maybe it's fine. I don't know that a break at five years is any better than a break at two years. I don't know. Hatem, how do you handle this in your practice?

Dr. Hatem Azim: Well, I completely agree with you, Ann. I mean, it's very much decided on a patient by patient basis. The level of uncertainty that some patients accept to take is not necessarily like others. And sometimes we as physicians, we adopt this. I agree with this paternalistic approach. Nevertheless, it's very important for the patient who is 32, is not necessarily counseled like the patient who's 39, and her acceptance and the feasibility of waiting a bit longer as well in order to attempt pregnancy - the success of pregnancy afterwards is not necessarily the same. So I'm not sure we could adapt a one size fits all approach here. And I do not necessarily tend to factor much the elements around the stage. I think my point to patients is usually, well, you do have give and take this amount of risk of relapse, for example, and whether we accept to take such, what we could refer to as relatively unconventional approach of temporary interrupting endocrine therapy, and when we are comfortable to go ahead with this journey, depending on the feasibility of getting pregnant afterwards as well. So, yeah, I completely agree. It's very customized, based on and tailored according to the patients' situation.

Giselle Carvalho: Thank you. I really appreciate your response to this. So, moving forward, tamoxifen alone was the most commonly prescribed endocrine therapy, followed by tamoxifen plus ovarian function suppression. The latter was preferred over aromatase inhibitors ovarian function suppression in the selected population. Endocrine therapy prescription changed in the second half of the recruitment period after July 2017 across all continents, likely due to the results of the SOFT and TEXT trials. It demonstrated absolute improvements in all disease outcomes by escalating endocrine therapy, which was more clinically meaningful in patients with high risk disease. Dr. Azim, how do you imagine this change could impact positive outcomes?

Dr. Hatem Azim: Honestly, I'm not necessarily sure that it impacts significantly the way you interpret the data and the way we counsel our patients. So, in our study, some 50% of patients received GnRH analogs and around 15% received AI. And most of the patients, I would say, were recruited in the second half of the study after we had the results from, for example, SOFT and TEXT. Furthermore, as we alluded to earlier, we had 60% of patients who received chemo. So most of our patients had a stage 1 and 2 disease in which you would argue that the absolute difference between the different hormonal therapy options is not necessarily massive. Whether or not this would impact much, I'm not sure. I think the main counseling recommendations would apply, that patients who receive endocrine therapy would be asked to interrupt it for at least three months and then they attempt pregnancy afterwards.

I don't know what you think, Anne, but I'm not sure that if we have more patients, and this is pretty much the case now, we have more patients treated with AI. I tend to do this a lot, especially if I'm thinking of interrupting, so I think I'm giving them maybe the best option first. I'm not sure this is necessarily, I mean, affecting me much, while interpreting that it does not appear that temporary interruption on the short term has an impact.

Dr. Ann Partridge: I completely agree with your strategy. Depending on the patient and their tolerance, if they have enough risk to warrant ovarian suppression with AI or tamoxifen, of course I recommend that. And yet, at the same time, I agree with you in this group that was in POSITIVE, I think the groups are relatively low enough risk. Although 40% had no positive disease, the majority got chemo, so they weren't that low risk. And so I think over time, these kinds of patients are more and more going to get ovarian suppression. I'm doing that more in my practice as tolerated. And I hope that all that means is that their breast cancer outcomes will be better independent of a pregnancy.

Giselle Carvalho: And on the topic of women with higher risk disease, CDK4/6 inhibitors are now used in the high risk adjuvant setting. How do you envision this impacting fertility?

Dr. Hatem Azim: Well, this is a very good question. Of course, this is something, this is an area of research that we have to address. Some analysis from some of the adjuvant studies, for example, the PENELOPE-B, I think they reported on some of the results of their study in which they were evaluating palbociclib in the adjuvant setting and did not appear that there was significant differences in terms of the level of estradiol levels and FSH and anti-Müllerian hormone, for example. I think these were the parameters that were evaluated in this study. So, of course, more information. Of course, palb is not the CDK4/6 inhibitor approved in the adjuvant setting. So we need more information as well about the other CDK4/6 inhibitors and longer follow-up. 

In my view from a counseling perspective, I think maybe you would have a certain level of uncertainty regarding whether or not this could have a mental impact on fertility. But the concept as well of possibly proposing a temporary interruption as we adopted in POSITIVE, would still apply. These patients would be treated as well, often, because if they are receiving CDK4/6 inhibitors in the adjuvant setting, it means that they have a high stage disease, so often they will be treated as well with GnRH analogs. I would counsel them pretty much the same, acknowledging a certain level of uncertainty regarding the data we have today on CDK4/6 inhibitors.

Dr. Ann Partridge: Yeah, if they got a full course, they would generally be further out than many people on POSITIVE, because we treat with, for example, the abemaciclib for two years and then you want to wash out and things like that. In POSITIVE, the average was two years. And so you'd expect people of higher risk to be a little further out, which I think would make everybody a little more comfortable too, because someone who's very high risk, you'd worry about very early bad recurrence, too.

Giselle Carvalho: Yeah. Thank you.

So, Dr. Partridge, regarding adherence to endocrine therapy resumption after the two year break, what was the percentage of patients who resumed treatment and which strategies would you suggest to increase adherence in this case?

Dr. Ann Partridge: That's a really great question. In the study, it was well over 70%, which is actually higher than you see in the general population of breast cancer survivors, especially young women. So in some cases, and I can tell you anecdotally, I experienced in my clinic that patients were more likely to start and take their endocrine therapy when they had the promise of the POSITIVE trial, to take a break to have a baby, because some of them don't want to start it, let alone stay on it, if they're told they have to take a full five to ten years. So it actually promoted adherence, ironically. And then for the people who got back on in the real world, the data suggests that by four years, somewhere close to half to 30% to half are no longer taking it. And so in POSITIVE it was, I think, 74% got back on, and that was only at the time point cut off when we did the initial primary data report. And of course more people will have gone back on because some people were still having babies and in the middle of things. And so I think that it's not as much of an issue with POSITIVE. In part, these are very compliant people, right? They're participating in a clinical trial to share the data with the rest of the world. They could have gotten pregnant on their own and they want to do it with their doctors. And so I think this is a little bit of a different group, but it was very reassuring to see that most people got on hormonal therapy after their interruption.

Giselle Carvalho: And recurrence of hormone receptor positive breast cancer may occur late. How long do you plan to follow patients enrolled in the POSITIVE trial?

Dr. Ann Partridge: So our plan is to follow them for at least 10 years. And it's interesting because we're starting to get close to that. We started enrollment in 2015, so I saw someone earlier this week who will have her 10 year mark next year because she got on in 2015. And that's very exciting. Obviously, it would be great to follow them even longer because ER positive breast cancer can recur many years later. But I do think that we feel as though at least 10 years will give us a good, very evidence-based feeling about the safety.

Giselle Carvalho: Thank you. Thanks for sharing. With enrollment occurring at 116 institutions in 20 countries across four continents, this representation of different races and ethnicities provides strength to support this recommendation for this group of patients worldwide.

Dr. Azim, what are your hopes for future analysis from this study and what future research in the area are you planning or would like to see performed? 

Dr. Hatem Azim: So Ann mentioned, of course, it would be crucial to conduct the long term follow up of these patients, and provide more reassuring evidence on the safety of this approach of adjuvant endocrine therapy. So this is something we're really looking forward to. Other analysis that we are working on is the breastfeeding analysis. So looking at patients who underwent breastfeeding and how far the feasibility of this approach, obviously, but how far as well this had an impact on their breast cancer outcome. So this is something that hopefully we are going to report on soon, expected end of this year. As well, we are working on evaluating, we had a large translation research program within POSITIVE, addressing several questions, including the evolution of ovarian function parameters over time and the ovarian reserve. Also, we are working on reporting on this information. We hope that this could happen maybe in the coming year.

Giselle Carvalho: Great. And finally, what advice do you give young women in your clinic who have been diagnosed with early stage hormone positive breast cancer and who are hoping to attempt pregnancy.

Dr. Hatem Azim: We address these kinds of questions relatively early in their treatments and often they are very much concerned about their chance of future fertility. Usually early on, for example, before going for chemo and so on, I just share the information that this is something that we certainly could discuss and certainly there are the possibility that we could consider in the future that it's not a 'no go' at least. And definitely it's something that we could work on once treatment is completed and recover from the adverse events of therapy. And because throughout the journey of treatments as well, women's wishes evolve over time and their perception of their pregnancy project as well evolve and change over time. So I think it's important to acknowledge, in my view, it's very important to acknowledge that this is feasible, this is possible, and because this as well provides an important psychological boost for them. And then as the patient comes over for their follow up after therapy and so on, start understanding, getting a little bit deeper into these kind of questions regarding feasibility, timing. If they are ER positive, then if it's okay to interrupt, not to interrupt, to explain a bit better and to consider a bit better regarding what kind of risk we're talking about. Articulating better, what do we mean by risk? So that sometimes you have a patient that is willing to accept a 10% risk, although others 1% risk for them represent a major threat. Also, it matters nulliparous versus a patient who already has two or three kids. So I think I tend to go a bit more granular in this kind of information as patients are out of chemo and on hormonal therapy and start addressing these matters. But I think it's important early on to share the information that nowadays we do have sufficient information not to discourage women who would like to have a pregnancy in the future.

Giselle Carvalho: Thank you. Thank you. Dr. Partridge, would you like to add some final comments on this?

Dr. Ann Partridge: Yeah, I think this is just such an important issue for our young breast cancer survivors and cancer survivors diagnosed at a young age, regardless of the type of cancer. So I think paying attention to this at diagnosis and through their survivorship is critical, both for their thriving in survivorship as well as for their long term health and cancer outcomes. Getting back to that adherence issue, people, if they're unhappy, won't do all the right things for themselves, sometimes medically and emotionally. And we know that infertility can be associated with long term distress for patients with and without cancer. So we need to pay attention to this and I'm really happy that ASCO is doing a podcast on this and I'm really happy that JCO is doing a podcast on this. 

Giselle Carvalho: Thank you. I really would like to thank you both, Dr. Azim and Dr. Partridge for attending this interview.

This is Giselle Carvalho. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows asco.org/podcast.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

 Dr. Azim
Employment Company name: Pierre Fabre, EMERGENCE THERAPEUTICS Stock and Other Ownership Interests Company name: Innate Pharma, Diaacurate Travel, Accommodations, Expenses Company name: Novartis

Dr. Partridge
Research Funding Company name: Novartis Patents, Royalties, Other Intellectual Property Company name: UpToDate

TRANSCRIPT

Dr. Davide Soldato: Hello, and welcome to JCO After Hours, the podcast where we sit down with others from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Sana Raoof, Physician at Memorial Sloan Kettering, to talk about her article, "Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures."  

Thank you for joining us today, Dr. Raoof.

Dr. Sana Raoof: Thank you so much. It's lovely to be here.

Dr. Davide Soldato: So, Dr. Raoof, I just wanted to start a little bit about the theme of your article, which is really centered around multi-cancer early detection tests. And this comes from the results of several studies that showed their reliability and efficacy in identifying cancer in the average risk population. But I just wanted to ask you if you could give us and our readers a brief overview of how these tests work and how they were designed for this specific population.

Dr. Sana Raoof: Of course. Well, there's an interesting story. The origin of multi-cancer early detection tests actually begins with insights that come from the field of obstetrics and gynecology. So about six or seven years ago, in the peripheral blood of pregnant women, we discovered that you can actually find fetal DNA floating around. And that was an early discovery of cell free DNA coming from the baby into the mother's bloodstream. But in some of those young, otherwise healthy women, we also discovered that there's another clonal signal, unfortunately not coming from the fetus, but coming from an undiagnosed tumor. And that led to the entire field of circulating tumor DNA and all of its applications. 

Of course, scientists in the last six or seven years have harnessed the fact that DNA and the methylation patterns on the circulating tumor DNA, as well as other analytes like glycosaminoglycans, proteins, and other analytes, are secreted by tumors into the peripheral blood in order to try and screen for tumors, hopefully at early stages, when there are still curative, definitive interventions that are available. There's several different tests now that are providing the ability to detect cancers at many stages, including early stages. They're in different phases of preclinical to clinical development, and one is even commercialized and available by prescription in the United States.

Dr. Davide Soldato: Okay. So I think that in most of these tests, they really look at the tumor DNA, so they identify mutations or, for example, methylation patterns. But do we also have some tests that integrate some other type of biomarkers that we can identify in the blood? Like, are they integrated all with the others, or are we just relying on circulating tumor DNA?

Dr. Sana Raoof: It's a great question. There's a lot of really fascinating biology that different companies predominantly are using in order to find signs of early cancer. One of the analytes that I find really interesting, other than looking for small variants in circulating tumor DNA and looking at methylation patterns, as you mentioned, is looking at fragment length. So, for example, the company DELFI looks at the different patterns of the length of DNA fragments that are floating around in the peripheral blood. And not only is fragment length tissue specific, so in theory, a fragmentomics based multi-cancer early detection test could tell us what is the tissue that this aberrant signal is coming from, but they can also tell you if there's likely a cancer present, because there's a difference in fragment length patterns in cancer versus non cancer. 

There are also other analytes. I mentioned glycosaminoglycan. There's another company that doesn't yet have prospective data, to my knowledge, that is making a test that looks at these analytes instead. There are other companies, again, without prospective data yet, that are looking at circulating tumor cells. And I'm sure that in the next few years, we're going to start getting prospective data from all of these players and also hear about other analytes that scientists have found can predict cancer from non cancer and maybe even protect tissue of origin based on artificial intelligence.

Dr. Davide Soldato: So you mentioned artificial intelligence. So, basically what you're suggesting, but correct me if I'm wrong, is that when we use this test, we are actually measuring something in the bloodstream, but at the same time, we are actually applying some type of artificial intelligence to actually interpret these results and then give us the definitive results, or what we would call like a positive and a negative of the tests, is that right?

Dr. Sana Raoof: Yeah, absolutely. And it's an important distinction that you're making, we are measuring something in the blood, but we're not just measuring it. We're using machine learning algorithms that have been trained on thousands and thousands of patients with cancer and thousands and thousands of patients without cancer, and have measured various analytes and analyzed the patterns, for example, of DNA sequence, or bisulfite sequencing of methylation patterns of patients with and without cancer, and have been trained to look for the differences between them. And so the analyte that we're looking for is not a specific mutation per se, but is a pattern that looks like patterns that you typically find more so in cancer patients.  

There's many different companies, they are trained on different types of cancer. So some companies, like GRAIL, have a test that looks for a very expanded list of over 50 cancer types. Other tests have a narrower focus and were trained and validated on a smaller list of cancer types. So there's just a great diversity in this space. These tests are trained to look for different types of cancer. They're trained and validated on different populations of interest. So, for example, some of the populations that these tests were trained on are predominantly white, and that will have impacts, potentially on how these tests perform in non-white populations. And that's a really interesting area of future research. These tests may or may not have included cancer survivors in their populations, and that could ultimately impact how these tests perform in those populations. 

So there's just so much to learn, so much data that's going to be coming out in the next few years from all of these different key players in the multi-cancer early detection space. But one thing that I'm sure of is between all of the different analytes, all of the different training and validation studies, and all of the different prospective studies, we're going to learn a tremendous amount about the potential clinical utility of using multi-cancer early detection tests to complement the few standard of care surveillance cancer screening tests that we have recommended today.

Dr. Davide Soldato: So just taking a step back and going back to the fact that we actually use machine learning algorithms to identify a pattern that can give us an idea of whether cancer is present or not, I believe that there is also some room for calibration of these types of tests. And I think that this is one of the key arguments that you make in your paper where you say that we can actually personalize a little bit more these types of tests to understand and then to decide what we are looking for. Is that correct and can you expand a little bit on that?

Dr.Sana Raoof: Yeah, absolutely. This is the central concept of the paper that we're discussing. Because these tests are machine learning based, as I said, they're trained to say cancer versus not cancer, and some of them are further trained to say, coming from this organ or coming from that organ. But what does it mean to say cancer or not cancer? There are specific thresholds that are defined to say, above this threshold of signal detection, we're going to say this is a positive cancer signal detected, and below it we're going to say negative. And so right now, these tests are kind of designed to have this binary output, and the concept that I wanted to put forth in the paper is it doesn't necessarily have to be binary, and the thresholds don't have to be static. So, for example, you can imagine that in an average risk population where the pretest probability of cancer in your lifetime for Americans, it's pretty high, roughly 40% for lifetime. But at any given moment in time when you're getting a test, it's lower. For example, in Americans, 50 to 80, the chance of having cancer at any given moment is just under 3%. So you don't necessarily want a test that is very nonspecific, you don't necessarily want to tell a lot of perfectly healthy people that are asymptomatic screening populations that they have cancer if they don't. And so these tests were designed to have very high specificity, predominantly across the board, across the different companies making them at the cost of, in some cases, having lower or moderate sensitivity in early stages.  

And it's important to keep in the back of your mind that we cannot ever expect the types of early stage sensitivities from multi-cancer early detection tests that we're used to thinking about for single cancer screens that are just optimized for one single organ. They work in a completely different way. So I don't expect a future where the sensitivity of a mammogram, which is only for breast cancer, is going to be analogous to the sensitivity of a blood-based test that's looking for all cancers in your entire body. I don't think it's fair to expect that. But I do think it's possible to imagine a future where we do change the thresholding of these tests that were trained and validated in average risk screening populations, and say, "Let's turn the knob on the dial and let's take the sensitivity a little bit higher, even if it means the specificity drops from 99%, for example, which is the very high number of the gallery test, down to 98%, down to 97%. Let's see how this affects the positive predictive value and the negative predictive value of the test." And how having a higher negative predictive value by having a higher sensitivity may or may not make it more clinically useful for higher risk populations that have higher pretest probabilities, in which case we are kind of more interested in being sure that we're ruling out cancer. 

Another concept that I talk about in the paper, aside from just turning the knobs, is to make it a continuous variable rather than a binary report. Rather than saying signal detected or not signal detected, I can also imagine a future where we personalize the output of multi-cancer early detection tests to return a score, for example, from 1 to 100 or 1 to 10, and give physicians the ability to use that continuous variable in addition with other clinical findings, physical exam findings, other labs, symptoms, patient's past medical history, family history, all of that together to make decisions about should we pursue further workup, should we do an invasive biopsy. This is kind of the way that we use other scoring tests in oncology, like the oncotype tests for breast cancer, decipher test in prostate cancer. And I think physicians like having continuous variables to work with and to help them make very personal decisions for patients' diagnostic workups.

Dr. Davide Soldato: To summarize a little bit, what you're arguing in the paper is that we could potentially modify a little bit these tests as they fit the type of population that we are looking for. For example, if we are looking at the average risk person in America, there we just want to be sure that we are just doing additional workout and additional follow ups and additional invasive procedure, for example, biopsy, when we have a very high probability of finding that cancer. At the same time, if we have someone who has a baseline risk which is higher, like cancer survivors, in that case, we are more interested in seeing if there is really cancer at that point, and so we can increase the sensitivity and go down on specificity, but still looking at the overall outcome that we want to have for that specific patient. 

One thing that I was wondering is, do you also see a future where we personalize a little bit more also including additional information that comes from risk factors, environmental or behavioral patterns, type of diet, or these types of risk factors that we already know from epidemiology are associated with a higher risk? So could we potentially customize this test even more, saying, this patient has a higher risk of developing colorectal cancer, so could we look more specifically to that specific cancer type and that specific risk compared to tobacco associated cancers, that for that specific patient, they are not so relevant? 

Dr. Sana Raoof: What you're saying is actually a fascinating and really compelling idea, and it reminds me of the way that noninvasive prenatal testing works. So, again, back to the world of obstetrics and gynecology, you have a woman at the end of her first trimester having fetal DNA testing to look for chromosomal abnormalities. And when you order that test, you actually do put in various features about the woman to help you understand her baseline risk for carrying a fetus that has chromosomal abnormalities, including her age, the status of her other children, and other things in order to help you calculate a pretest probability. And so after that, the non invasive prenatal test takes that into consideration and returns a probability of carrying a fetus that might have those aberrations, and it's not a binary risk. It's, as I said, a continuous variable.

So I think what you're proposing actually goes beyond what I wrote about in the article. I think it's a fabulous idea. And I think that in the near future, I can imagine that as natural language processing is exploding, and in general, large language models and the ability to extract features about a patient from the EMR are exploding, we might have a better stratification in general of patients into average risk, low risk, high risk, and really high risk, using EMR data, using real world data that could help us feed a really accurate picture of a patient's pre-test probability into this test, so that these tests could be further refined and further trained and validated on patients, taking into consideration more factors and help us improve the predictive power of the tests as they're returned in a report to the physician. So I think maybe you should even write an article about the idea just proposed. It's a great idea.

Dr. Davide Soldato: So another aspect that I was really interested in is I've looked at one of the papers that you cited, and I wanted to discuss this with you as you are an expert on the topic. In one of the articles that you cited that used this type of test, they identified some of the cancers that we also normally identified with standard screening procedures, like breast or lung or colorectal. So for those cancers, we add a certain proportion, or like, for example, for breast cancer, a higher proportion identified with conventional screening. But still we had some other cancer that eluded those types of screening and were identified using liquid biopsy tools. So do you envision a strategy where we would use the screening methods that we already add as a complement to those liquid biopsies, or do you think that someday liquid biopsy could potentially completely substitute standard screening procedures? 

Dr. Sana Raoof: I think we're too far from a day where liquid biopsies are going to replace standard of care screens. The scope scans and smears that the United States Preventive Services Task Force has recommended are gold standard screening interventions because, number one, for all of them, except for cervical cancer screening, we have randomized data with definitive endpoints that tell us that there are mortality benefits from doing those screens. We don't have that type of data yet from the world of multi-cancer early detection. And as we talked about earlier in this podcast, those tests are kind of designed with a different approach where they have higher sensitivity and much lower specificity than multi-cancer early detection tests. 

So I think that the molecular cancer screening companies have done a very careful job of creating tests that are really more optimized to be complementary tests rather than a standalone catch all test, to have higher specificity at the cost of lower sensitivity. So I don't imagine a near future, at least not in my career, where we're going to stop doing colonoscopies and mammograms and pap smears. I don't think that that's going to happen. But I do think that whereas right now 75% of cancers that Americans die from, we lack cancer screening mechanisms for them, I think that that number has the potential to really drop. If in the next few years, one of these multi-cancer early detection tests is ultimately approved and covered, then I think that a lot more cancers could be detected by screening rather than by symptoms, and we might ultimately see a big stage shift. 

Dr. Davide Soldato: Yeah, I think you're absolutely right. In the same article that I was mentioning before, there were several of those cancers which can be lethal if diagnosed at an advanced stage, that were diagnosed at an early stage, for example, ovarian cancer, bladder cancer. So I really think that we really have potentially the way to screen, or at least have a signal for cancer that currently we just diagnosed when symptoms associated with higher stage appear. 

But moving on to turning the knobs on this type of test, and so going to the higher risk population, for example, cancer survivors, which is something that you speak a lot about in the manuscript. So you also discuss a little bit the question of whether we should use multi-cancer testing versus single cancer testing. So are we looking at a specific recurrence from that specific tumor, or are we looking at a general risk of cancer in a population that has a common risk factor, like tobacco? And so I was wondering if you think, and this is probably just your perception or just your opinion, that that is another way that the physician should turn the knob. Should we evaluate the risk of those cancer survivors and say, in this specific patient right now, the risk of recurrence is higher so I should use or I should be more in favor of a test that is more centered on the risk of recurrence versus I have a general risk of several cancers that could appear, and so should I use something that is more multi-cancer? This, of course, is merely speculative because we still don't have definitive data regarding the efficacy of this test. But it is just your perspective on this type of approach in the near future or not so near future. 

Dr. Sana Raoof: Well, I think if we're speculating, then I think that the fantasy situation for any oncologist is that you have two types of liquid biopsies. One is a multi-cancer early detection liquid biopsy. And it would be great if you could select whether you want it to be optimized for highest NPV, negative predictive value, or highest PPV, positive predictive value. And then you also have a host of single cancer screening liquid biopsies that can help you specifically figure out if there's a recurrence of a single cancer type that you're suspicious about.  

So, for example, in the article, I talk about how there will be clinical gray areas, and it's not always going to be obvious which test you should reach for. But one example that I think we can all relate to in the oncology community is you have some indeterminate imaging finding, and you don't know what to do about it. So, for example, you have a woman that has a history of breast cancer, has had no evidence of disease for a few years, now, has back pain. You do a spine MRI, you see a lesion. Maybe it's an atypical hemangioma that's causing pain, maybe it's a breast cancer metastasis. You're not sure. What should you do? Should you do a biopsy of that lesion in the spine? Should you wait and see if it grows and do another MRI in two or three months? What are your options? And so in this situation, I think we can all agree that if you had a liquid biopsy that was optimized for really high sensitivity, specifically for breast cancer, and had a very high negative predictive value, and if it came back negative, then in that setting, it might help you avoid an invasive test, like a biopsy in the spine, and give you a little bit more comfort as a physician to say, "You know what? I'm going to come back in two or three months and do another spine MRI. I'm going to see how this woman is feeling, and I don't need to biopsy this right now. Maybe it really is just hemangioma." 

Dr. Davide Soldato: And in this specific setting, let's take the same patient. So it's a female patient, she had a previous diagnosis of breast cancer. Do you think that there is a difference between tumor-informed tests, really based on the molecular aberration that the primary tumor had for these women, versus just a standard test that gives us information regarding the presence of breast cancer cells or not? And if you think that there is a difference, what would you think would be the advantage of one? And the disadvantages, for example, is a tumor informed essay more complex to obtain? Do we need more time? Is it more expensive versus a commercial test that is already available or something like this? This is my understanding as someone who's not so much in the topic, but I think that this is a point that many oncologists probably wonder about, and probably we should speak a little bit more about with someone who is an expert on the topic. 

Dr. Sana Raoof: Absolutely. And I think that you've actually hit all of the major points on the head. So comparing a tumor informed versus a tumor agnostic test is like really comparing apples and oranges. A tumor informed test where you're starting with a patient's pathology and you are looking specifically for mutations and other molecular features that you know the patient has in their tumor, is going to, of course, result in a test that is, number one, more expensive and harder to make, but also, number two, more sensitive, more specific, more predictive, and in every way probably just more powerful than a test that is, in general, optimized for a single cancer type, but is almost certainly going to be trained and validated on people with a mix of histologies, a mix of molecular features, and will not be as sensitive or specific as a test that is actually informed by that single individual's tumor. One of the things that matters a lot to me is health equity in oncology. There are just huge disparities in outcomes in patients that are advantaged and disadvantaged. And it stems from lots of different things. In no small part, it stems from later stages of diagnosis in disadvantaged patients, and then even once you have a diagnosis, delays to confirmatory workup, delays to starting treatment, disparities in the treatments offered. 

I don't imagine a world where everyone on earth is going to have access to tumor-informed liquid biopsies. I do imagine a future where tumor agnostic liquid biopsies, both for single and multi-cancer screening, should be a lot more economical than they are now, and should be more available for multiple cancer types, and should be more available to patients that aren't at just the Memorial Sloan Ketterings and the Dana-Farbers of the world. And so I do think that those types of off the shelf tests have the potential to really revolutionize the way that we work up suspicion of cancer, not just in advantaged patients, but also in patients that are diverse, in patients that are not at academic cancer centers, but at other cancer centers around the world. And I think it's a really exciting prospect.  

Thinking about the chance of recurrence in the breast cancer patient is a perfect example of when you want to test that is optimized just for breast cancer, because you see something in the spine, you know her history, and you're less worried about a new primary and a new MET from that primary. But there are other situations that are also interesting to consider. For example, patients that have had lung cancer and have a history of smoking, because they've had a history of smoking, they're actually at risk for a dozen different cancers, not just lung cancer. And when you think about what we do to follow lung cancer survivors, we're just doing CTs of their chest and of course, physical exams. But the vast majority of cancers that people with lung cancer history will get may not be present in the field of view of a CT of the chest. They may also get renal cancer, bladder cancer, they might get leukemias, they might get pancreatic cancer. So there are a lot of things that you're not going to catch in a CT of the chest. And so in that situation, you care not only about recurrences, which in thoracic oncology, it's kind of a gaussian probability distribution, where the tail is almost close to 0 after five years, but also a uniform distribution of roughly 3% per year of a second cancer, a new primary cancer that goes on for the rest of their life. And so in that clinical setting, you can imagine that having an off the shelf multi-cancer early detection test may be dialed up for higher negative predictive value, would be extremely useful.

Dr. Davide Soldato: Yeah, I totally agree, but thank you for clarifying these points, because I think that there is a little bit of confusion also in the oncology community, as this type of tests, they're also based on very complicated molecular biology, sometimes could be potentially integrated, and we could potentially integrate them in the clinic. 

And so I wanted to close up with kind of a personal question. I was wondering how you came to be so interested in this field of molecular screening or early diagnosis and prevention associated with molecular data. 

Dr. Sana Raoof: Well, it's an interesting story. I did my MD PhD at Harvard Medical School, and my PhD was in the opposite world from molecular cancer screening. I was designing drug combinations that could be used in advanced oncogene mutant lung cancers. And I thought I would become a medical oncologist and spend my life designing new systemic therapies for advanced malignancies. And what I saw every day in the lab during my PhD is drug resistance emerges and it's a process of evolution by natural selection happening on a cellular level. And although we have some really great slam dunk drugs that come to mind, for example EGFR inhibitors in certain lung cancers, immunotherapy in melanoma, on average, the median overall survival gain from all of the FDA approved drugs in the last 10 years is roughly two months.  

By the end of my PhD, I really started feeling like, is the best use of my life to continue fighting a battle against natural selection in cancer cells, or is it a better strategy, to me, it seemed like a more sensical strategy to just try and find cancers in these patients earlier, when you don't have to engage with the complex signaling mechanisms of a cancer cells biology, and instead can just provide a definitive local intervention, like surgery or radiation, which already is curing many patients with non metastatic cancers. And as I looked around the world, I just didn't see that many people investing heavily in early detection research at the time. It was the very early days of multi-cancer early detection. And so I became involved with all of the groups, the companies, the organizations that were developing these tests, and really fell in love with, number one, just the concept of the tests, the concept of multi-cancer early detection, rather than single cancer screening alone, because no one knows what cancer they're ultimately going to get. But I also really fell in love with methylation biology, fragmentomics. I fell in love with the types of clinical trials that were being designed and the new types of endpoints that we have to think about when we're designing clinical trials for a multiverse of single cancer screening. And it's just such an exciting time in that community, it's the early days. So that's how I came to this space, and it's just the perfect time to be in this space, because everything is exploding. 

Dr. Davide Soldato: Thank you very much. And thank you also for sharing the personal side of the story.

Dr. Sana Raoof: Thank you so much. I'd like to thank Razelle Kurzrock, who's an amazing medical oncologist who's worked with me on two really fun papers so far, one on real world data, and this one on turning the knobs on liquid biopsies. It's always great to bounce ideas around about multi-cancer early detection with friends and collaborators, and Razelle did an absolutely amazing job helping write this piece. 

Dr. Davide Soldato: So this brings us to the end of the episode. Thank you Dr. Raoof, for joining us and sharing more on your JCO article titled, "Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures."  

If you enjoy our show, please leave us a rating and review, and be sure to come back for another episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

 Disclosures:

Dr. Raoof

Stock and Other Ownership Interests Company name: Illumina Radiopharmaceuticals Honoraria Company name: AstraZeneca Consulting or Advisory Role Company name: Verily Company name: GRAIL Company name: Exact Sciences Travel, Accommodations, Expenses Company name: Grail

TRANSCRIPT

The guests' disclosures can be found in the transcript.

Dr. Rohit Singh: Hello and welcome to JCO's Article Insights. I am your host Rohit Singh and today we will be discussing the JCO article, "Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade." And we are joined by the senior author of the article, Dr. Ticiana Leal. Dr. Leal is an Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and she serves as director of Thoracic Medical Thoracic Oncology Medical Program and Multidisciplinary Thoracic Oncology Leader at the Winship Cancer Institute. She also served as a member of the Board of Directors at the Georgia Society of Clinical Oncology. 

Dr. Leal, welcome to our podcast and thank you for joining us.

Dr. Ticiana Leal: Thank you, Rohit. Thank you for this interesting opportunity to discuss our editorial. My co-authors and I are very glad to be here today. So, Dr. Jennifer Carlisle and Dr. Liu were co-authors with me on this editorial.

Dr. Rohit Singh: It's a really good article. And just for our audiences, the article again, titled "Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade," it discusses the challenges and the potential strategies for overcoming resistance to immune checkbox inhibitors in patients with non-small cell lung cancer. In this article, Dr. Leal and colleagues talk about the second line of drug when the patient developed disease progression while immunotherapy and they develop resistance and their definitions and what to do. 

So, to Dr. Leal, can you please explain the mechanisms of primary and acquired resistance to immune check prohibitors in non-small cell lung cancer? I also saw in your article you proposed the definition of immunotherapy resistance in solid tumors, distinguishing between primary resistance and acquired resistance. So, if you can please share your thoughts and explain their mechanism.

Dr. Ticiana Leal: So primary resistance and acquired resistance are related to tumor intrinsic and tumor extrinsic factors. And this is mainly clinically defined as of now according to previous response patterns and timing of occurrence, and these definitions can be heterogeneous, and we certainly think that biologically they can be very different. And it can be different according to prior therapy, whether patients got immunotherapy as PD-1, PD-L1 inhibitor alone or combination strategy with CTLA-4, or the combination with chemotherapy. But the patterns of resistance can be very different and can be based on defects and antigen presentation. It can also be due to tumor microenvironment immunosuppressive effects, and there are also additional inhibitory checkpoints that can be involved. 

The definition in terms of when to call it primary or acquired resistance at this point has really been based on consensus guidelines by SITC, by Esmo, as well as our group Lung-MAP has developed clinical trials in this space. Specifically, through Lung-MAP, we've defined and incorporated the definition of acquired resistance as patients who have had prior exposure of 84 days or greater and then have had progression of their disease. 

Dr. Rohit Singh: I can see why it is so challenging to come up with a standard definition for immune checkpoint resistance and I think incorporating these definitions and predictive biomarkers for clinical trial design is going to be more important going forward. Your article talks about CONTACT-01 study, so can you please discuss the CONTACT-01 study and how the shifting treatment paradigm in the first-time study impacted it and at the same time also discuss the potential implication of the differential outcome observed between the men and women in the CONTACT-01 study.

Dr. Ticiana Leal: CONTACT-01 was a much-awaited study. The authors, Dr. Neal et al, looked at a very important question in the area of immunotherapy resistance. So, CONTACT-01 was a randomized phase three global study that investigated the combination of cabozantinib plus atezolizumab versus docetaxel in patients previously treated with chemotherapy and immunotherapy. And as background, cabozantinib is an inhibitor of multiple receptor tyrosine kinases including VEGFR-2, MET, RET and TAM family kinases. Preclinically, cabozantinib could lead to immuno permissive tumor microenvironment and so it was rational to combine it with a PD-1 inhibitor. In early results of a phase 1B expanded cohort of COSMIC-021 showed really promising results of this combination which led to the rationale of CONTACT-01. In this study, however, patients that were included had different prior treatment sequences. They could have had prior immunotherapy alone followed by chemo or the opposite, or they could have had prior immunotherapy and then upon progression gotten a combination of immunotherapy plus chemotherapy. That to say that immunotherapy rechallenge is something that people are doing in clinical practice given the unmet need and the desire to overcome immunotherapy resistance. But perhaps that also includes a more resistant population of patients, and these patients certainly could have had heterogeneous mechanisms of resistance which could have impacted these results.  

The study did not meet the primary endpoint of overall survival. We saw a median overall survival of 10.7 months with the combination of atezo plus cabo and 10.5 months with docetaxel alone. In terms of the differences between sex that we saw in the CONTACT-01 study, just to go back in terms of the preclinical studies that have been done, there have been some preclinical studies that demonstrated that perhaps there may be some biological differences in models of different genders in mice. However, in the clinical setting, there have been, I think, contradicting results. A meta-analysis showed that perhaps women derive less benefit than men. Other studies have shown that perhaps women have more adverse events to immunotherapy. In this study specifically, only about 20% of the patients enrolled were women and the majority actually had non squamous histology. And we saw here less benefit for immunotherapy in women. But again, I think the numbers here are quite small. This is an exploratory analysis and I do think it highlights though the importance of making sure that we include populations and have higher rates of accrual, not only in women, but in other representative populations. In this study, only about 1% of the patients were black.

Dr. Rohit Singh: Yeah. Thank you so much for highlighting those disparities. I think it's very important to make sure that we have proper representation of all the groups in our trials. I think based on just coming off the VEGF inhibitors, I think the Lung-MAP trial S1800A, showed a significant improvement in median OS with the combination of pembrolizumab and ramucirumab compared to standard of care. Do you envision any future commission therapies targeting the VEGF pathway with immune prohibitors in non-small cell lung cancer? 

Dr. Ticiana Leal: I definitely think that targeting VEGF with multikinase TKIs based on the studies that we have seen, several now randomized phase 3 studies showing that this strategy is ineffective. So, this has been quite disappointing. But we've now seen the results of CONTACT-01, that we're just discussing here, but also other studies, including SAPPHIRE, which was also a randomized phase 3 that investigated nivolumab plus another VEGF multikinase TKI, sitravatinib. And then we also saw LEAP-008, which was a negative study investigating lenvatinib plus pembrolizumab. There still is a question though, whether you can target the VEGF pathway inhibition with a monoclonal antibody, so that's ramucirumab targeting VEGFR-2 plus ICI, and whether that can actually be an effective strategy. In our Lung-MAP trial, the S1800A, this study was a randomized phase 2. Here we used the definition of acquired resistance of patients receiving prior immune checkpoint inhibitor for a minimum of 84 days, and they were randomized to the combination of pembrolizumab plus ramucirumab versus investigator's choice of standard of care, which did include docetaxel, ramucirumab, docetaxel gemcitabine and methotrexate. This was a positive study. It led to significant improvement in median overall survival and there weren't any significant safety signals here. And we're waiting for another confirmatory study called the Pragmatica-Lung study. 

Dr. Rohit Singh: Yeah, I did have one patient who raced through pembro, and I utilized this combination and was able to get some responses. 

You mentioned Pragmatica-Lung trial. Can you provide more information about the ongoing Pragmatica-Lung trial and its potential impact on the treatment paradigm?

Dr. Ticiana Leal: Yeah, the Pragmatica-Lung trial is an ongoing study, S2302. This is an effort that is ongoing. Dr. Karen Reckamp is the chair of this study. And this is a study that actually has a very, I think, modern study design. The term Pragmatica, this is an effort that is supported by the NCI to really propose a clinical trial design that is pragmatic to promote diversity and inclusion in clinical trials. The aim of this trial specifically is to validate what we saw in terms of overall survival in S1800A. So, in this study, patients with previously treated advanced non-small cell lung cancer are randomized 1:1 to the combination of pembrolizumab plus ramucirumab versus standard of care for patients previously treated with immunotherapy and chemotherapy for stage 4 recurrent non-small cell lung cancer. Primary endpoint here is overall survival. And I think this kind of highlights what we were talking about in terms of empowering investigators to treat patients in a clinical trial more so like a real-world setting. And I think this can be paradigm changing and decrease barriers to enrollment and also include now the real-world population that we see in clinical practice.

Dr. Rohit Singh: Yeah, changing gears a little bit. I think your article also mentioned other agents that have been tested in ICI resistance settings, like lenvatinib-sitra. However, those trials results have been disappointing. What are the possible reasons behind those dose point results with multikinase inhibitors? 

Dr. Ticiana Leal: We saw some really interesting, promising overall survival results with these combinations in phase two setting. In the phase 1B expansion with CONTACT-01, we saw prolonged overall survival that we thought would be promising enough to investigate in a phase 3. Ultimately, I don't know because there weren't any biomarkers that we could really tease out what was going on. Again, to highlight that both in LEAP-008 as well as CONTACT-01, there was no definition of immunotherapy resistance, which could have impacted, and we did choose the definition for SAPPHIRE, that patients had to have acquired resistance and immunotherapy had to be the most recent prior therapy. Ultimately, one potential reason for why these are not effective could be that this targeting with a multikinase TKI with multiple targets is ineffective, and you really have to target VEGF more precisely, which is the case here of ramucirumab, which targets VEGFR-2, and whether there are differences between a TKI and a monoclonal antibody may also impact the outcomes here. 

Dr. Rohit Singh: You mentioned biomarkers. Do you think, are there any other potential biomarkers beyond PDL-1 or human mutation burden expression that can help us predict the response image checkpoint, especially in non-small cell lung cancer?

Dr. Ticiana Leal: I think that's a great question. I definitely think that more effort needs to be dedicated, and of course, there are multiple efforts in this direction. One of the challenges, obviously, has been to obtain tissue to do this biomarker testing in clinical trials. When you look at CONTACT-01, they did PDL-1 expression, but this was all based on archival tissue and it was all based on standard of care, local testing. So, a lot of heterogeneity there, and certainly using PDL-1 at baseline from initial diagnosis for a second line trial may have significant flaws there. Ultimately, right now, for clinical practice, there isn't anything that's ready for prime time. But certainly, it sounds like, based on what we're seeing, that combining biomarkers is more likely to improve the accuracy. And I think a single biomarker alone is probably going to have insufficient predictive capacity. It'd be great to be able to better comprehensively characterize an individual's tumor, to individualize immunotherapy strategies in this relapse setting. 

Dr. Rohit Singh: Yeah, definitely. We need more, better biomarkers. Coming to your point of heterogeneity, PD-L1. I myself had a patient, when we got PDL expressions from one site, they gave us one to 49%. However, for the testing, I sent the patient to a further lab at outset and PDL turned out to be 80%. But that was from a different site because of the bio sets only. Yeah, to your point, it's very heterogeneous and definitely we need to be more cautious interpreting those. 

In that trial, in CONTACT-01, we have, through the patient who have oncogenetic lung cancer. Are there any plans to explore the role of immune checkpoint in oncogenetic lung cancer, especially like non-EGFR, non ALK? I know those are the ones that we have seen in multiple studies that don't respond but are other oncogenetic lung cancer is getting more and more target treatments coming out for non-small lung cancer?

Dr. Ticiana Leal: Yeah. So, for patients with driver mutations, the paradigm has been well established that if there is a driver mutation, the patient should receive the appropriate targeted therapy. Immunotherapy as monotherapy has been ineffective in a lot of the patients with driver mutations beyond EGFR and ALK, certainly RET and HER2, ROS1, or other driver mutations that we believe that immunotherapy alone is ineffective. However, we are seeing some interesting ongoing clinical trials, or completed clinical trials investigating immunotherapy in patients with driver mutations. Going back to the EGFR population, we recently saw the results of HARMONi-A, which investigated ivonescimab, which is a bispecific antibody hitting PD-1, and VEGF, that in combination with chemotherapy, improved progression free survival in patients with EGFR mutated, non-squamous, non-small cell lung cancer with progression on prior TKI treatment. So, I think it is still an area of active investigation, and I do think that ongoing trials, perhaps with different PD-1, PD-L1 combination strategies such as bispecifics may be interesting but does require investigation.

Dr. Rohit Singh: Yeah, definitely. It looks like combination therapy is going to be the most likely answer coming forward with more research, we're able to figure out the best possible treatment in this subgroup of patients. Considering the current challenges and ongoing research efforts, how do you see the field of non-small cell treatment evolving in coming years?

Dr. Ticiana Leal: This is an interesting and important question. I think it's been really exciting to be working in thoracic oncology research. We have seen that these research efforts have led to advancement in the field. I think we need to continue to partner and collaborate with institutions, partner with industry, and also with patients and patient advocates to design clinical trials that are really going to focus on the needs of our patients in clinical trials. The gap in the second line and beyond after immunotherapy failure is a significant one. So, I do think that the challenges are to continue to develop biomarkers, to really understand who will benefit from immunotherapy strategies, who benefits from combinations, and most importantly, who does nothing. I think biomarkers are going to be something that we need to continue to incorporate in clinical trials, and I do think that there's a lot of room for hope and promise in the field. We've seen some interesting results with antibody drug conjugates and the combinations there may also be of interest. And then other important strategies, we're looking at T Cell engagers and different drugs with different mechanism of actions, including CAR T and vaccines. So beyond immune checkpoint inhibitors, I think we have different classes of drugs that may lead to different treatment strategies for patients in second line and beyond. 

Dr. Rohit Singh: Yeah, certainly we have seen such extensive development in lung cancer. However, there's still a lot to be done as you just mentioned. 

Thank you so much Dr. Leal for your time and great insights discussing your article with us.

Dr. Ticiana Leal: Thank you.

Dr. Rohit Singh: Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You'll find all ASCO shows at asco.org/podcast.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Leal Disclosures

Consulting or Advisory Role
Company name: Novocure
Company name: Amgen
Company name: Roche
Company name: AstraZeneca
Company name: Regeneron
Company name: Novocure
Company name: Takeda
Company name: Jazz Pharmaceuticals
Company name: Catalyst Pharmaceuticals
Company name: Pfizer
Company name: Janssen
Company name: Genentech
Company name: Novartis
Company name: Sanofi
Company name: BMS GmbH & Co. KG
Company name: Abbvie
Company name: OncoC4

Research Funding
Company name: Pfizer
Company name: Daiichi Sankyo/Astra Zeneca

Travel, Accommodations, Expenses
Company name: Regeneron
Company name: Sanofi

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare. 

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with authors and manuscripts that have been published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, gynecologic oncologist by trade and Social Media Editor for the JCO. And it is my pleasure to welcome Dr. Cao, a research fellow in medicine, Department of Medical Oncology, Dana Farber, Cancer Institute, Boston, Massachusetts. Welcome.

Dr. Cao: Thanks for having me.

Dr. Shannon Westin: Of course. And we're going to be discussing your very important work, "The Prevalence and Cancer Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022," which was published in the Journal of Clinical Oncology on April 4, 2024. And Dr. Cao has no conflicts of interest in regards to this podcast. 

So let's get right into it. I'd love to level set. Can you speak a little bit about the definition of cancer survivorship and the number of cancer survivors currently in the United States? 

Dr. Cao: I think this is an important question because everyone somewhat has confusion about the definition of cancer survivorship. So based on the definition by the National Cancer Institute, cancer survivorship refers to the phase of life following the diagnosed cancer. And nowadays, it's estimated about 80 million American individuals are living after being diagnosed with cancer. And this number is projected to rise to 26 million by 2040.

Dr. Shannon Westin: Wow. So obviously, any research that we can do in this population is going to be so important as that number absolutely continues to grow. 

And before we get into the specifics of your work, I'd love for you to speak a little bit about the importance of functional disability, which is what we studied in this work and why it might be observed in cancer survivors. 

Dr. Cao: Yeah, sure. So, maintaining physical function is fundamental to perform life tasks and engage in fruitful jobs. In terms of cancer survivors, many cancer survivors experience side effects from cancer and its treatment. These side effects, include the pain, fatigue, and musculoskeletal dysfunction, which can induce physical limitation and eventually physical disability. And specifically, this is such a burden for the US, social, societal and economic burden. Here I have the specific number: so in 2019, an estimate of over 100,000 people living with and beyond cancer were unable to work and they received a Social Security Administration disability benefit with the resulting cost of US$1.8 billion in disability claims.

Dr. Shannon Westin: Wow. We always think about the impact on the survivor, on their family, but I think it's also really important to look at those other objective data about the impact on society as a whole. Thank you, that was great detail.  

Do we know anything about who might be proportionately more affected by cancer induced physical impairments and disabilities?

Dr. Cao: Actually, this is our key question for our manuscript, but before we developed our hypothesis, we also looked at the data from the general population. So we observed that visual minorities and underserved populations, such as people with lower socioeconomic status and living in the rural area, and also those with unhealthy types of behavior, for example, smoking, obesity, and physical inactivity, are more likely to have physical limitations and disabilities. And also the comorbidity in cancer survival, such as diabetes, cardiovascular disease, also increase the likelihood of physical disability. We also have cancer survivors, particularly for cancer patients who are currently receiving cancer treatment, for example, chemotherapy and radiation therapy, they also are more likely to report side effects from the treatment, also have the reduced physical function. So we also think the cancer patients during the treatment also have a higher likely chance to have physical disability.

Dr. Shannon Westin: Absolutely. That makes sense, and that really dovetails nicely into the objective of your study. We'd love for you to briefly summarize your objective and the methods you employed to achieve that goal. 

Dr. Cao: Yeah, sure. We used the six-year data, 2017 to 2022 from the Behavioral Risk Factor Surveillance System to investigate problems and factors of functional disability in over 47,000 cancer survivors and 2.4 million adults without cancer diagnosis aged 80 years and older. And we specifically focused on two types of functional disability. The first one is mobility disability, which is defined as self reported severe difficulty walking or climbing stairs. And also another one is self care disability, which is defined as self reported difficulty dressing or bathing. And also we examined the factors, for example, social demographic characteristics, lapse of behavior, and health related factors, and some cancer related factors, how these factors related to the functional disability.

Dr. Shannon Westin: Okay, great. So before we get into your findings, I'd love to hear just a little bit more about the BRFSS, the Behavioral Risk Factor Surveillance System. Why did you choose data from this survey for your study? 

Dr. Cao: This is a very key question, because nowadays there are no specific cohort studies for cancer survivors. And also actually, in the population based study, there is no field data specifically for the cancer survivor. But fortunately, in the United States, the CDC conducted several nationally representative surveys to examine the health status of the people living in the United States. So we used the data from the Behavioral Risk Factor Survival System, we also called BRFSS. So BRFSS is a nationwide telephone based survey conducted by the CDC and it collects information on health related risk factors and chronic micro conditions among the US adults aged 80 years or older. And specifically for our papers, because recently, the BRFSS also added a section on the cancer survivorship, which included a lot of the variables on cancer, diagnosed cancer type, and also cancer related factor symptoms, for example, the cancer or cancer treatment related pain. So we used this data to realize our idea. 

Dr. Shannon Westin: Okay, great. So let's start with what you found in regards to the first aspect with mobility disability. 

Dr. Cao: First, we observed the problems of mobility stability are much higher in cancer survivors than non-cancer adults. And also among cancer survivors, more than 25% of cancer survivors reported mobility disability. We also observe the prevalence of mobility disability is much higher in racial minority groups and underserved populations and those with unhealthy behavior and medical conditions.

Dr. Shannon Westin: In addition to the underrepresented minorities, were there any other kind of socioeconomic, demographic factors associated with high prevalence of mobility disability?

Dr. Cao: Yes, the factors like lower level of education, income, being unmarried, and living in non metropolitan areas were associated with higher prevalence of mobility disability. And also, I forgot to mention another factor is cancer related factors. We're also including several cancer related factors such as cancer and cancer related pain. So we also observed a higher prevalence of the mobility disability in people, in cancer survivors with cancer and cancer related pain. We also see the prevalence of the mobility disability is much higher in the patients who are currently receiving the cancer treatment than those who already completed the cancer treatment.

Dr. Shannon Westin: Yeah, that makes a lot of sense. And to that end, with regards to treatment, were there any cancer specific patterns of mobility disability?

Dr. Cao: Yeah, and also, I think this is another strength of our study, because the BRFSS high sample size, which clearly evaluates the mobility disability in over 47,000 cancer survivors,  which allowed us to do the cancer specific part of mobility disability. We observed that the survivors of lung cancer and brain cancer and bone cancer have the highest prevalence of mobility disability. And interestingly, we also observed that the women with cancers also had, for example, ovary, cervical cancer survivors also have higher problems of mobility disability. Probably you know, better than me, and I just tell the data.

Dr. Shannon Westin: Well, it's interesting, I was thinking, it seems like we have a lot, but I have no, obviously, frame of reference with other cancer types. So it's intriguing to me that that's definitely what we see in our clinic. So I'm intrigued to understand more about this. 

But before we get into the next steps and that type of thing, I do want to make sure we touch on that other aspect that you looked at, the self care disability and give the listeners a little bit of an idea of what you found there? 

Dr. Cao: The self care disability is kind of the more severe of the functional disability, which means, we say candidates, lower prevalence compared to the mobility disability, but still the patterns or factors associated with self care disability are much similar with mobility disability. An interesting finding is that in terms of the mobility disability, we find that older survivors are more likely to report mobility disability than younger survivors. In contrast, in terms of the self care disability, younger survivors are more likely to report than the older cancer survivors. 

Dr. Shannon Westin: You've touched a little bit on some of the socioeconomic and demographic factors that were different with self care disability. Was there anything else that really caught your eye? Cancer specific factors or anything else like that?

Dr. Cao: Yeah, besides this, I think also we observe that women are more likely to report self care disability. I think also this is driven by the cancer specific, particularly the woman cancers have a higher prevalence of the self care disability.

Dr. Shannon Westin: Well, it's definitely something for me to take back to my clinic. Now that you've covered all these results, how are your data compared to existing literature in this area? 

Dr. Cao: Yeah, we have tended to do comprehensive literature reviews. When we discuss our results and compare it with existing literature, our result is quite aligned with previous literature and particularly we clearly see the racial ethnic minority have a higher prevalence of physical limitation and physical function decline. But our paper focused on the physical disability which is much more severe than the physical function. And also we also looked at another study conducted in Australia, we quite find very similar results even for cancer specific patterns of the functional disability. 

Dr. Shannon Westin: I guess the next question I have is was there anything that surprised you about your results? 

Dr. Cao: I just mentioned that what surprised me the most is that the older people are more likely to report the mobility disability, but the younger people are more likely to report self care disability. Our data don't support or explore why this happened and what's the etiology behind this. But our hypothesis is that the younger cancer survivor, younger cancer patients are more likely to receive the aggressive treatment that can play a significant role in the functional outcome. 

Dr. Shannon Westin: Yeah, it sounds like that's definitely an area of unmet need for more research. But I like your hypothesis. I do wonder if that's somewhat related.  

And I guess that leads us to our final question. What are your next steps and how can I potentially use this in practice? How can our listeners employ these findings in their practice? What do you recommend?

Dr. Cao: I think our findings highlight the importance of screening for functional limitations at the baseline and throughout the cancer treatment and even the cancer survivorship. Oncology providers also should encourage patients to be physically active. And also American Society of Clinical Oncology and also American College of Sports Medicine recommend that regular exercise during the treatment can help cancer patients preserve their fitness and reduce the incidence and the severity of the cancer related disability. And also providers can provide referral to rehabilitation services and support groups for additional care. 

For the next step, our finding highlights the importance of developing ways to limit the long term side effects of cancer treatment both during and after treatment to preserve fixed function and prevent disability. Particularly, target intervention should in particular address special needs in vulnerable populations, including the racial ethnic minorities and those living in the rural areas to improve their quality of life during a long term survivorship. And also due to the advance in the technologies, now we want to see whether wearable sensors, wearable devices can be a novel tool to monitor their physical functions during the treatment because better monitors can lead into their better treatment and their prevention.

Dr. Shannon Westin: That's great. Yeah, what a great way to end. I think that exercise clearly is key not only for preventing these issues, but also we know that it potentially can even improve response to therapy and recurrence free survival. So I think lots of reasons to be focusing on physical activity in our clinics and ensuring our patients and our cancer survivors are really participating in those types of activities. 

Well, Dr. Cao, it was such a pleasure. I cannot believe you are only a research fellow. I can't wait to see where your career takes you. Congratulations on this great work.

Dr. Cao: Thank you. Thank you for this great opportunity to share my work and I look forward for my future work in the field.

Dr. Shannon Westin: Oh, yeah. So you guys, if you're looking for somebody to come and push the boundaries of functional disability and activity, you know where to look. 

And again, thank you all our listeners for tuning in to another episode of JCO After Hours. Again, we were discussing, "The Prevalence and Cancer Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022." Original research published in the JCO, April 4th, 2024. So if you're looking for more podcast offerings, check out other JCO After Hours offerings wherever you get your podcasts. Have an awesome day.