ASCO Daily News

Drs. Hope Rugo, Diana Lam, Sheri Shen, and Mitchell Elliott discuss key strategies and emerging technology in early-stage breast cancer survivorship, including mitigating risk through lifestyle modification, surveillance for distant recurrence, and optimization of breast imaging. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. I'm also an associate editor of the ASCO Educational Book. There are currently about 4 million breast cancer survivors in the United States, according to the American Cancer Society, and this number is expected to rise as more women are being diagnosed at early stages of this disease, thanks to advances in early detection and the delivery of more effective adjuvant and neoadjuvant treatment leading to successful outcomes. In today's episode, we'll be discussing current and emerging clinical strategies for the survivorship period, focusing on a multidisciplinary approach. Joining me for this discussion are Drs. Mitchell Elliott, Sherry Shen, and Diana Lam, who co-authored, along with others, a recently published article in the 2024 ASCO Educational Book titled, "Enhancing Early-Stage Breast Cancer Survivorship: Evidence-Based Strategies, Surveillance Testing, and Imaging Guidelines." They also addressed this topic in an Education Session presented at the recent ASCO Annual Meeting. Dr. Elliott is a drug development fellow and clinician scientist trainee at the Princess Margaret Cancer Center in Toronto, Canada. Dr. Sherry Shen is a breast oncologist and assistant attending at the Memorial Sloan Kettering Cancer Center in New York. Dr. Diana Lam is a breast radiologist and associate professor at the University of Washington Fred Hutchinson Cancer Center in Seattle. Our full disclosures are available in the transcript of this episode. It's great to have you all on the podcast today. Thank you for being here. Dr. Mitchell Elliott: Thank you so much. Dr. Sherry Shen: Thank you. Dr. Hope Rugo: Let's go into the meat of the article now and try to provide some interesting answers to questions that I think come up for clinicians all the time in practice. Your article points out that addressing the challenges in early-stage breast cancer survivorship requires a comprehensive, patient-centered approach, focusing on mitigating risk through lifestyle modification, surveillance for distant recurrence, and optimization of breast imaging. Dr. Shen, surveillance can facilitate the early detection of recurrence, but ultimately the goal is to prevent recurrence. Lifestyle modifications are a key component of survivorship care, and there are many interventions in this context. Could you summarize the best approaches for mitigating risk of breast cancer recurrence through lifestyle modification and how we might accomplish that in clinical practice? Dr. Sherry Shen: Absolutely. This is a question that we get asked a lot by our breast cancer patients who are so interested in what changes they can make within their lifestyle to improve their breast cancer outcomes. I always tell them that there are three main things, three main lifestyle factors that can improve their breast cancer outcomes. Firstly, enough physical activity. So the threshold for physical activity seems to be around 150 minutes of a moderately vigorous level per week. So moderately vigorous means something that gets the heart rate up, like walking quickly on rolling hills, for example. Or patients can do a vigorous level of physical activity for at least 75 minutes per week. Vigorous meaning playing a sport, swimming, for example, running, something that really gets the heart rate up. The second really important lifestyle modification is limiting alcohol use. Keeping alcohol to less than 4 to 7 drinks per week is particularly important for breast cancer outcomes, especially in women who are postmenopausal and have hormone receptor positive diseases. That's where the strongest connection is seen. Lastly, maintaining a healthy weight. We know that women who gain more than 5% to 10% of their diagnosis body weight have a higher risk of breast cancer recurrence and worse breast cancer outcomes. That, of course, is easier said than done, and it's primarily through dietary modifications. I always tell women that in terms of specific things in the diet, it's really hard to study at a population level because diets vary so much between patients. But what is really important is consuming a plant-forward whole foods diet that prioritizes nutrients and the quality of the diet. A little bit more specifically, it's important to limit the amount of red and processed meats in the diet, really limit the amount of sugar sweetened beverages, ideally to cut that out of the diet entirely, and to consume an appropriate amount of dietary fiber in the range of 20 to 30 grams per day. Those are more specific things that have been associated with breast cancer outcomes. Dr. Hope Rugo: This is such helpful, practical information for clinicians and for patients. Thank you. But let's move on to another area, surveillance testing for distant recurrence, an area of great interest, in fact highlighted in a special session at ASCO 2024. In clinic, we've seen that many cancer survivors expressed surprise at the less intensive approach to surveillance testing for recurrence, with the whole idea that if you detected it earlier, the outcome would be better. But it does raise an important question. What is the optimal strategy for monitoring for recurrence? And importantly, can early detection through surveillance testing impact outcome? Dr. Elliott, your research has focused on ctDNA surveillance and the evolving role of minimal residual disease, or MRD. Can you comment on the current surveillance guidelines for distant recurrence, and then, how we really define true MRD? Dr. Mitchell Elliott: Those are excellent questions, and I think leaving that Education Session at ASCO left us with even more questions than answers with the current role of MRD in this setting. I think a lot of this comes from wanting to help patients and trying to identify the patients at highest risk of cancer recurrence, with the goal of intervening with effective targeted therapy to prevent metastatic relapse. Current international guidelines in the United States done by ASCO and the NCCN, as well as ESMO guidelines in Europe and even our local Canadian guidelines, do not suggest that patients undergo routine screening in asymptomatic individuals, whether it be blood work or routine radiographic imaging, as there were some studies that were done in the late 1990s and early 2000s that didn't actually show benefit and actually maybe favored a little bit of harm in these situations. So these recommendations are based on these initial studies. However, we know that in the last 10, 15 years, even 20 years, that breast cancer and the landscape of breast cancer has changed significantly with the introduction of our typical standard classification of breast cancer, the emergence of HER2 positive breast cancer, and thus triple negative breast cancer, which was not actually routine standard testing at the time of these studies, and also the most effective therapies we have to date, including immunotherapy, HER2 targeted therapy and the advent of antibody drug conjugates. We're at prime time right now to potentially revisit this question, but the question is, do we have the right technology to do so? And this is where the circulating tumor DNA has really emerged as a potential option, given its minimally invasive opportunity with a standard blood test to actually identify tumor specific DNA that is highly predictive of distant metastatic recurrence or patient recurrence in general. The evolving role – we still have a lot of questions in this setting. There have been a lot of retrospective analyses of cohort studies and clinical trials that have shown that modern fit for purpose MRD based tests actually have a high positive predictive value at identifying patients with imminent risk of breast cancer recurrence. The most important thing in this setting is that there are different fit for purpose tests. The initial ctDNA assays were actually genotyping based assays, which look for the presence of mutations in the blood. But we know that the sensitivity of these assays is quite challenging at the level of ctDNA required to actually diagnose patients with very small amounts of residual disease. So the fit for purpose MRD assays are now emerging on the market. And we have several that are in clinical development, several that are in research development, but the high specificity in the setting is very important, which we're seeing some evolving and emerging technologies in this setting. We really don't have the data about if these interventions, so if we were to effectively deploy these MRD based ctDNA assays prospectively in patients, if they will actually improve patient outcomes, and how do we correct and address lead time bias, which might potentially affect study results? Also, the important thing to think about in this setting is if we are able to find something, we also should have an effective therapy to actually intervene for patients, because the outcome in these trials will actually be dependent not only on identifying early breast cancer occurrence, but also delivering the best targeted intervention for that individual patient, which currently we don't understand fully. Another really interesting thing is there was a trial, the ZEST trial, as many of our listeners may know, that was randomizing patients with patients with ctDNA detected in the adjuvant setting were randomized through either intervention or standard follow up. And going forward, is it actually an opportunity, or is it possible to actually randomize patients knowing that they have a near 100% likelihood of breast cancer recurrence to observation? So these are several ongoing questions that we have to address as we move forward to deploying this technology in the clinical space. Dr. Hope Rugo: Really fascinating, and thanks for sharing that. I think really broad and helpful information on these ctDNA [assays] and also our surveillance guidelines, which I think really suggests that you only do surveillance for cause, other than looking for local recurrence and new cancers with breast imaging. So it is really an interesting time where we're seeing evolving technologies and evolving understanding of how we can best do this kind of testing when there are so many different assays out there. I think it's going to take a little while. And also understanding, as you pointed out, trying to target treatments when patients have emerging ctDNA to mutations. And we just have no idea yet if we're going to ultimately change outcomes. This is really helpful, and I think we'll give people a good understanding of where to think about this right now, what to look for in the future. Now, of course, it's a nice segue into the idea of breast imaging for early breast cancer survivors because that's where we do have data. Dr. Lam, let's talk about how we optimize breast imaging in early-stage breast cancer survivors, because there's such a wide variation in breast cancer imaging survival protocols between different centers and different countries. And of course, here our group is representing two countries and really a broad geographic area. So some of the variations are when to do imaging in terms of frequency, when to start imaging and what kind of examination to do, screening versus diagnostic, MRI versus mammogram. And of course, there are some emerging imaging techniques as well. Could you tell us a little bit about the variation in imaging surveillance protocols in survivors, and the challenges and what you recommend? Dr. Diana Lam: First off, I want to say that surveillance mammography saves lives and annual intervals are uniformly recommended among both national and international guidelines. However, we know that in practice there are variations in imaging surveillance protocols, with approximately 40% of sites performing imaging at more frequent or six-month intervals for at least one to two years. In addition, there's variation in what type of mammogram someone gets in terms of the indication. They might be getting initial diagnostic mammograms for a short period of time or screening mammograms. However, overall, there is limited evidence in improved outcomes in women getting a diagnostic versus a screening exam for asymptomatic surveillance. In addition, there is limited evidence in increased frequency of surveillance, for example, every six months versus one year. The real difference between a screen and a diagnostic mammogram, if someone is asymptomatic in the surveillance population, primarily has to do with workflow. For screening examinations, the imaging is generally viewed after a patient leaves the facility, and it might actually take days, maybe even weeks, for the results to be delivered to the patient. In addition, if more imaging is needed, the patient will need to return back to the facility, which does diagnostic imaging work for us to work up this finding. And this practice approach causes diagnostic delays in care. It also disproportionately affects Black and Hispanic women. For diagnostic mammography surveillance, there's generally real time interpretation with immediate results. However, there are both access and scheduling limitations, as not all facilities actually perform these types of examinations. There may also be out of pocket costs which are increased due to the diagnostic indication of this exam. So what we found, which is an approach that can aid in minimizing patient costs and decreasing these health disparities, is to provide immediate interpretations of these screening mammography surveillance exams, or so-called online screens where diagnostic workup and potential biopsy can be performed on the same day. Dr. Hope Rugo: This is all very interesting, but what do we tell our patients? How do we, as oncologists, decide on how frequently to get mammograms? Should we be getting diagnostic or screening? And do we sequence MRI with mammograms for everybody or just for certain patients? And then some patients will say, "Well, my doctor does an ultrasound to mammogram." We don't do that for screening. When do you recommend that? Dr. Diana Lam: We do know that compared to people without a personal history of breast cancer, surveillance mammography is actually less sensitive. It's only about 70% versus 87% or so percent sensitive with over four times more interval cancers or cancers diagnosed after a negative surveillance mammogram compared to the general screening population without a personal history of breast cancer. In addition, about 35% of invasive second breast cancers are actually interval cancers or those not detected by surveillance mammography. However, there is currently no guideline consensus on supplemental breast imaging or additional imaging beyond surveillance mammography. Contrast-enhanced breast MRI is most often recommended, particularly for patients who are already at high risk for breast cancer, such as those with genetic mutations, or patients who have had primary breast cancer diagnosed at a younger age to less than 50 years old, or those patients who have dense breast tissue on mammography. There is a question about whole breast ultrasound and this is generally not specified or recommended unless the patient is unable to undergo breast MRI. This is primarily due to the number of false positive examinations or findings that are seen that do not amount to breast cancer. We do have the opportunity here to tailor surveillance imaging by selecting people who are at high risk for interval second breast cancers in order to decrease harms and improve patient outcomes. We know that there are a number of factors such as primary breast cancer subtype which affects second breast cancer risk. We know that women who have ER negative and/or hormonal negative breast cancers have significantly higher recurrence rates within the five years of treatment with no significant difference after that 5 years. We also know that there are certain factors such as imaging factors where patients are more likely to develop an interval second cancer with mammography surveillance only. And these are factors such as if their primary breast cancer was hormone negative, if they had an interval presentation to start, or if they had breast conservation without radiation therapy. So, in terms of the future of local breast imaging surveillance, this can be improved with upfront risk prediction and stratification based on the patient, primary breast cancer and treatment factors, as well as looking at imaging test performance to optimally guide the modality and frequency of surveillance imaging. Dr. Hope Rugo: Really interesting. Well, thank you all three of you for sharing your valuable insights. This has been so interesting and a great addition to the ASCO Daily News Podcast. I would encourage everyone to actually read the article as well because there's some really great tables and interesting information there that of course we don't have time to cover, but thank you, all three of you. Dr. Diana Lam: Thank you. Dr. Mitchell Elliott: Thank you for having us. Dr. Hope Rugo: And thank you to our listeners for joining us today. You'll find a link to the article that you can read and look at and cut out the tables discussed today in the transcript of this episode. I encourage all of our listeners also to check out the 2024 ASCO Educational Book where there is an incredible wealth of useful information. Finally, if you value the insights that you've heard today and here on ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thanks again. Disclaimer: 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 opinion of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Follow today's speakers: Dr. Hope Rugo @hoperugo @MitchElliott18 Dr. Sherry Shen @SherryShenMD Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Hope Rugo: Honoraria: Mylan/Viatris, Chugai Pharma Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Sanofi Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Merck, Daiichi Sankyo, AstraZeneca, Gilead Sciences, Hoffmann-LaRoche AG/Genentech, Inc., Stemline Therapeutics, Ambryx Dr. Diana Lam: No relationships to disclose Dr. Sherry Shen: Honoraria: MJH Life Sciences Research Funding (Inst.): Merck, Sermonix Pharmaceuticals Dr. Mitchell Elliott: No relationships to disclose

Dr. Nathan Pennell and Dr. Christopher Booth discuss Common Sense Oncology, a global initiative that aims to advance patient-centered, equitable care and improve access to treatments that provide meaningful outcomes. TRANSCRIPT Dr. Nate Pennell: Hello. I'm Dr. Nate Pennell, your guest host today for the ASCO Daily News Podcast. I'm the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research at the Taussig Cancer Center, and I also serve as the editor-in-chief of the ASCO Educational Book. My guest today is Dr. Christopher Booth, a professor of oncology and health sciences at Queen's University in Kingston, Ontario, where he also serves as the director of the Division of Cancer Care and Epidemiology. He joins me today to discuss his recently published article in the 2024 ASCO Educational Book titled, "Common Sense Oncology: Equity, Value, and Outcomes that Matter." Dr. Booth also addressed this topic during a joint ASCO/European Cancer Organization session at the 2024 ASCO Annual Meeting. Dr. Booth, welcome. Thanks for joining me. Dr. Christopher Booth: Thanks for inviting me here, and I look forward to our conversation. Dr. Nate Pennell: In your article in the Educational Book, and again, thank you so much to you and your co-authors for writing that for us, and during your presentation at the ASCO Annual Meeting, I think your topic really resonated with a lot of people. You explained that the essence of oncology is delivering compassionate care, and I really was struck by the statement, "the treatments need to provide meaningful care, meaningful improvements in outcomes that matter regardless of where the patients live." Can you just tell us what exactly is Common Sense Oncology? What's your vision for what it can do to help address some of our growing challenges today? Dr. Christopher Booth: Thanks, Nate. So, the Common Sense Oncology initiative was launched just over a year ago, and it really was a grassroots gathering of clinicians, policymakers, academics, as well as patients and patient advocates who recognize that there's many things we do well in the current cancer care system, but there's also areas that we can improve. And so it was created as a space for us to advocate for greater access for the things that we know really help people, but also to create a space where we can be willing to have some tough conversations and some humility and look within our field at some of the things that maybe aren't working as well as they should, and try to be constructive and not just be critics of the system, but actually be solution-focused and to try to move things forward. The Common Sense Oncology initiative, which has really taken off over the last year, really brings together people from all health systems who care deeply about people and their families who are with cancer. And our mission is that cancer care systems deliver treatments that have outcomes that matter to patients. And the vision is that, as you stated in your introduction, regardless of where someone lives, they have access to those cancer treatments which really do make a difference in their lives. Dr. Nate Pennell: That certainly sounds like something everyone should be behind. Before we talk about some of what Common Sense Oncology may be doing to help address some of the inequities in cancer care, one of the challenges that is addressed in your paper is the focus on modern clinical trials and perhaps some of the mistakes that we're making in how they are designed. In many ways, we sort of live in a golden age of clinical trials with biomarker driven treatments, which can be incredibly effective in small populations of people, sometimes at great expense. So, focusing on our modern clinical trials, some of the criticisms that have arisen are that perhaps the endpoints that are being designed really aren't ones that are meaningful for patients, or that the gains that they're trying to look for in these trials may not be particularly meaningful. So, talk a little bit about that, if you might. Dr. Christopher Booth One day, I might write a book called Paradoxes in Cancer Care. But there's a number of these things I think about. I'll start, Nate, in response to your question by talking about something I think of called the 'three buckets paradox.' The three buckets paradox, I think, reflects a communication failure on the part of our field whereby if a patient or member of the public only reads the newspapers about cancer, they might wonder why we even have cancer hospitals and why Dr. Pennell and Dr. Booth even have a job, because everything we're doing is curing cancer. But we know the reality is different. And so, I conceptualize cancer treatments as going into three different buckets. We have the red bucket, which are those treatments, which really are transformational, and I've been working in oncology for 20 years now and we've seen a number of these treatments. They markedly increase cure rates or help people live for many, many months or extra years of life. And we have those treatments; they're almost out of a science fiction movie. The green bucket is a series of treatments. They're not perhaps transformational, but they're very, very good. They offer substantial benefits to our patients, and we have quite a few of those. The concern that I think many of us recognize, and just to state emphatically that the problems that CSO is thinking about are not new problems; I think every oncologist has struggled with these things throughout each of our own careers. The concern is the third bucket, which includes many of our newer treatments, some of which, of course, are transformational. But many of the new treatments fall into this bucket, which have important side effects. They have major financial toxicity for patients' families and the system. They have time toxicity, especially in the last year of life. And the reality is most of these new treatments, either there's no proven benefit they help people live longer or better lives, or if they do, it's measured in a number of weeks. I think we need to reconcile the fact that we need to maybe speak honestly about some of the challenges in our field to recognize there's probably too many treatments going into that last bucket, and we need to push harder in the research ecosystem and the policy space to ensure we have more treatments in the first two buckets and that they remain widely available to everyone. So, to get to the specific issues you raised in your question, Nate, some of the effect sizes and the endpoints we're choosing are problematic, I think. We have many, many examples of incredible clinical trials and new treatments that really make a difference for the lives of our patients. I want to state emphatically that the RCT remains the best tool we have to identify new treatments for patients of tomorrow, and any challenges with clinical trials, actually, it's not the fault of the RCT; these are self-inflicted by us who design, interpret, and act on clinical trials. And so the use of surrogate endpoints is a major issue in our field. And I just want to also state emphatically that there are circumstances where surrogate endpoints make a lot of sense and we should be using them. The problem is, I think with our excitement to get treatment answers more quickly, we've really embraced surrogate endpoints in a very, very rapid way. And in fact, I shouldn't even refer to them as surrogate endpoints. Maybe we should use the term alternative endpoints because in many cases they have been found to not be valid surrogates for those things which we know matter to patients: overall survival and quality of life. So certainly, there's a place for surrogate endpoints. I think we live in an era now where the majority of clinical trials are being designed to detect improvements in progression-free survival rather than overall survival. So historically, most clinical trials were being launched to see if we could help people live longer or feel better. Now, the default endpoint is progression-free survival, which largely is based on tumor measurements on a CAT scan. And certainly, there are circumstances where those tumor measurements do relate to how someone feels or how long they live, but in most circumstances, that's not the case. I think we need to take a step back and just see the big picture here about where it is that we're going, and how can we raise the bar and ensure that we're identifying treatments that really offer meaningful gains to patients. Because we have to be honest about the fact that the patients and families are the ones who need to live through the side effects, the time toxicity and financial toxicity of these treatments. So, this is about maybe raising the bar and aiming a bit higher than we currently are. Dr. Nate Pennell: And it looks like CSO basically is putting together teams around evidence generation, evidence interpretation and evidence communication that I guess, is trying to advocate and influence this? Dr. Christopher Booth: Yeah. So, when we launched this initiative, which now is this large global coalition of people, we wanted it to be really solution focused. So, our workstream is oriented around trying to improve how we generate evidence, how we interpret evidence, and how we communicate evidence. So, the evidence generation workstream is being led by a series of leading clinical trialists from all over the world, together with patients and patient advocates who are looking at how we can come up with a framework and principles to design, perhaps a more thoughtful approach to the design, reporting, and conduct of clinical trials. So that's kind of a clinical trials workstream. And I should mention all of these project teams are populated by clinicians, academics, members of the public, as well as patient and patient advocates who, in some cases, are co-leaders of the workstreams. The evidence interpretation workstream is an educational bucket being led by clinicians and educators, together with patients, to see how we can improve the skill set of the next generation of oncologists to be better equipped in skills and epidemiology, critical appraisal, and critical thinking, so we can better dissect trials which have been well designed from those which might have some limitations, identify those treatments which have very substantial gains from those which are perhaps more marginal. And then the third workstream relates to how we communicate evidence. And this is communication broadly, how we talk about these very complex and nuanced issues at the bedside between oncologist and patient. But how we talk more broadly in society, through the media, with public and policy makers, about some of the challenges in cancer care, recognizing, of course, that no one individual, group or person is going to have the answer for what treatments matter for any specific patient. This is going to vary by every patient with their unique values, preferences and goals in life. But we think we can do a better job of talking about these issues and empowering patients to have the information they need so they can make the treatments that match their own goals and wishes. Dr. Nate Pennell: Oh, thank you. Another thing that I was interested in in your paper, and when we talk about value and whether these endpoints that are being released for drugs that become approved are meaningful to patients, the other aspect of value is, of course, the cost. And we know that basically every new drug that gets approved, just an astronomical cost these days, which doesn't often factor into whether to approve them. It doesn't often factor into a doctor's decision about whether to use them. Can you talk a little bit about this? And is cost of drugs something that CSO is interested in addressing, or is that more of just a part of the equation in determining value of these? Dr. Christopher Booth: No, I think it's a really important point. So the value construct, I'm not an economist, so I think about this as a simple Canadian chemotherapy doctor would, which is the interface of what you get - so the magnitude of benefits, that's the endpoint, and the effect size - relative to the downsides, the cost, the clinical toxicity, time toxicity, and financial toxicity. So historically, I mean, I think, Nate, you and I will remember maybe 10 or 15 years ago when this really came on the scene, all the conversations focused on the denominator, the cost of cancer medicines, which became astronomical over the last 10 or 20 years. And we've learned a few things about that over time, and I'll get to that in a moment in reference to your question. But I think as individual clinicians or investigators, or even people writing guidelines, we don't have a lot of ability to influence the price of cancer medicines, although I think we still need to speak out about these prices, which are largely unjustified. I'll come back to that. But where I think there's growing interest, and we've seen this in the last five years, is the numerator in that value construct, which is the magnitude of benefit, the endpoint, the effect size. And I think that's where we actually have much more ability to influence. We are the doctors who make treatment recommendations, the experts who write guidelines, the investigators who design trials and so I think we need to take a bit more ownership when it comes to this magnitude of benefit construct. And that's where a lot of the work that Common Sense Oncology is doing rests. But to answer your question about cost, this is a major problem. We've known that it's been shown by several groups that the price of a cancer medicine is not justified by the R and D cost, that's been shown over time. We also have a problem where the magnitude of benefit offered by that drug also has no bearing to the price. And so this speaks to the need to really, I think, undertake more rigorous health technology assessment and think very carefully about- you know every other economic model that you and I live in, Nate, if, you know, if we have a growing family, we need a larger apartment or house, we spend more money, we get a bigger house. If we want to keep up with our kids on their fast bicycles, we spend more money, we get a better bicycle. And when it comes to cancer medicines, we found that not only is there no relationship between how well the drug works and its price, our group and others have found, if anything, there's an inverse relationship, whereby the drugs with the smallest benefit have the largest price tag. And I don't think you need a PhD in economics to know that is an incredibly broken system. So, I think there's a lot that we need to talk about when it comes to cost. Common Sense Oncology cares deeply about this because it's a huge issue about health justice and global equity and access to cancer medicines. And I think we need to work on that. But we also can't forget about the numerator, which is, to what extent do these treatments help people? Dr. Nate Pennell: I know that every time I see one of these fabulous new presentations at ASCO Plenary or something like that, I just imagine many of the doctors and patients who live outside the U.S., maybe in low- and middle-income countries, who don't have the same access to basic oncology care and specialty oncology care that we do in Western countries, and what goes through their minds when they think about this. And so, I know that this is another big part of what CSO is doing, is thinking about global equity and access to cancer care. And so, can you tell me a little bit about how you're hoping to address that? Dr. Christopher Booth: Yeah. And so, you're right. I guess I'll tell you another Booth cancer paradox. I call this the cancer medicine paradox, which is, on the one hand, in many health systems, I think we'll recognize that there's often overutilization of cancer medicines that are toxic, expensive, and small benefits, especially in the last year of life. So, we have that kind of overutilization paradigm in some parts of the world, but we also have this paradox where we have massive underutilization of those treatments that we know actually have large benefits. And the tragic part of this is many of those treatments are old, generic drugs that actually should be very affordable. Some of this work comes out of myself and a number of my founding colleagues of Common Sense Oncology have a policy role with the World Health Organization Essential Medicine list. My interest in this started, I guess, many years ago when I had a sabbatical in India and lived and worked at a large government cancer hospital for a period of time. And so, from this WHO working group, we launched a project. It's been called the Desert Island study. It was called the Desert Island Project for reasons I'll tell you in a moment. But essentially it was a survey of 1,000 oncologists on the frontlines of care in 82 countries worldwide. And what we are interested in doing is in our role as an advisory group to the WHO Essential Medicine List, we come up with a list of those medicines which are really most important and should be provided in all health systems. And we were interested in going to the frontlines of care, leaving the boardroom of Geneva, and going to the frontlines of care and asking real doctors in the real world, "What medicines do you think are the most important for the patients that you look after?" So, it was a survey. We asked a lot of demographic questions about their clinical practice and their health system, but we called it the Desert Island Project, because the core question of the survey was based on the thought experiment that you and I have done many times with friends at dinner parties. For example, if you're moving to a desert island and you could only take three books, what would those books be? If you're going to have dinner with any famous podcast host in the world other than Dr. Pennell, who would that person be? And so the thought experiment was, imagine your government has put you in charge of cancer care for your country. You can choose any cancer medicines you want that will be freely available for all cancers and all people in your country. Cost is not an issue, but you can only choose 10. You can only choose 10 of those medicines to take to the desert island to look after all the people in your country, what would those medicines be? And it's amazing; of those thousand oncologists, we found, first of all, remarkable convergence between doctors, regardless of where they work, whether it was a high-income country, middle-income country, lower-income country, the doctors were very pragmatic. When we looked at the drugs that went in that suitcase over and over again, the most common drugs were the good old fashioned cytotoxic chemotherapy drugs and hormone drugs we've been using for 20 or 30 years that we know have very, very large benefits, and in the modern era now should be very affordable because they've been off patent for many years. In that list of medicines that went to the desert island, there also were some of our newer drugs that are new and they're very expensive. But they are those drugs that have very large benefits. And, of course, all of us would want access to those for our patients. So we found that the doctors are pretty pragmatic about which medicines if they're pushed to offer the largest benefit. But the next part of the question was, okay, you've told us which medicines you want to put in your suitcase to take to the desert island, please now tell us the reality in your health system to what extent can you deliver these medicines? And it was shocking. The vast majority of oncologists, a huge number of them, said they could not even provide doxorubicin or cisplatin without causing major financial toxicity for that patient and family. Even for trastuzumab, now available as a biosimilar, only 15% of oncologists globally said they could provide it universally to all women with breast cancer. Two thirds of oncologists said, "Look, I can give it, but I will catastrophically ruin that patient's family's finances for generations to come." So, we have a big problem in the sense that we need to focus on those treatments which make a big difference and ensure that they're available to all patients who could benefit, while at the same time raise the bar so that the modern treatments that we're offering also have large benefits. Dr. Nate Pennell: I think that's really eye opening, and I hope lots of people take away from this, that this is the reality for a huge number, potentially billions of people on the planet that don't have easy access to the same kinds of drugs. We're not even necessarily talking about the expensive drugs with the three-week DFS benefit, but ones that actually could be curing them of their breast cancer and their testicular cancer and their lymphomas, and they can't even get access to those, even though here we might say that they're inexpensive and relatively accessible. So how do we fix that? Maybe this is too big a question for a few minutes in a podcast, but I'm curious to see what CSO is doing to try to help. Dr. Christopher Booth: Well, the challenges are substantial, and so that's why we've kind of created this group, because it's going to require kind of collective input, I think, of everyone in our field and beyond. And I also think, one of the reasons we've been overwhelmed with interest by the next generation, the young, the trainees, the young oncologists who are very interested in this, and I think they're recognizing that this might be an alternative place for them to put their energy, talent, as they build their own academic careers, is tackling some of these really, really tricky problems where the solutions are not immediately obvious. One thing I think, Nate, that's important is for us to talk about these things and recognize that there's a range of cancer treatments, and that this might help set better expectations for the patients and families when they walk into our cancer centers, let alone in the U.S. and Canada, but also globally. We've seen challenges with all of us as human beings are technophiles, we're drawn towards the new shiny targeted therapy or a robot or treatment in cancer care, and we've seen that play out somewhat tragically. Some of my friends and colleagues in LMICs have told stories where the Minister of Health is about to make a major investment in cancer care, but they want the shiny new monoclonal antibody, because that's perceived as being newer and better, when the reality is that that might add two months of PFS compared to other agents that are much, much- have much larger benefits and, of course, are much more affordable. And there's modeling where even just one of these new medicines, for one cancer, would wipe out the entire cancer medicine budget for that country. Yet we don't have tamoxifen, doxorubicin, cisplatin or even morphine for palliative care available. So, some of this is about socializing these issues, talking about these things that, again, these are not new problems. I think every oncologist worldwide has wrestled with these things, but just at least creating a space where we can talk honestly about this and work towards solutions. Dr. Nate Pennell: Yeah, I think even just having the framework and the awareness and getting people involved is going to make a big difference. And of course, the people who ultimately are impacted the most by this are the patients with cancer. One of the big aspects in your paper is talking about how patients and patient advocates are central to the CSO movement. So, tell me a little bit about how they became involved and what role they play in CSO. Dr. Christopher Booth: Yeah, so this has been a very intentional and deliberate part of the building of the Common Sense Oncology initiative. So this started with a planning meeting of- a very small planning meeting of 30 people in Kingston, here at Queen's University just over a year ago, with 30 people from 15 different countries, a mix of academics, clinicians, editors, and in that room were five or six patients and patient advocates from day 1, because we wanted to make sure that this is really all about their needs and creating a system that revolves around the outcomes that matter to patients and families. So since then, we've continued to engage broadly. We have a patient priorities project team. There's co-leadership there. One is a colleague and oncologist from New Zealand, but the other co-leader is a patient advocate from- a breast cancer patient advocate from the United States. And all of our project teams have patients and patient advocates as part of their membership. The Patient Priorities Team is working to design a patient charter to guide the design and implementation of clinical trials from the patient's perspective. And as part of that exercise we've been undertaking, we call the CSO speaking and listening tour, where we've had a series of webinars with patient advocacy groups from all over the world, where part of the webinar is us talking about the CSO mission vision, workstream and some of the challenges and solutions we see so that we can provide some education, but also get honest feedback from the front lines to learn kind of where we might be off, what we might be missing, what we should focus on. But then also, the second part of the webinar is about sharing this kind of draft patient charter and getting more broad input from patients and families about what it is they're looking for in a cancer system. And I can tell you that some of the most gratifying correspondence I've had since launching CSO, which has been essentially become my third full time job, is letters from patients and family members of former patients who have since deceased or active patients on treatment, who are saying how much they appreciate this work and how much they feel that oncology can perhaps do a better job talking about some of these things. And they've been giving us some very good ideas and suggestions that, in fact, I'm already incorporating into my clinical practice, because ultimately all of us came into this field to help people with cancer, and I think they can and should and are remaining the center of everything. Dr. Nate Pennell: I think, thankfully, that is a movement throughout medicine, certainly cancer medicine, that patients are becoming more involved much earlier in the process of designing trials. And hopefully that alone will help change the endpoints that we're building into these studies to make them much more meaningful. So, people are going to read your paper, they're going to get excited, they're going to listen to this podcast, they're going to get even more excited about how they're going to change the world through a little more common sense. So how can they get involved? Is this something that you're open to people working with you? Are there other things people can do to try to help solve some of these frustrating problems? Dr. Christopher Booth: Yeah, absolutely, Nate. So, we have a website at commonsenseoncology.org. Some of our co-leaders are very active on social media, so they can follow us through social media channels. If you go to our website, there is a membership button where people can join. There's no fee and we won't bombard you with too many emails. But what that has allowed us to do is build this network of people who have diverse interests and skill sets that we can then tap into various projects and workstreams where we could use the help and support. And members have access to things like virtual webinars, journal clubs, critical appraisal sessions, and they get a newsletter from us every two or three months about activities and about ideas and allow exchange of dialogue going back and forth. So certainly, we look forward to growing this initiative, and the challenges are large, but we think that with the collective input of stakeholders from around the world, we could make a difference in moving towards some solutions. Dr. Nate Pennell: And for our listeners, that is commonsenseoncology.org. You can go check this out and join if you are interested in learning more. Chris, thanks so much for sharing your insights and for all of your work on addressing these complex challenges in cancer care. Dr. Christopher Booth: Thanks, Nate. Grateful for the interview and also for ASCO for giving us the opportunity in the Educational Book and at the Annual Meeting to talk about this work. Dr. Nate Pennell: Thank you. And I also want to thank our listeners for joining us today. You'll find links to the article discussed today, as well as Dr. Booth's presentation at the Annual Meeting, in the transcript of the episode. Finally, if you value the insights that you heard on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: 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. Find out more about today's speakers: Dr. Nathan Pennell @n8pennell Dr. Christopher Booth Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Nathan Pennell: Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi Dr. Christopher Booth: No relationships to disclose

Dr. Pedro Barata and Dr. Lillian Siu discuss recent advances in cancer vaccines and biomarkers, including the potential of the neoantigen and immune modulatory vaccines and the challenges surrounding cancer vaccine development. TRANSCRIPT Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata, your guest host for the ASCO Daily News Podcast today. I'm a GU medical oncologist at the University Hospitals Seidman Cancer Center in Cleveland, Ohio, and an associate professor of medicine at Case Western Reserve University School of Medicine. I'm also an associate editor of the ASCO Educational Book. And today we'll be discussing a timely article that was recently published in the Educational Book titled, "State-Of-The-Art Advancements on Cancer Vaccines and Biomarkers." I'm delighted to welcome one of the article's co-authors and a world-renowned oncologist, Dr. Lillian Siu. She is a senior medical oncologist and director of the Phase 1 Program at the Princess Margaret Cancer Center and a professor of medicine at the University of Toronto. Welcome, Dr. Siu. Dr. Lillian Siu: Thank you, Dr. Barata; it's great to be here. Dr. Pedro Barata: Wonderful. Dr. Siu will discuss new tools for cancer vaccine development, strategies for combating the immunosuppressive and tumor microenvironment. She will also address cancer vaccine guidelines and patient recruitment strategies to optimize patient selection and access to cancer vaccine trials. I should say that Dr. Siu and her co-authors also addressed this topic during an Education Session at the ASCO 2024 Annual Meeting. Finally, our full disclosures are available in the transcript of this episode. So again, Dr. Siu, great to be speaking with you today. I'm looking forward to our discussion. Dr. Lillian Siu: Thank you, Dr. Barata. And before I begin, I want to acknowledge Dr. Jeffrey Weber and Dr. Inge Marie Svane, who both presented during the ASCO session you mentioned. They gave excellent presentations related to the topic of neoantigen vaccines and immune-modulatory vaccines, which we will talk about later. Dr. Pedro Barata: Wonderful. So let's get started. Cancer vaccines are among the most promising frontiers for breakthrough innovations and new strategies in the fight against cancer. The successes in vaccine development during the COVID-19 pandemic, I think, inspired further research in this area. Why do you think it's important that we harness these recent successes and technological advances to really accelerate progress in vaccine development? Dr. Lillian Siu: Absolutely. I think all of us who have lived through COVID really appreciated how important the COVID vaccine development was to all of us. It saved millions of lives. And I think we witnessed a paradigm change in drug development that none of us thought was possible, that we're able to actually bring a concept to a drug from bench to bedside within an extremely short time. That timeline is not something we would ever imagine to have happened, and it did. And I think it gives us hope that perhaps this is not just limited to the COVID vaccine; it's also extrapolatable to other therapeutics – that we can bring promising medicines to our patients in a really expedited timeline, obviously without compromising their safety. We now know that cancer vaccines have entered a new, or maybe I should say, renewed era of promise. And it's holding promise on many fronts, Pedro, if I may. It's very exciting in the area of molecular residual disease. In other words, a setting where the cancer is treated definitively by surgery or radiation, plus adjuvant treatment. And we know some patients will relapse because we know they're at high risk. And now we also have different ways to detect these microscopic risks, such as by ctDNA, circulating tumor DNA, or biomarkers. And we know that having some therapeutic that can eradicate these cancers at such microscopic levels would be very attractive, especially with low toxicity, and I think cancer vaccine is such a candidate. And of course, we can even look further into the future of using such treatment in cancer prevention, especially in those with high risk of developing cancer, for example, those with hereditary syndromes like lynch syndrome. We're not there yet, but I think it holds that promise. So I think, going back to your original question, if we can develop such a therapeutic that is showing promise in a very short period of time, it brings the timeline and the hope to a much shorter timeframe to really deliver to our patients in a very timely manner while safeguarding all the important parts, such as safety and tolerability. Dr. Pedro Barata: Wow, those are such important points. I couldn't agree with you, more. It's really exciting. As I think through this, and as I was reading through your piece, I was thinking it would be great if you could highlight some of the novel approaches to personalized neoantigen vaccine development that are driving progress in this space. Dr. Lillian Siu: Absolutely. And during the session, Dr. Weber spoke about the neoantigen vaccine, and he's a pioneer in this space. So I can only try to iterate some of the points he had delivered during his talk. Neoantigen is a very exciting space for immunologists because we know that tumors express these neoantigens. Many of these are unique antigens that are only expressed in tumors, so-called tumor specific antigens, that we can use as our targets, including vaccines, but not limited to vaccines. And with these altered sequences in DNA in different forms, they could be mutations and splice alterations, etc. We expect that we have modified proteins that are expressed by tumor cells, and these become targets for our drug development of vaccines. And now we can have very specific strategies, very sophisticated algorithms to figure out which neoantigens are more so called immunogenic, more likely to stimulate or activate the immune system, and they can be recognized by T cells. So leveraging this knowledge and technology, we have been able to develop especially mRNA vaccines that are deliverable to our patients through different mechanisms, for example, in lipopeptides, etc., so that we can deliver to the patients in a safe way, such that we can use it to deliver vaccines, such as in the MRD setting that I mentioned earlier, as well as in the advanced disease setting. So Dr. Weber, in his presentation, highlighted one of such vaccines that have been tested in a randomized controlled trial that is KEYNOTE-942, which randomized 157 patients to the mRNA vaccine plus pembrolizumab versus pembrolizumab alone in patients with advanced melanoma. This is a vaccine against 34 mutated neoantigens, and it showed a significant difference in the recurrence free survival with a hazard ratio of 0.56. And if you look at the 18-month relapse free survival rate, it was 78.6% versus 62.2%. Obviously, these are still fairly early data and numbers are still small. I think we would definitely look forward to the randomized phase 3 study of neoantigen vaccine in melanoma and other cancers. Dr. Pedro Barata: No, absolutely. And I agree, it's really exciting. Dr. Weber did a fantastic job going through some of that data. So let me ask you Dr. Siu, as you think about this cancer vaccine field, what are the limitations that you'd highlight when you think about cancer vaccine development? What challenges do you encounter, obstacles do you encounter? Dr. Lillian Siu: There are many, many potential challenges. And to some extent, that's probably why cancer vaccine development has been somewhat slow for the many decades until more recently. We know first of all; the target has to be recognized. So we need immunogenic targets. So I think a lot of the effort has been put into trying to understand which antigens expressed by cancer cells are immunogenic, able to activate the immune system. They're obviously assay based methods. You're going to try and see if you can ex vivo stimulate immune cells on dishes and models, etc. But we need to also develop in silico computerized algorithms, and now with AI, I think that makes it even more tangible and exciting that we can actually understand through a large number of neoantigens or other antigens, whether we can choose the ones that are most likely going to actually stimulate T cells to be activated. And I think that is one area that there is a lot of interest in development, how to really develop ways to select out the most attractive antigens. I would also want to highlight that the platforms, which is how we deliver the vaccine, can also pose significant challenges. For example, vaccines can be delivered using peptide-based formulation, cell-based formulation, nucleic acids and viral vectors. For some of these formulations, for example, the peptides very often are restricted to HLA. They can be rapidly degraded in the body, such that they become not really visible to the T cells anymore. Some of the formulations can be very complex. For example, the cell-base; it may need to have cells isolated from patients, cultured, stored and transported to the site of delivery, which can be very complex. For some of the nucleic acid vaccines, they can have very low transfection efficiency. It could be at risk for also having, for example, DNA vaccines integrated into the host genome. And then lastly, there's also the immune suppressive environment in the TME, such that it does not really have the effect when you give it repeatedly. It becomes attenuated and no longer effective. So these are some of the challenges associated with cancer vaccines. Dr. Pedro Barata: Thank you for that summary. I think it's really important for folks out there, including researchers getting into this field, to be aware of potential obstacles they might encounter. So let me ask you the opposite question as we see more compelling preclinical and clinical data emerging in this field of vaccine development, what is really exciting you the most about the newest technologies that are shaping the future of cancer vaccines, in your opinion? Dr. Lillian Siu: I think one I want to highlight is the immune-modulatory vaccine that Dr. Svane, Dr. Inge Marie Svane had presented during the presentation at ASCO. This is a completely different strategy from the neoantigen vaccine. It targets antigens in the tumor microenvironment. And we know that in the tumor microenvironment, we have tumor cells, we have immune cells, and there are many types of cell types, including, for example, macrophages, cancer associated fibroblasts, regulatory T cells, etc. And using these particular cell types, we know that we can really develop vaccines that can stimulate the body's immune system to attenuate, to downgrade some of the negative factors in the tumor microenvironment. And this is what Dr. Svane and her group is trying to do. For example, they have an IDO vaccine that is able to actually target these antigens in the tumor microenvironment, and by that, not just suppressing the negative forces, so to speak, but also activate T cells to help attack cancer cells. I think that's a very interesting area. Very early promise has been seen already in non-small cell lung cancer in early phase trials using the immune-modulatory vaccine. But going back to your question, what kind of advances; I mentioned earlier about having novel ways to select our antigens that are most immunogenic. There are many algorithms that are being developed, and I think we can try and leverage that kind of knowledge from artificial intelligence, machine learning. So I think that's definitely very exciting. There are also new vaccine platforms coming out. For example, there's recent data using modification of peptides, so called amphiphile vaccines, that already show very early promise in colorectal cancer, microsatellite status, colorectal cancer, as well as in pancreatic cancer in the molecular residual disease setting, where these long peptide vaccines targeting KRAS mutants together with adjuvant oligonucleotide DNA, combined together, can actually be given to patients and reduce the chance of cancer relapse in patients with resected colorectal cancer, as well as pancreatic cancer, with endpoints such as ctDNA or biomarker being downregulated. I think that's a very exciting example. Another very exciting example is cell-based vaccines that are being developed in Europe by the NKI Netherlands Cancer Institute Group, where they are looking at plasmacytoid dendritic cells that are loaded with peptides from different tumor associated antigens and then given to patients, which, again, in non-small cell lung cancer, together with pembrolizumab, has yielded very high response rate. And we will almost certainly see more trials coming out using that particular platform with the dendritic cells. So that's just some of the examples of exciting things that are happening in the vaccine field. Dr. Pedro Barata: Thank you. I'm wondering if you can share with our listeners about what really are the existing guidelines for using these new tools for discovery, methods of treatment, and perhaps optimizing patient selection to access trials. Dr. Lillian Siu: To be honest, the latest guideline that was published from the FDA that I can find is almost 13 years ago in 2011. So I think it is time for a new guidance, or at least a draft guidance, to give some additional support and guidance in terms of what to do with these new treatments from the FDA and perhaps other regulatory agencies as well. I think we're now entering a very exciting time that cancer vaccines are no longer an ineffective therapeutic. It is now showing evidence of efficacy, not just in the advanced setting, but also in the molecular residual disease setting. There're so many questions to be answered, like how to develop these trials in early disease; what's the end point? Can we incorporate them into the neoadjuvant setting, and if so, how do we give these drugs before surgery, and do we give them maintenance after surgery? I think guidance from the regulatory authorities would be extremely helpful and informative to guide academic groups as well as the pharmaceutical sector to develop these agents in the right way. Dr. Pedro Barata: Dr. Siu, this is a fantastic summary, and we certainly are on the cusp of a new dawn of discovery and development in cancer vaccines, and super interesting to hear from you talking about it. Before letting you go, do you have any final thoughts that you'd like to share with the listeners, with all of us about this topic? Dr. Lillian Siu: I think as a drug developer like you are, I'm extremely excited because we now have yet another way to leverage the host immunity as a cancer therapeutic, and it is going to be opening a new door to combination therapy because we can imagine combining these treatments with other immunotherapeutics such as bispecific molecules such as CAR Ts and even vaccine plus vaccine combination is feasible. That came up actually during the session as a question from the audience. Can we combine neoantigen vaccines and immune-modulatory vaccines together? And both of our speakers who presented felt that it was possible. Obviously, we have to understand the sequence question and the endpoints question, but the fact that it opens a new door to combinatorial therapy, not just with immunotherapeutics, but perhaps with other therapeutics as well, antibody drug conjugates, etc., really, I think, is very exciting for this field to become further explored. I mentioned earlier in the podcast that the whole area of cancer prevention is something that we have not been tapping into for the last decade with vaccines because it has not been very effective. Viral vaccines, of course, HPV and other vaccines targeting viruses, but targeting cancer cells is not something we have been successful using vaccines to prevent cancer from developing. I think we would be very interested to see if this will become a reality in the next decade. I think we would start off with patients with high risk of developing cancers such as, as I mentioned earlier, those with lynch syndrome, those harboring BRCA alterations, for example. Can we use these vaccines to actually prevent the cancers from developing in such high-risk individuals? I think the field is definitely open to that consideration. Dr. Pedro Barata: Definitely. And I'd like to thank you, Dr. Siu, for sharing these great insights with us today on the ASCO Daily News Podcast. Dr. Lillian Siu: Thank you so much for your time. Dr. Pedro Barata: And thank you to all the listeners for your time today. You'll find a link to the article discussed today in the transcript of this episode, and I encourage you to check out the 2024 ASCO Educational Book. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So again, thank you so much for your time and see you soon. Disclaimer: 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. Follow today's speakers: Dr. Pedro Barata @PBarataMD Dr. Lillian Siu @lillian_siu Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Pedro Barata: Honoraria: UroToday Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Dendreon Speakers' Bureau (Inst): Caris Life Sciences, Bayer, Pfizer/Astellas Research Funding (Inst.): Blueearth, AVEO, Pfizer, Merck Dr. Lillian Siu: Leadership (Immediate family member): Treadwell Therapeutics Stock and Other Ownership Interests (Immediate family member): Agios Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen

Dr. Neeraj Agarwal and Dr. Rana McKay discuss promising studies in GU cancers featured at the 2024 ASCO Annual Meeting that highlighted improved outcomes in urothelial carcinoma, improved survival in renal cell carcinoma, and the role of ctDNA as a potential biomarker for predicting outcomes. TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I am the director of the Genitourinary Oncology Program, a professor of medicine at the University of Utah's Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I am delighted to welcome Dr. Rana McKay, a GU medical oncologist and associate professor at the University of California San Diego. Today, we'll be discussing some key GU abstracts featured at the 2024 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode. Rana, we're thrilled to have you on the podcast today to share your insights on key advances in GU oncology from ASCO24. Dr. Rana McKay: Thank you so much, Neeraj; it's a pleasure to be here. Dr. Neeraj Agarwal: So, Rana, let's start with some bladder cancer abstracts. Could you tell us about Abstract 4503, titled "Impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer"? Dr. Rana McKay: Of course, I would be delighted to. First, I would like to remind our listeners that enfortumab vedotin (EV) was approved as a monotherapy for the treatment of locally advanced or metastatic urothelial cancer based on the results of EV-201 and EV-301 trials. In these pivotal studies, EV was initiated at a dose of 1.25 mg/kg, and dose modifications, such as reductions and interruptions, were used to manage adverse events. In the abstract presented at ASCO 2024, Dr. Daniel Petrylak and colleagues conducted a post-hoc exploratory analysis to evaluate the association between EV plasma exposure and outcomes. They used multiple pharmacokinetic samples collected during the first two cycles and pre-dose samples from 3 EV monotherapy studies, namely EV-101, EV-201, and EV-301, that were conducted in patients with previously treated locally advanced or metastatic urothelial carcinoma. Dose reductions to 1 mg/kg were required in 42.1% and 35.1% of patients in the EV-201 and EV-301 trials, respectively, and reductions to 0.75 mg/kg were required in 13.6% and 11.1% in the EV-201 and EV-301 trials, respectively. Higher EV exposure during the first two cycles was associated with a higher objective response rate. The ORR was 21.4% for the dose of 0.75 mg/kg, while it was 18.5% for the dose of 1.0 mg/kg. Interestingly, increasing the dosage to 1.25 mg/kg improved the ORR, which ranged from 40 to 51.1% across various studies. In the EV-301 trial, when comparing the efficacy of EV to chemotherapy, EV improved PFS and OS across all dose quartiles, and there was no evidence that recommended dose modifications impacted long-term efficacy outcomes. Dr. Neeraj Agarwal: Thank you, Rana, for this great summary. I would like to add that the meticulously conducted pharmacokinetic studies demonstrated that serum levels of EV correlated with responses. Importantly, patients who had to decrease the dose did not experience compromised outcomes as EV improved PFS and OS outcomes vs chemotherapy in across all exposure quartiles in the EV-301 trial where EV was compared with chemotherapy. These findings highlight the need to start at the recommended dose of 1.25 mg/kg and reduce it, if necessary, however, clinicians should not start at a lower dose. Dr. Rana McKay: I totally agree with you, Neeraj. Now, moving on to a different setting in bladder cancer, what can you tell us about LBA4517, titled "Perioperative sacituzumab govitecan alone or in combination with pembrolizumab for patients with muscle-invasive urothelial bladder cancer: SURE-01/02 interim results"? Dr. Neeraj Agarwal: Of course! So, SURE was a multicohort, open-label, phase 2 study in patients with muscle-invasive bladder cancer assessing sacituzumab govitecan as a neoadjuvant therapy either alone in SURE-01 or as a combination with pembrolizumab followed by adjuvant pembro in SURE-02 in a flexible design allowing a bladder-sparing approach. In the abstract presented at ASCO 2024, Dr. Antonio Cigliola and colleagues report interim results of the SURE-01 study. Patients with cT2-4N0M0 urothelial carcinoma who were ineligible for or refused cisplatin-based neoadjuvant chemotherapy were planned to receive 4 cycles of neoadjuvant sacituzumab govitecan at a dose of 10 mg/kg followed by radical cystectomy. An extensive assessment was performed at baseline and after the 4 cycles for response assessment. Patients with clinical complete response defined with negative MRI, cystoscopy and ctDNA assays refusing radical cystectomy were offered redo transurethral resection of the bladder tumor or repeat TURBT followed by observation in the absence of viable high-grade tumor in the bladder. The primary endpoint was pathological complete response rate, while secondary endpoints included pathological downstaging rate and safety. After the first 8 patients were enrolled, the protocol was amended due to the occurrence of grade 3 and 4 neutropenia and diarrhea in 75% and 50% of patients, respectively, and 2 deaths – one of which was deemed to be treatment-related due to sepsis. Key protocol changes included the reduction of the dose of sacituzumab govitecan to 7.5 mg/kg, the introduction of G-CSF as primary prophylaxis, and the exclusion of patients at high risk of febrile neutropenia per ASCO guidelines. Among 21 patients who received at least one cycle of sacituzumab govitecan and included in the intention-to-treat population, 47.6% had a complete pathological response, and 52.4% had pathological downstaging. 11 patients underwent radical cystectomy, while 7 received repeat-TURBT due to complete clinical response or patient preference. Regarding the safety profile, grade 3 or more adverse events occurred in 42.5% of patients. Treatment-related adverse events leading to dose interruptions or discontinuations were more common before the protocol amendment. It is noteworthy that 3 patients died after treatment discontinuation, with one deemed treatment-related, as previously mentioned. Dr. Rana McKay: Thank you, Neeraj, for a great summary. The pathological complete responses observed show promising activity for sacituzumab govitecan as a neo-adjuvant therapy and a window for bladder-sparing approaches, which is definitely exciting news for our patients! However, although the 3 deaths encountered in a neo-adjuvant setting could be concerning, the improvement of the safety profile after protocol amendments is reassuring and supports the continuation of the study. Dr. Neeraj Agarwal: Before wrapping up the bladder cancer section, would you like to share your insights with our listeners on Abstract 4518, titled "Quantitative circulating tumor DNA (ctDNA) assessment in patients with advanced urothelial carcinoma treated with pembrolizumab or platinum-based chemotherapy from the phase 3 KEYNOTE-361 trial"? Dr. Rana McKay: Sure. So, the KEYNOTE-361 trial was a randomized phase 3 study with 3 arms that included pembrolizumab plus chemotherapy, pembrolizumab monotherapy, or chemotherapy alone in patients with previously untreated advanced urothelial carcinoma. The results showed that neither the combination of pembrolizumab plus chemotherapy nor pembrolizumab monotherapy improved survival outcomes compared to the chemotherapy arm. So, in this exploratory analysis presented at ASCO24, Dr. Tom Powles and colleagues sought to assess the role of ctDNA as a potential biomarker between the pembrolizumab monotherapy arm and the chemotherapy arm. Tumor tissue mutations were evaluated using whole exome sequencing, and plasma ctDNA was assessed with the Guardant 360 assay. Changes in ctDNA from pre-treatment cycle 1 to on-treatment cycle 2, so 3 weeks post-baseline assessment, were quantified by the maximum variant allele frequency of tumor tissue-specific mutations. Results showed that lower baseline ctDNA levels were associated with improved clinical outcomes of response in the pembrolizumab arm but not in the chemotherapy arm. This improvement in the pembrolizumab arm was also robust to adjustment for tumor mutational burden and PD-L1. Additionally, chemotherapy led to a ctDNA clearance rate of 41% compared to 11% in the pembrolizumab arm. Patients who had a large ctDNA reduction with pembrolizumab had significantly improved outcomes compared to those achieving a large reduction with chemotherapy with a hazard ratio of 0.25. However, this did not replicate in patients who did not achieve a large reduction, as these patients had similar outcomes across both arms. Let's switch gears to kidney cancer and start with Abstract 4508, reporting the final OS analysis from the JAVELIN Renal-101 trial. Neeraj, what would you like to tell us about this abstract? Dr. Neeraj Agarwal: Well, as a quick reminder, the JAVELIN Renal-101 was a randomized phase 3 trial where patients with previously untreated advanced or metastatic clear cell renal cell carcinoma were randomized to receive either the combination of avelumab plus axitinib or sunitinib. In previous analyses, the combination of avelumab and axitinib significantly improved PFS compared to sunitinib and was subsequently approved by the FDA for the first-line treatment of patients with advanced RCC in 2019. This superiority in PFS was maintained across the different analyses; however, OS data remained immature. In the abstract presented at ASCO24 by Dr. Robert Motzer from Memorial Sloan Kettering Cancer Center and colleagues, the authors reported OS results at a median follow-up of around 73 months and a minimum of 68 months for all patients, which is the longest follow-up for any ICI-TKI combination in RCC. The final analysis in the overall population favored the combination of avelumab plus axitinib with a median OS of 44.8 months compared to 38.9 months with sunitinib, however, this did not reach statistical significance with a hazard ratio of 0.88. The PFS results and safety profile were consistent with previous analyses. Dr. Rana McKay: Thank you, Neeraj, for such a nice overview of this abstract. These new data could make this regimen less optimal than other ICI-TKI combinations in the first-line mRCC setting. Dr. Neeraj Agarwal: I concur, Rana. Moving on to perhaps one of the most exciting GU abstracts featured, Abstract 4506, titled "Circulating kidney injury molecule-1 biomarker analysis in IMmotion010: A randomized phase 3 study of adjuvant atezolizumab vs placebo in patients with renal cell carcinoma at increased risk of recurrence after resection." Rana, what are your thoughts on this abstract? Dr. Rana McKay: Well, first, I would like to take a step back and remind our audience that in the IMmotion010 trial, patients with resected intermediate to high-risk RCC with clear cell and/or sarcomatoid component were randomized in a 1:1 ratio to receive either atezolizumab or placebo. Investigator-assessed disease-free survival, which was the primary endpoint, favored the atezolizumab arm but did not reach statistical significance. In the abstract featured at ASCO24, Dr. Laurence Albiges and colleagues build on data previously reported in the ASSURE and CheckMate 914 trials and report provocative findings regarding a molecule known as kidney injury molecule 1 or KIM-1, which is a type 1 membrane glycoprotein that has been identified as a minimally invasive potential peripheral blood circulating biomarker. The KIM-1 level of 86 pg/ml was identified as the optimized threshold for defining post-nephrectomy KIM-1 high vs KIM-1 low subgroups in the IMmotion010 trial. KIM-1 levels were measured at baseline or pre-treatment, at cycle 4 day 1, and at disease recurrence or discontinuation without disease recurrence. Baseline characteristics were balanced between the KIM-1 high and KIM-1 low groups, except perhaps for a slightly higher pathological stage in the KIM-1 high subgroup. I would like to highlight 3 key takeaways from this abstract. First, KIM-1 high level was associated with significantly worse DFS with a hazard ratio of 1.75. Second, patients in the KIM-1 high subgroup receiving atezolizumab had a 28% reduction in the risk of recurrence or death compared to those receiving placebo, while those in the KIM-1 low subgroup had comparable outcomes across both treatment arms. Third, patients in the KIM-1 high subgroup receiving atezolizumab were significantly less likely to experience an on-treatment increase in KIM-1 levels, which was associated with worse DFS in both high and low KIM-1 subgroups, regardless of treatment arm. Thus, these findings support the use of KIM-1 as both a predictive and prognostic biomarker in patients with RCC. Dr. Neeraj Agarwal: Yes, Rana, this is amazing data! I would like to add that these results warrant larger and, ideally, prospective studies to validate the utility of KIM-1 as a noninvasive biomarker for identifying minimal residual disease after nephrectomy and for predicting outcomes to immune checkpoint inhibitors. Dr. Rana McKay: Also, in the field of biomarkers, 2 abstracts interrogating different biomarkers in a different setting, so in patients with advanced or metastatic RCC were presented. Neeraj, could you tell us more about these abstracts? Dr. Neeraj Agarwal: Of course! I think you are referring to Abstracts 4504 and 4505. In abstract 4504, Dr. Toni Choueiri and colleagues sought to assess the clinical implications of different biomarkers in the CLEAR trial, which was a randomized phase 3 trial that led to the approval of the combination of pembrolizumab plus lenvatinib in the first-line mRCC setting. On the other hand, in abstract 4505, Dr. Brian Rini presented biomarker results in KEYNOTE-426, which was also a randomized phase 3 trial based on which the combination of pembrolizumab plus axitinib was approved in patients with mRCC. The authors in both trials sought to investigate the role of biomarkers in predicting treatment outcomes from 3 different angles. Starting with PD-L1 expression, the superiority of the combination arms over sunitinib was not impacted by PD-L1 status in both trials. Moving on to RCC driver gene mutations on whole exome sequencing, such as VHL, SETD2, PBRM1, and BAP1, ICI combination therapies improved outcomes regardless of mutation gene status, and this improvement was statistically significant with PBRM1 mutations in KEYNOTE-426 compared to wild-type PBRM1, but this did not replicate in the CLEAR trial. Finally, using transcriptomic signatures derived from RCC trials, especially the IMmotion 151 and JAVELIN Renal 101 trials, where 7 clusters or molecular subtypes were identified, the combination arms outperformed sunitinib in all clusters in both trials and the magnitude of this benefit differed across clusters. Dr. Rana McKay: Thank you for this very interesting summary and comparison of the results of these 2 abstracts. These findings support the use of ICI-based combinations in all patients with mRCC as a first-line option. Although these abstracts could not identify specific biomarkers that could guide us clinicians in treatment selection, they provide very interesting biological insights on these molecular biomarkers that are, however, not yet clinically actionable. Dr. Neeraj Agarwal: Very interesting point, Rana. Moving on to prostate cancer, let's start with abstract LBA5000 titled, "Cabazitaxel with abiraterone versus abiraterone alone randomized trial for extensive disease following docetaxel: The CHAARTED2 trial of the ECOG-ACRIN Cancer Research Group (EA8153)." Rana, what is your takeaway on this abstract? Dr. Rana McKay: As a reminder to our audience, the CHAARTED2 trial was a randomized open-label phase 2 study that compared the combination of cabazitaxel and abiraterone to abiraterone alone in patients with mCRPC previously treated with ADT plus docetaxel in the hormone-sensitive setting. The primary endpoint was progression-free survival. After a median follow-up of 47.3 months, Dr. Christos Kyriakopoulos and colleagues reported in LBA5000 that patients receiving the combination of cabazitaxel plus abiraterone had a 27% reduction in the risk of progression or death. However, there was no significant difference in overall survival between the two arms, with a median OS of 25 months in the cabazitaxel+abiraterone arm and 26.9 months in the abiraterone arm, although the study was underpowered for this endpoint. Regarding the toxicity profile, the combination of cabazitaxel and abiraterone was overall well tolerated with more cytopenias, as expected. Dr. Neeraj Agarwal: Very nice summary of this abstract, Rana. I would like to add that the treatment landscape of patients with mHSPC has evolved since the design of the study and now includes combination therapies of ADT + ARPI with or without docetaxel, and ADT + docetaxel is no longer a standard of care, which limits the applicability of these results in clinical practice today. Dr. Rana McKay: Excellent point, Neeraj. Let's discuss Abstract 5001, titled "CYCLONE 2: A phase 3 study of abemaciclib with abiraterone in patients with metastatic castration-resistant prostate cancer". Dr. Neeraj Agarwal: Sure! In the abstract featured at ASCO24, Dr. Matthew Smith and colleagues report the primary results of the CYCLONE 2 trial, which was a randomized phase 2/3 study that investigated the combination of abemaciclib plus abiraterone versus abiraterone monotherapy in patients with mCRPC. Stratification factors included radiographic progression at study entry, presence of measurable disease, and prior docetaxel for mHSPC. Part 1 of the study established the recommended phase 2 dose of abemaciclib at 200 mg twice daily. In part 2, patients were randomized to placebo or abemaciclib, and an adaptive interim analysis using prespecified criteria was performed and recommended the expansion of the study to part 3. The primary endpoint was investigator-assessed radiographic progression-free survival by RECIST 1.1 and PCWG3 criteria in the intention-to-treat population. At the time of the primary analysis, adding abemaciclib to abiraterone did not improve rPFS, with a hazard ratio of 0.83. The median rPFS was 22 months for the combination arm and 20.3 months for the abiraterone arm. The combination was well tolerated, and the safety profile was consistent with the known adverse events. Dr. Rana McKay: So, the addition of abemaciclib to abiraterone did not improve outcomes in patients with mCRPC. These findings suggest that no further investigation is warranted for abemaciclib or CDK4/6 inhibitors in biomarker-unselected patients with prostate cancer. Dr. Neeraj Agarwal: Rana, what's your take-home message on Abstract 5006, titled "Health-related quality of life results from PRESTO (AFT-19), a phase 3 randomized trial of intensification of androgen blockade in patients with high-risk biochemically relapsed castration sensitive prostate cancer"? Dr. Rana McKay: So, as a reminder to our audience, the PRESTO trial was a randomized phase 3 study that assessed the effects of intensified androgen receptor blockade in patients with biochemically recurrent prostate cancer following local therapies. Patients with a PSA doubling time of less than 9 months and no evidence of metastatic disease were randomized to receive either 52 weeks of ADT alone, ADT plus apalutamide, or ADT plus apalutamide plus abiraterone. In their paper published earlier this year in the Journal of Clinical Oncology, the authors showed that patients receiving ADT plus apalutamide with or without abiraterone had significantly longer PSA-progression-free survival than those receiving ADT alone. In the oral presentation featured at ASCO24, Dr. Ronald Chen and colleagues report health-related quality of life outcomes that were assessed using various questionnaires or scales at baseline, at cycle 7, which is around 6 months on treatment, and at the end of treatment. Results showed that this intensified approach with apalutamide did not significantly increase severe adverse events, did not lengthen the time to testosterone recovery, and did not meaningfully increase common treatment-related symptoms such as hormonal symptoms, sexual dysfunction, hot flash interference, and fatigue. Importantly, additional intensification with abiraterone did not further improve PSA-PFS but did increase the rate of serious adverse events, lengthened the time to testosterone recovery, and increased hot flash interference. Dr. Neeraj Agarwal: So, in conclusion, the PRESTO trial supports using intensified androgen blockade with apalutamide to improve PSA-PFS in patients with high-risk biochemically recurrent prostate cancer without compromising health-related quality of life. However, adding abiraterone did not offer additional benefits and increased side effects. Dr. Rana McKay: Let's move on to LBA5002 titled, "A randomized, double-blind, placebo-controlled trial of metformin in reducing progression among men on expectant management for low-risk prostate cancer: The MAST (Metformin Active Surveillance Trial) study." Would you like to share your insights on this abstract with our listeners? Dr. Neeraj Agarwal: Absolutely. MAST was a randomized, double-blinded, placebo-controlled trial that investigated the impact of metformin on the progression of low-risk localized prostate cancer in patients choosing to undergo active surveillance. Eligible patients had biopsy-proven, low-risk, localized prostate cancer diagnosed within the past 6 months, characterized by a Gleason score of less than 6 observed in less than one-third of the total cores, less than 50% positivity in any one core, a PSA level of less than 10 ng/ml, and a clinical-stage between T1c and T2a. Patients were randomized in a 1:1 ratio to receive either metformin 850 mg twice daily or placebo for three years. All patients underwent repeat prostate biopsy at 18 and 36 months. The primary endpoint was time to progression, defined as the earliest occurrence of primary prostate cancer therapy, such as prostatectomy, radiation, hormonal therapy, or pathological progression on subsequent biopsies, which was defined as more than 1/3 of total cores involved, at least 50% of any one core involved, or Gleason pattern 4 or higher. The study included 407 patients, with 204 receiving metformin and 203 receiving a placebo. Results presented by Dr. Anthony Joshua showed no statistically significant difference in progression-free survival, including therapeutic and pathologic progression, with an unadjusted hazard ratio of 1.08. Interestingly, there was a signal that patients with a BMI more than 30 had a detriment to taking metformin with a higher risk of progression compared to those receiving placebo with an unadjusted HR of 2.39 and a p-value of 0.01. Dr. Rana McKay: I would like to add that this study showed that metformin use does not prevent the progression of low-risk localized prostate cancer on active surveillance and could represent a potential detriment for patients with high BMI at study entry. Dr. Neeraj Agarwal: Yes, Rana, I concur. Any final remarks before we conclude today's podcast? Dr. Rana McKay: Thank you, Neeraj; it's been wonderful being here with you today and you having me on the podcast to highlight these important advances and the amazing work that many investigators are conducting and the patients who were involved in the context of these trials. It's really excellent to see these updated results. Dr. Neeraj Agarwal: Before we wrap up this podcast, I would like to say that we have reviewed a selection of abstracts addressing prostate, bladder, and kidney cancer, which are significantly impacting our medical practices now and in the near future. Rana, thank you for sharing your insights today. These updates are undoubtedly exciting for the entire GU oncology community, and we greatly appreciate your valuable contribution to the discussion. Many thanks. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Find out more about today's speakers: Dr. Neeraj Agarwal @neerajaiims Dr. Rana McKay @DrRanaMcKay Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas Dr. Rana McKay: Consulting or Advisory Role: Janssen, Novartis, Tempus, Exelxis, Pfizer, Bristol-Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion, Calithera, AstraZeneca, Myovant, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seattle Genetics, Telix, Eli Lilly, Pfizer, Bayer, Tempus

Drs. John Sweetenham and Angela DeMichele discuss groundbreaking abstracts in breast and lung cancer from the 2024 ASCO Annual Meeting. They highlight advancements in AI, targeted therapy, immunotherapy, and virtual health interventions, showcasing how these innovations are shaping the future of oncology care.

Drs. John Sweetenham and Marc Braunstein discuss practice-changing studies in hematologic malignancies that were featured at the 2024 ASCO Annual Meeting, including the ASC4FIRST trial in chronic myeloid leukemia and IMROZ and CARTITUDE-4 in multiple myeloma. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. On today's episode, we'll be discussing practice-changing abstracts and other key advances in hematological malignancies that were featured at the 2024 ASCO Annual Meeting. Joining me for this discussion is an old friend, Dr. Marc Braunstein, a hematologist and oncologist from the NYU Langone Perlmutter Cancer Center. Our full disclosures are available in the transcript of this episode. Marc, it's great to have you back on the podcast again. There were some important studies in the heme space at the Annual Meeting this year, and we're very pleased that you're able to share your takeaways. Dr. Marc Braunstein: Thank you, John. It's great to be back again. Dr. John Sweetenham: Let's start out, Marc, with LBA6500. This abstract reports the primary results of the ASC4FIRST trial, and this was a trial comparing asciminib with investigator selected tyrosine kinase inhibitors in newly diagnosed patients with chronic myeloid leukemia. Could you tell us a little about the trial and how you think it's going to impact clinical practice? Dr. Marc Braunstein: Absolutely. So, asciminib is an oral tyrosine kinase of the ABL kinase domain. As we know in CML, the BCR-ABL translocation is characteristic of the disease, and asciminib is approved for chronic phase CML with a T315I resistance mutation or for patients who have received 2 or more prior lines of therapy. So the ASC4FIRST trial was a randomized trial of 405 patients with newly diagnosed chronic phase CML who are randomized one to one to receive either asciminib at 80 milligrams once daily, or investigator's choice of a first generation TKI imatinib or one of three second generation TKIs nilotinib, dasatinib, or bosutinib. The primary endpoint of the study was the major molecular response, or MMR, at 48 weeks. Pretty much, the study met its primary endpoint with a 67% rate of MMR at 48 weeks, with asciminib versus 49% in patients treated with the investigator's choice of TKI. And in addition, the major molecular remission or MMR of 4.5, which is a deep remission, those rates were higher as well, with asciminib versus investigator's choice at a rate of 39% versus 21% when comparing the groups. Furthermore, when we looked at toxicity, there were fewer grade 3 or higher adverse events, with the asciminib at 38% versus either 44% with the first generation, or 55% with the second generation TKI, and fewer discontinuations as well with asciminib. So I think this abstract is practice-changing. I think it offers compelling data to use asciminib upfront for chronic phase CML. Those who don't agree with that sentiment might argue that we want to see longer term follow up. There's a planned follow-up at 96 weeks. We would want to see the rate of progression to acute myeloid leukemia and of course overall survival as well. But I think the abstract certainly shows an improvement in outcomes with asciminib versus our current array of TKIs. Dr. John Sweetenham: Yeah, I think it certainly is, at least at minimum, potentially practice changing. I agree with you. Just one question, and this may be a little bit speculative, but do you have any thoughts about treatment free survival with asciminib and how that might line up against some of the other TKIs? Dr. Marc Braunstein: Yeah, that's a great question. The abstract did not necessarily address that, patients were treated until progression, but we know that with the current landscape of TKIs, that in patients who have achieved a deep MR of 4 or 4.5 for at least 2 years who discontinue their TKI, the rate of relapse is about 50%. The current study, the ASC4FIRST, doesn't address that, but I think it's a really good question about whether, for those patients who have achieved a deep remission, whether they can eventually stop asciminib down the line. Dr. John Sweetenham: Yeah, I guess it's one of those 'watch this space' things. So we'll see how the data mature out. And let's move on to what I think is another potentially practice-changing study, at least in certain parts of the world. And that's [the] LBA7000 study in classical Hodgkin lymphoma. As you remember, this was a German Hodgkin lymphoma study group trial which looked at the tolerability and efficacy of a novel regimen, BrECADD versus eBEACOPP for patients with advanced stage classical Hodgkin lymphoma in their study, which is known as GHSG HD21. Can you give us your thoughts and take home messages from this trial? Dr. Marc Braunstein: Yeah, John, absolutely. So the German HD21 study is a phase 3 study of 1,500 patients with classical Hodgkin lymphoma. The majority were stage 3 or 4, 84%, that compared two regimens BEACOPP to BrECADD. The major difference between these 2 groups being that the newer BrECADD regimen swaps out bleomycin for brentuximab vedotin, which is an anti-CD30 antibody drug conjugate. Also, in the BrECADD regimen they eliminate vincristine that's incorporated into BEACOPP. Those are kind of the global differences between these 2 regimens. And when comparing these, they looked at the primary endpoint of progression-free survival. Of note, in this study there was a PET adjusted approach where if patients achieved interim PET negativity after 2 cycles, that was followed by an additional 2 cycles of their treatment as opposed to 4 cycles if they were PET positive after the initial 2 cycles of their respective treatment. And of note, there were similar rates of PET2 negativity between both arms, about 58% in both arms. So at a median follow-up of 48 months, the 4-year progression-free survival was significantly better with the brentuximab containing BrECADD regimen at 94% versus 91% with a hazard ratio of 0.66. And the overall survival of the BrECADD arm was 98.6%, which is very high and impressive. The 4-year overall survival was similar between the arms at around 98%, but of note, there were fewer severe adverse events with BrECADD, the brentuximab containing arm versus BEACOPP at about 42% versus 59% and interestingly less peripheral neuropathy with the brentuximab containing BrECADD. So we're doing extremely well in treating advanced stage classical Hodgkin lymphoma. So the bar is set very high. But in this study, the rates of progression-free survival and overall survival are very impressive. While these intensive regimens tend to be used outside of the U.S., there are several notable benefits of the study, including greater than 50% PET2 negativity and high rates of progression-free survival at 4 years. In discussing this abstract, it's worth noting that there are other competing regimens, if you want to call it that, that are more commonly used in the U.S. So the ECHELON-1 study looked at brentuximab AVD compared with ABVD with bleomycin and it was a 94% versus 89% 6-year overall survival rate favoring the brentuximab containing A+AVD regimen. And lastly, more recently, the SWOG S1826 study that hasn't been published but was presented in abstract form looked at nivolumab AVD versus brentuximab AVD at a median follow up of 12 months showed a progression-free survival of 94% versus 86%. And that study still has yet to be published and needs to mature. But both of those regimens are in the NCCN guidelines. So, we're definitely pushing the bar higher in terms of improving responses in treating advanced classical Hodgkin lymphoma. Dr. John Sweetenham: I think that there's no question that these results from BrECADD are very impressive. But I'm taken back to what I think has been a kind of philosophic discussion in Hodgkin lymphoma now for a number of years about balancing disease control and efficacy against the potential short-term and long-term toxicity of the regimens, particularly when you have very effective salvage therapies for those patients who may suffer a relapse. So I think that this is a discussion over whether you take a very intensive, upfront approach to Hodgkin lymphoma versus something that may be less and slightly less intensive. I suspect that's a discussion that's going to continue for a long time. I don't know what you feel, but my own feeling about this is that this study will likely have a major influence over treatment of Hodgkin lymphoma, particularly in western Europe. Less likely in the US.., I would think. I don't know what your thoughts about that are. Dr. Marc Braunstein: Well, it's a great question. In SWOG S1826, that study did include pediatric patients. In HD21, the median age was 31 and did not include pediatric patients. So I think we have to be selective in terms of fitness and which patients may be better suited for different regimens. But I think what all these studies show is certainly when we incorporate novel immunotherapies, whether it's brentuximab vedotin, nivolumab, we improve progression-free survival and even overall survival. Dr. John Sweetenham: Absolutely. So let's shift gears now and take a look at Abstract 7500, the IMROZ study. This was the study of isatuximab, bortezomib, lenalidomide and dexamethasone versus VRD alone for transplant ineligible patients with newly diagnosed multiple myeloma. I know we discussed this in our preview podcast a few weeks back, Marc, but I just wonder now, having seen the data in more detail, what do you think of the important takeaways? And again, are we looking at a new standard of care? Dr. Marc Braunstein: You know, there are many standards of care in multiple myeloma, but we're always looking to make improvements on the regimens we have at our disposal. So, just to recap, IMROZ is a phase 3 randomized study of the anti-CD38 monoclonal antibody isatuximab with the backbone of bortezomib, lenalidomide, dexamethasone or VRD versus VRD alone, specifically, in transplant ineligible newly diagnosed multiple myeloma patients age less than 80. They studied 446 patients in this study, randomized 3 to 2 to Isa-VRD versus VRD alone, with the primary endpoint of progression free survival. Now, similar to other studies where they included a monoclonal antibody up front, the study met its primary endpoint of improving progression-free survival with the quad regimen containing the monoclonal antibody isatuximab versus VRD alone. So what was interesting about the study, it's really the first of its kind to be presented that specifically looked at transplant ineligible patients, which is presumably a less fit or perhaps more frail population that wouldn't go on to consolidation with stem cell transplant. And in this study, the progression-free survival at 5 years was 63% versus 45%, clearly superior when you included isatuximab. And the rates of complete remission and MRD negativity were all significantly improved, too. However, that was also met with slightly more grade 3 or higher treatment emergent adverse events, 92% versus 84% in the control arm. There are also 11% grade 5 treatment emergent adverse events with the isatuximab group versus 5.5% with VRD alone. Although there was no major difference in treatment discontinuation. One small caveat worth noting, too, is that high-risk patients in this study, when presented at ASCO, did not necessarily show a difference in benefit, although there wasn't necessarily a detriment either. So, John, I think that clearly quadruplet regimens are superior in outcomes of efficacy to triplets, even in transplant-ineligible patients. But I think we have to tailor these treatments to individual patients because I think when it comes to transplant-ineligible patients, it's a spectrum of patients who may be more or less fit for quad regimens versus triplet regimens. It's also worth noting, though, that in this study, the patients are really only getting a quad regimen for 4 cycles. They get their Isa-VRD, and then you drop the bortezomib. So when we think about quads, it's not that they're getting the quad regimen indefinitely, it's really for the induction cycles. But still, I think we have to be aware of potential safety issues. Dr. John Sweetenham: Okay, great. And let's stay on the theme of multiple myeloma, Marc, and talk a little bit about Abstract 7504, which was a subgroup analysis of the CARTITUDE-4 study. This is a report on the use of ciltacabtagene autoleucel versus standard of care in patients with functional high risk multiple myeloma. Can you give us your thoughts on this and maybe put it into a bit of context for us? Dr. Marc Braunstein: Absolutely, John. It's really a great time to be in the field of multiple myeloma. We're making tremendous progress, but when we think about one of the unmet needs, it's just consistently the high-risk patients who have shorter responses and are at higher risk for poorer outcomes. Just to review, cilta-cel is one of the 2 available anti-BCMA CAR T-cell products available for the treatment of relapsed or refractory multiple myeloma. Very recently, the FDA approved cilta-cel for lenalidomide refractory patients after 2 or more prior lines of therapy based on the CARTITUDE-4 study, which was published by San-Miguel and colleagues in New England Journal of Medicine in July 2023. And that study randomized 419 patients with multiple myeloma with 1 to 3 prior lines of therapy to receive either cilta-cel or physician's choice of standard of care, which was either 1 of 2 triplet regimens, a pomalidomide, bortezomib, dexamethasone or daratumumab, pomalidomide and dexamethasone. It's worth noting that about 25% of the patients in the CARTITUDE-4 study had prior anti-CD38 antibody treatment previously and the carfilzomib was not included in one of the standard-of-care arms, and we know that those regimens containing carfilzomib do increase survival in relapsed myeloma. Nevertheless, the primary outcome of progression-free survival was not reached in the CAR T-cell arm versus 11.8 months in the standard-of-care arm, with a significant reduction in progression of 74%. So clearly a positive study and CAR T-cell therapy is included in the NCCN guidelines for patients who have an early relapse from their myeloma. The current abstract by Costa et al focused specifically on a subgroup of 79 patients from CARTITUDE-4 in second line of treatment and looked at what they called functional high-risk myeloma, defined as progression of disease within 18 months of initial treatment or after stem cell transplant. Again, the study showed a retained benefit of cilta-cel with significant improvement in progression-free survival either not reached or 12 months with the control standard of care arm, as well as complete remission rate and rates of MRD negativity of 65% versus 10% in the control. The overall survival outcome was still immature and not presented. Nevertheless, cilta-cel is clearly superior to standard-of-care triplet regimens. I think that for patients with high risk, they clearly derive a benefit from CAR T-cell therapy if they have short progression-free survival after initial therapy. Dr. John Sweetenham: Thanks, Marc. So let's round this out by talking about another area of unmet need, I guess in a way in a difficult to treat patient group. And that's Abstract 7007, the SYMPATICO study. This is a study which looks at the efficacy and safety of ibrutinib and venetoclax in patients with mantle cell lymphoma who had a mutated TP53. Can you just briefly review this for us and tell us what you think we should be taking away from this studys? Dr. Marc Braunstein: So, mantle cell lymphoma typically has an aggressive behavior, but the subgroup of patients with a P53 mutation tend to have the poorest outcomes and do represent an area of unmet need. Although BTK inhibitors are making important improvements in mantle cell lymphoma, they have yet to be approved in newly diagnosed mantle cell lymphoma. Acalibutinib and zanubrutinib are FDA-approved BTK inhibitors for previously treated mantle cell lymphoma. Ibrutinib was withdrawn from the market in the U.S. for mantle cell lymphoma. Dr. Michael Wang's group presented late-breaking data from the phase 3 SYMPATICO trial at ASH 2023, in which 267 patients with relapsed refractory mantle cell lymphoma were randomized to receive either ibrutinib plus the BCL2 inhibitor venetoclax or ibrutinib plus placebo after 1 to 5 prior lines of therapy. And that study showed a 32 versus 22 months progression-free survival at a median follow up of 51 months. The current abstract, also by Dr. Wang and colleagues, looked at the subgroup of patients who had a P53 mutation and included an open label cohort of 44 patients in the first line of treatment and a relapse refractory cohort of 75 patients, and compared this subgroup of patients with P53 mutation to those without. When we look at the outcomes, the patients who did not have a P53 mutation clearly did better in terms of progression-free survival being not reached in first-line treatment compared to 22 months progression-free survival in those patients with first-line [treatment] with a P53 mutation. As well as in the relapsed refractory setting, the PFS without the P53 mutation was 47 months versus 21 months with the mutation. However, when you look at these patients treated with ibrutinib and venetoclax comparing whether they got treated in first line or the relapse refractory setting, the overall response rates are very similar at about 80% to 90% and the CR rates were very similar at about 55% to 58%, which to me suggests that although patients with P53 mutation do worse than those without it, whether they're treated in the first-line or the relapse setting with this combination of venetoclax, they tend to do somewhat similar, suggesting that you can overcome resistance to prior therapy in the relapse setting. So I think further data are certainly warranted to explore the role of combination therapies that include novel agents such as BTK inhibitors in the first line setting. It's worth noting that the TRIANGLE study was recently published, and this study looked at including ibrutinib at various phases, including at induction in combination with intensive chemotherapy and during the maintenance phase. And that study showed encouraging outcomes in patients who received ibrutinib even without stem cell transplant compared to those who received stem cell transplant. So the role of BTKIs in mantle cell lymphoma is certainly evolving, and I think it offers a very effective intervention without the same kind of toxicities we see with cytotoxic chemotherapy that's traditionally used in mantle cell lymphoma. But I think the subgroup of patients with P53 mutation in this disease still represent an area of unmet need that unfortunately have worse outcomes. But novel agents may be able to overcome some of those adverse outcomes. Dr. John Sweetenham: Yeah, I agree. I think these are intriguing data, and obviously it needs more follow-up and probably more prospective studies. But nevertheless, I think there are some signals there for sure that need to be followed up on. Marc, as always, it's great to have your insights on key advances in the heme space from ASCO. An important year this year, and we really appreciate your time and effort in sharing with us your thoughts on what we've learned this year. So thank you as always. Dr. Marc Braunstein: My pleasure. Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: 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. Find out more about today's guest: Dr. Marc Braunstein @docbraunstein Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Marc Braunstein: Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp Speakers' Bureau: Janssen Oncology Research Funding (Institution): Janssen, Celgene/BMS

Drs. Velcheti and Pennell discuss key studies presented at ASCO 2024 about novel lung cancer treatments. They cover Plenary abstracts LAURA and ADRIATIC, advancements in palliative care, LORA study on Osamertinib, targeted therapies, next-gen inhibitors, and new treatment efficacy and tolerability.

Dr. Shaalan Beg highlights practice-changing studies in GI cancers featured at the 2024 ASCO Annual Meeting, including the ESOPEC trial in esophageal adenocarcinoma and durable responses to PD-1 blockade alone in mismatch repair-deficient locally advanced rectal cancer. TRANSCRIPT Geraldine Carroll: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Shaalan Beg, an adjunct associate professor at UT Southwestern Simmons Comprehensive Cancer Center. Dr. Beg will be discussing practice- changing abstracts and other key advances in GI oncology that were presented at the 2024 ASCO Annual Meeting. His full disclosures are available in the transcript of this episode. Dr. Beg, thanks for being on the podcast today. Dr. Shaalan Beg: Thank you for having me. Geraldine Carroll: Let's begin with LBA1, the ESOPEC trial. This was featured in the Plenary Session, and this study compared two treatment strategies for locally advanced esophageal adenocarcinoma that could be treated with surgery. The strategies include the CROSS protocol, which consisted of chemoradiotherapy before surgery, and the FLOT protocol of chemotherapy before and after surgery. Can you tell us about this practice-changing study, Dr. Beg? Dr. Shaalan Beg: Yes. According to this study, perioperative chemotherapy with FLOT was better than neoadjuvant therapy with chemoradiation and carbo-taxol for people with adenocarcinoma of the esophagus. There were 438 patients enrolled on this phase 3 study. R0 resection rates were fairly similar across both groups. The PCR rates were a little higher on the FLOT group. But when you look at the median overall survival difference, 66 months in the FLOT group versus 37 months in the CROSS group, 3-year survival was 57% versus 50% favoring FLOT therapy as well. So a couple of caveats on this clinical trial, because the first thing to note is that the standard treatment for this disease has evolved because we now don't only give CROSS chemoradiation, we also give immunotherapy after the completion of chemoradiation for this group of patients. And in this study, since it predated that standard of care, patients did not receive immunotherapy. But having said that, the take home for me here is that chemotherapy is better than chemoradiation for this group of patients, recognizing the fact that 1) they only enrolled adenocarcinoma patients, and 2) patients with high T stage were not included. So the folks with high T stage would be those who we would expect would benefit from the radiation aspect. So my take home here is that more chemotherapy is better in the perioperative space. Radiation should be considered for individuals who need more local control. But in general, I think we're going to see us moving more towards chemotherapy-based regimens with FLOT for this group of patients. Geraldine Carroll: Great. So moving on to rectal cancer, in LBA3512, investigators reported durable, complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. Can you tell us more about the promising durable responses that occurred in this trial? Dr. Shaalan Beg: On first glance, seeing that immunotherapy has good activity in patients with mismatched repair deficient rectal cancer isn't really headline breaking news anymore. We've known about this activity for this group of patients for many years. Earlier at ASCO, the investigators presented early results of this compound for people receiving six months of dostarlimab therapy for people with mismatched repair deficient, locally advanced rectal cancer, and showed that they had a very high complete response rate. At that time, it generated a lot of interest and there was a lot of curiosity on whether these outcomes will be sustained. We don't know other characteristics of their biologic status and whether this was some sort of reflection of the patients who are selected or not. So here in this presentation at ASCO 2024, they did come back to present follow-up data for people with mismatch repair deficient colorectal cancer, having received 6 months of dostarlimab. Forty-seven patients had been enrolled, and the 41 patients who had achieved a clinical complete response continued to have disease control with no distant metastases. So that's very compelling information. There were no additional serious adverse events greater than grade 2 that they saw, and they did follow circulating tumor DNA, and those did normalize even before they had their colonoscopy to examine their tumors. So, again, we're continuing to see very encouraging data of immunotherapy, and the response rate with dostarlimab seems to be very interesting for this disease, and it will be interesting to see how this pans out in larger studies and how this translates into the use of dostarlimab across other diseases where other checkpoint inhibitors are currently being used. Geraldine Carroll: Absolutely. So, moving on to LBA3501. The COLLISION trial looked at surgery versus thermal ablation for small cell colorectal liver metastases. This was an international, multicenter, phase 3, randomized, controlled trial. How will this study change clinical practice? Dr. Shaalan Beg: Kudos to the investigators here. They looked to understand the difference in outcome in treating people with colorectal cancer with liver only metastases. These clinical trials are extremely difficult to design. They're very difficult to enroll on because of the multidisciplinary aspect of the interventions and patient and provider biases as well. So on this clinical trial, the investigators enrolled people with resectable colorectal cancer, liver metastases so they did not have any metastases outside the liver. Patients were required to have 10 or less known metastases that were less than 3 cm in size. There were other allowances for larger tumors as well. And after an expert panel review, patients were randomized to either resection or ablation. It was up to the physicians whether they performed these laparoscopically or openly or percutaneously, depending on the biology of the patient and the anatomical presentation. There was a predefined stopping rule at the half-time for this clinical trial, which showed a benefit in the experimental arm of ablation compared to standard of care. The overall survival was not compromised. Progression-free survival was not compromised with local therapy. But there were differences in morbidity and mortality, as we would expect, one being a surgical procedure and the other being ablation, where, according to this study, of the 140 or so patients who received either treatment, 2.1% of people who underwent resection died within 90 days of surgery. The AE rate was 56% in the resection sample compared to 19% in ablation, and the 90-day mortality for ablation was 0.7%. So less morbidity, improved mortality, reduced adverse events with ablation versus surgical resection without compromising local control and overall survival. And I think for practice here in the United States, this does provide very interesting data for us to take back to the clinic for lesions that are relatively small and could generally be addressed by both surgery and ablation. Historically, there are various non biologic factors that could go into deciding whether someone should have surgery or ablation, and it could be based on who the physician is, who's seeing the patient, what the practice patterns in a specific organization are, and where their expertise lie. But here we're seeing that ablation for the small lesions is a very effective tool with very good local control rates, and again, in this selected group of patients with liver only metastases. And I think it is going to make tumor board discussions very interesting with data backing ablation for these lesions. Geraldine Carroll: Well, let's move onto the MOUNTAINER study. This study created some buzz in the colorectal cancer space. That's Abstract 3509. Can you tell us about the final results of this phase 2 study of tucatinib and trastuzumab in HER2-positive metastatic CRC? What are your thoughts on this treatment option, which seems to be well tolerated? Dr. Shaalan Beg: So, HER2 overexpression or amplification occurs in about 3 to 5% of patients with metastatic colorectal cancer and up to 10% of people who have a RAS/RAF wild type disease. On the previous episodes of the podcast we have covered precision targeted therapy in colorectal cancer, focusing on c-MET, focusing on BRAF, and here we have updated results targeting HER2 for colorectal cancer. And the results of the MOUNTAINEER study have been out for a while. This is a phase 2 study looking at combining tucatinib which is a highly selective HER2 directed TKI with trastuzumab, the monoclonal antibody for HER2 targeting. And what they found on this study is the confirmed overall response rate was 38%. Duration of response was 12 months, overall survival was 24 months and these are the results that have been already released and now we have an additional 16 months of follow up and these results continue to hold on. PFS and overall survival gains were held, which makes it a very interesting option for people with colorectal cancer. You mentioned the tolerability aspect and side effects. I think it's important to know the spectrum of side effects for this disease may be a little different than other TKIs. There's hypertension, but there's also the risk of diarrhea, back pain and pyrexia, with the most common grade 3 treatment related adverse event was an increase in AST level seen in 10% of people of grade 3 and above. So where does that really leave us? There is a confirmatory randomized first-line trial of tucatinib and trastuzumab in the first line setting, which is currently ongoing. So we'll stay tuned to see where that leads us. And with the HER2 space right now for colorectal cancer with the development of antibody drug conjugates, we may have more than one option for this group of patients once those trials read out. Geraldine Carroll: Excellent. Well, moving on to LBA4008, that's the CheckMate-9DW trial. This trial reported first results looking at nivolumab plus ipilimumab versus sorafenib or lenvatinib as first-line treatment for advanced hepatocellular carcinoma. Can you tell us about this trial? Will there be a potential new standard of care in advanced HCC? Dr. Shaalan Beg: When we think about patients with advanced HCC, the only treatment option that they had for about a decade and a half were just oral track tyrosine kinase inhibitors that had modest to moderate clinical activity. Since then, we've seen that combination therapy is better than TKI therapy, and the combination therapy has taken two different forms. One is a combination of checkpoint inhibitor and antiangiogenic therapy, such as in the combination of atezolizumab and bevacizumab. The other is a combination of dual checkpoint inhibitor therapy. Here we are talking about the results of nivolumab and ipilimumab. Previously, we've talked about the combination of durva and tremi for the treatment of patients with HCC. So in this study, nivo was given for the first 4 cycles, nivo and ipi were given together, nivo 1 mg per kg, and IPI 3 mgs per kg every 3 weeks for 4 cycles. And then the CTLA-4 inhibitor ipilimumab was stopped. And this was followed by monotherapy nivolumab every 4 weeks until disease progression or up to 2 years. And it was compared to dealers' choice, lenvatinib or sorafenib. The median overall survival of nivo-ipi was 23 months versus 20 months with lenvatinib-sorafenib. The 24-month overall survival was 49% with ipi-nivo versus 39%. And the overall response rate with nivo-ipi was 36% compared to 13%. So again, significantly improved clinical activity. And when we talk about immunotherapy combinations, the question that comes to mind is how well is this tolerated? There's a lot of work and iteration that took place in figuring out what the right combination strategy of ipi and nivo should be, because some of the earlier studies did demonstrate fairly high adverse events in this group of patients. So on this study, we saw that grade 3 or 4 treatment related adverse events were seen in 41% of people who received nivo-ipi and 42% if they received lenvatinib or sorafenib. So, certainly a high proportion of treatment related adverse events, but probably also reflective of the disease population, which is being tested, because those numbers were fairly similar in the control arm as well. So we've known that nivo-ipi is active in HCC. There is an approval in the second-line space, so it remains to be seen if this data helps propel nivo-ipi to the first-line space so we end up with another combination regimen for patients with advanced hepatocellular carcinoma. Geraldine Carroll: Excellent. Well, before we wrap up the podcast, I'd like to ask you about LBA3511. In this study, investigators looked at total neoadjuvant treatment with long course radiotherapy versus concurrent chemoradiotherapy in local advanced rectal cancer with high risk factors. So this was a multicenter, randomized, open label, phase 3 trial. What are your key takeaways here? Dr. Shaalan Beg: Key takeaway here is that total neoadjuvant therapy was better than the conventional chemoradiation followed by chemo. So this clinical trial enrolled people with T4a/b resectable disease with clinical N2 stage, and they were randomized, as you mentioned, to receiving chemoradiation with radiation capecitabine followed by surgery, and then CAPOX or capecitabine versus chemo, short-course radiation, and additional chemotherapy followed by surgery. And when we compare both arms, the total neoadjuvant therapy led to improved disease-free survival, improved PCR rates compared to standard concurrent neoadjuvant chemo radiotherapy in this group of patients. The two arms were fairly well-balanced. The number of T4 lesions was a little higher in the chemoradiation group. There were 49% in the chemo radiation group versus 46% had clinically T4 disease, but the nodal status was fairly similar. We should keep in mind that the other baseline characteristics were fairly well balanced. And when we look at the outcomes, the disease-free survival probability at 36 months was 76% in the total neoadjuvant group compared to 67% with chemoradiation. And the metastasis free survival in total neoadjuvant therapy was 81% versus 73%. So a fairly compelling difference between the two arms, which did translate into an overall survival of 89% versus 88% in the two groups. So definitely higher disease-free survival and metastasis free survival, no difference on the overall survival with these groups. And it talks about the importance of intensifying chemotherapy upfront in this group of patients who can have a fairly high burden of disease and may struggle with receiving chemotherapy postoperatively. Geraldine Carroll: Excellent. Well, thank you, Dr. Beg, for sharing your fantastic insights with us on these key studies from the 2024 ASCO Annual Meeting. It's certainly a very exciting time in GI oncology. Dr. Shaalan Beg: Absolutely. Thank you for bringing these studies out, because I think a lot of these are practice-changing and can start impacting the clinical care that we're giving our patients right now. Geraldine Carroll: Thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: 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. 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. Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Shaalan Beg: Consulting or Advisory Role: Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen Speakers' Bureau: Sirtex Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in the neoadjuvant immunotherapy space that were presented at the 2024 ASCO Annual Meeting, including promising outcomes in high-risk melanoma from the NADINA trial, as well as other new treatment options for patients with advanced cancers. TRANSCRIPT Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I am an associate professor of medicine and the clinical director of the Melanoma Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I am delighted to have my colleague and friend Dr. Jason Luke on the podcast today to discuss key late-breaking abstracts and advances in immunotherapy that were presented at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the associate director of clinical research, and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Hillman Cancer Center. You will find our full disclosures in the transcript of this episode. Jason, it's always a pleasure to hear your insights on the key trials in these spaces and to have you back as a guest on this podcast that highlights some of the work, especially advances, that were just presented. Dr. Jason Luke: Well, thanks very much for the invitation. I always love joining the podcast. Dr. Diwakar Davar: We'll start very quickly by talking about some advances and really interesting things that happened both in the context of melanoma but also in immunotherapy in general. And we'll start with what I think was certainly one highlight for me, which was LBA2, the late-breaking abstract on the NADINA trial. It was featured in the Plenary Session, and in this abstract, Dr. Christian Blank and colleagues reported on the results of this phase 3 trial of neoadjuvant ipi-nivo. This is the flipped dose of ipi1/nivo3 versus adjuvant nivolumab in PD-1 naive, macroscopic, resectable, high-risk stage 3 melanoma. By way of background, neoadjuvant immunotherapy for those listening is an area of increasing interest for drug developers and development for both approved and novel agents. Neoadjuvant immunotherapy has been studied with multiple approved agents, including PD-1 monotherapy, PD-1 LAG-3, PD-1 CTLA-4, T-VEC, as well as investigational agents and multiple randomized and non-randomized studies. The benchmark pathologic response rates with these agents range from 17% PCR with PD-1 monotherapy, 45% to 55% PCR with PD-1 CTLA-4 combination therapy, and slightly higher 57% PCR with PD-1 LAG-3 has recently reported by Dr. Rodabe Amaria from MD Anderson. However, as we embark on phase 3 comparisons for various neoadjuvant compared to adjuvant immunotherapy trials and combinations, we're increasingly moving towards event-free survival as the primary endpoint for neoadjuvant versus adjuvant studies. And this was most recently studied in the context of SWOG S1801, a study that was led by Dr. Sapna Patel. So, Jason, before we start on NADINA, can you briefly summarize the SWOG S1801 trial and the event-free survival statistic reported by Dr. Patel and her colleagues? Dr. Jason Luke: Well, absolutely. And these data were reported at ESMO about two years ago and then in the New England Journal last year. The S1801 study answered a very simple question: What would happen if you took three of the doses of standard adjuvant therapy with pembrolizumab and moved them prior to surgery? And on a high level, the study is as simple as that. And many of us were somewhat skeptical of this trial design because we thought that just moving the doses earlier may not actually have a major impact. In the study, you alluded to the event-free survival statistic, and that alludes to what was considered an event. And so, without reading all of it, there were several different aspects that were included in terms of time, based on the date of randomization until the first of a series of events, such as disease progression, toxicity from treatment, if the patient was unable to go to surgery or had surgical complications, or if they had delay in starting the adjuvant therapy due to toxicity, and obviously, recurrence of melanoma or death from any cause. In that context, merely moving the 3 doses of pembrolizumab to the neoadjuvant setting saw an improvement in this two-year event free survival to 72% for the neoadjuvant therapy compared to 49% for the adjuvant therapy. That was quite an outstanding change. And again, noting the power of neoadjuvant treatment, really dictating the impact of anti PD-1, again, just with 3 doses moving from adjuvant into the neoadjuvant setting, and I think all of us were somewhat surprised to see that magnitude of a benefit. But it set up the current study very well, where we now look at combination therapy. Dr. Diwakar Davar: So let's move on to the phase 3 NADINA trial. Do you want to perhaps discuss the study design, particularly focusing on the EFS primary endpoint and maybe also touching on the different schedules? So, SWOG S1801 was a neoadjuvant study of 3 cycles of pembrolizumab and how did that compare and contrast to the neoadjuvant combination that was studied in NADINA? Dr. Jason Luke: Well, as you alluded to, NADINA investigated the regimen of nivolumab plus ipilimumab and compared that against adjuvant therapy with nivolumab alone. So, in the study, as you alluded, the dose and schedule of the two drugs used was nivolumab at 3 milligrams per kilogram, and ipilimumab with 1 milligram per kilogram. That was based on a series of signal finding and safety studies that had been previously done by the same group of authors identifying that as the optimal treatment regimen. And it's worth noting that's slightly different than the labeled indication that's generally used for those same drugs for metastatic melanoma, albeit that the NCCN also endorses this schedule. So, in the trial, 423 patients were randomized, 1:1 to receive either neoadjuvant therapy with those 2 doses of nivolumab plus ipilimumab as compared with standard adjuvant therapy with nivolumab following surgery. Now, one interesting tweak was that there was an adaptive nature to the study, meaning that patients had a fiducial placed at the index lymph node, and after the neoadjuvant therapy in that arm, that lymph node was removed. And if the patient had a major pathological response, they did not go on to receive the adjuvant portion of the treatment. So it was adaptive because those patients who did very well to the neoadjuvant did not require the adjuvant portion. And in those patients who did not achieve a major pathological response, they could go on to have the adjuvant therapy. And that also included the BRAF therapy for those whose tumors were BRAF mutants. It's also worth pointing out that the definition of event free survival was slightly different than in the S1801 study that was alluded to just a second ago. And here, EFS was defined from the date of randomization until progression due to melanoma or due to treatment. So that's slightly different than the definition in the S1801 trial. So, a somewhat complicated study, but I really applaud the authors because I think this study does mirror what we would likely be doing in actual clinical practice. Dr. Diwakar Davar: So, just to briefly summarize the efficacy, and then to get your comments on this, the path response, the PCR rate was 47%. The major pathologic response rate, which is the proportion of patients with between 0% to 1/10% of residual viable tumors, was about 12%. And for a major pathologic response rate of 0% to 10% of 59%. And then the rest of the patients had either pathologic partial response, which was 10% to 50%, or pathologic non response or 50% or greater residual viable tumor, all assessed using central pathology grades. The one year RFS was 95% in the FDR patient population versus 76% in the pathologic partial response patient population, 57% in the pathologic non response patient population. So how do you view these results? Can you context the FDR rates and the EFS rates from NADINA relative to nivo-rela and also potentially SWOG 1801? Dr. Jason Luke: Well, I think these are very exciting results. I think that for those of us that have been following the field closely, they're actually not especially surprising because they mirror several studies that have come before them. When we put them in context with other studies, we see that these rates of major pathological response are consistent with what we've seen in phase 2 studies. They're relatively similar. Or I should say that the results from nivolumab and relatlimab, which was also pursued in a phase 2 study of somewhat similar design, are somewhat similar to this. So, combination immunotherapy does look to deliver a higher major pathological response than pembrolizumab alone, as was known in S1801. Which of course, the caveat being is these are cross control comparisons that we need to be careful about. So I think all of these are active regimens, and I think adding a second agent does appear to enhance the major pathologic response rates. When we look at the event free survival, we see something similar, which is that numerically it looks to be that combination immunotherapy delivers a higher event free survival rate. And that looks to be rather meaningful given the difference in the hazard ratios that were observed between these various studies. And here in the NADINA study, we see that 0.3 hazard ratio for EFS is just extremely impressive. So the abstract then, from ourselves, out of these specific studies, what does this mean more broadly in the real world, where patients exist and the rest of the landscape for clinical trials? I think we can't take enough time to stop for a second and just think about what a revolution we've come forward in with immune checkpoint blockade and melanoma. When I started my career, now, more than 15 years ago, melanoma was the cancer that made cancer bad. And now here we say, in the highest risk of perioperative patients, we can deliver 2 doses of nivolumab and ipilimumab, and essentially half of the patients then don't need to go on, and more than half the patients don't need to go on to have a full surgery and don't need adjuvant therapy. And from what we could tell of a very, very low risk of every heavy recurrence of melanoma. Of course, there's the other half of patients where we still need to do better, but these are just fantastic results and I think highly meaningful for patients. In the context of ongoing clinical trials, another abstract that was presented during the meeting was the update to the individualized neoantigen therapy, or V940 with pembrolizumab or against pembrolizumab alone. That's the KEYNOTE-942 study. In that study, they presented updated data at two and a half years for relapse free survival, noting a 75% rate without relapse. So those results are also highly intriguing. And these are in a similar population of very high risk patients. And so I think most of us believe that neoadjuvant therapy with this study in NADINA is now confirmed as the priority approach for patients who present with high-risk stage 3 disease. So that would be bulky disease picked up on a scan or palpable in a clinic. I think essentially all of us now believe patients should get preoperative immunotherapy. We can debate which approach to take, and it may vary by an individual patient's ability to tolerate toxicity, because, of course, multi agent immunotherapy does have increased toxicity relative to anti PD-1 alone. But we'll have to wait now for the full phase 3 results from the V940 individualized neoantigen therapy. And if those come forward, that will be an extremely attractive approach to think about for patients who did not achieve a major pathological response to neoadjuvant therapy, as well as of course to the other populations of patients with melanoma where we otherwise currently give adjuvant therapy stage 2B all the way through stage 4 resected. It's an amazing time to think about perioperative therapy in melanoma. Dr. Diwakar Davar: So this is clearly outstanding data, outstanding news. Congratulations to the investigators for really doing what is an investigative initiated trial conducted across multiple continents with a huge sample size. So this clearly appears to be, at this point in time at least, a de facto standard. But is this going to be FDA-approved, guideline-approved, or is it possible in your mind? Dr. Jason Luke: Well, that's an interesting question. This study was not designed with the intent to necessarily try to register this treatment regimen with the FDA. One would have to take a step back and say, with how powerful these data appear, it sort of seemed like it would be too bad if that doesn't happen. But all the same, I think the community and those of us who participate in guideline recommendations are fully supportive of this. So, I think we will see this move into compendium listings that support insurance approval, I think, very, very quickly. So, whether or not this actually becomes formally FDA approved or is in the guidelines, I think this should become the standard approach that is considered for patients, again presenting with high-risk stage 3 disease. Dr. Diwakar Davar: Fantastic. So now we're going to go in and talk about a slightly different drug, but also from the melanoma context, and that is the safety and efficacy of RP1 with nivolumab in the context of patients with melanoma who are PD-1 failures. So, this is Abstract 9517. And in this abstract, our academic colleagues essentially talked about these data, and we'll start by describing what RP1 is. RP1 essentially is a HSV-1 based oncolytic immunotherapy. And RP1 expresses GM-CSF as well as a fusogenic protein, GALV-GP-R-. And in this abstract, Dr. Michael Wong from MD Anderson and colleagues are reporting the results of IGNYTE, which is a phase I trial of intratumoral RP1 co-administered with systemic nivolumab in patients with advanced metastatic treatment refractory cutaneous melanoma. And the data presented in this abstract represents data from a registration directed, abbreviated as RD, registration directed cohort of RP1 plus nivolumab in PD-1 refractory melanoma. So, let's start with the description of the cohort. Dr. Jason Luke: Right. So, in this study, there were a total of 156 patients who were presented, and that included an initial safety and dose finding group of 16, as well as the RD cohort, as you noted, of 140 patients. And it's important to point out that this was a cohort that was selected for a very strict definition of progression on anti PD-1, or a combination immunotherapy as their immediately prior treatment. So, all of the patients in the cohort had exposure to anti PD-1, and 46% of them had anti PD-1 plus anti CTLA4, nivolumab and ipilimumab as their immediately prior therapy. This was also a group of relatively high-risk patients when one considers stage. So, within the stage 4 population, the entry here included 51% who had stage M1B, C, and D melanoma. And that is worth pointing out because this is an injectable therapy. So, trials like this in the past have tended to be biased towards earlier stage, unresectable or metastatic melanoma, meaning stage 3B, 3C, 3D and then stage 4m1a. Again, to emphasize the point here, these were pretreated patients who had a strict definition of anti PD-1 resistance, and over half of them, in fact, had high-risk visceral metastatic disease. In that context, it's very interesting to observe that the overall response rate was described in the total population, as 31%, and that included 12% who achieved complete response. And so, again, to make sure it's clear, we're talking about a treatment where the oncolytic virus is injected into one or multiple sites of recurrent disease, and then the patients administer nivolumab as per standard. And so, I think these data are quite intriguing. Again, such a high- risk population and their maturity now, with a follow-up of over a year, I think, makes this look to be a very interesting treatment option. Dr. Diwakar Davar: I guess on that topic of mature follow-up, it probably would be important for us to inform our audience that the top line data for the primary analysis was actually just released, I think, earlier today, and wherein the central confirmed objective response rate was 34% by modified RECIST and 33% by RECIST, clearly indicating that these responses, as you noted, very treatment refractory patient population, these responses were clearly very durable. So, you mentioned that there were responses seen in uninjected visceral lesions, responses seen in both PD-1 and PD-1 CTLA-4 refractory patients. Can you talk a little bit about the response rate in these high-risk subgroups, the uninjected visceral lesions, the patients who had both combination checkpoint and epidural refractory response rate by primary PD-1 resistance. Dr. Jason Luke: Sure. You know, I think, again, to emphasize this point in the study, we saw that there were responses in the non-injected lesions, and I think it's really important to emphasize that. Some have referred to this as a putative abscopal like effect, similar to what is described in radiation. But it implies that local treatment with the oncolytic virus is triggering a systemic immune response. In the higher risk patient population, we'll note that whereas the overall response rate in PD-1 refractory patients was 34%, in the combination of PD-1 and CTLA-4 refractory patients, the response rate was 26%. So, [this is] still very good. And when we looked at that split by stage, as I alluded to before, in the population of patients that had, what you might call earlier unresectable diseases, so 3B through 4A, the response rate was 38%, and in the stage 4 M1b through M1d, it was 25%. So slightly lower, but still very good. And that would be as expected, because, of course, the patients with visceral metastatic disease have more advanced disease, but those response rates look quite good. Again, looking at the combination refractory population as well as the more high-risk disease. Dr. Diwakar Davar: So, clearly, these are very promising data and exciting times for multiple investigators in the field and the company, Replimune, as well. So, what are the next steps? I believe that a registration trial is planned, essentially, looking at this with the goal of trying to get this combination registered. Can you tell us a little bit about IGNYTE-3, the trial design, the control arm, and what you foresee this trial doing over the next couple of years? Dr. Jason Luke: So, as this agent has been maturing, it's worth pointing out that the company that makes this molecule, called RP1, but I guess now we'll have to get used to this name vusolimogene oderparepvec as the actual scientific term, they have been having ongoing discussions with the FDA, and there is the potential that this agent could come forward on an accelerated path prior to the results being released from a phase 3 trial. That being said, the phase 3 confirmatory study, which is called the IGNYTE-3 study, is in the process of being launched now. And that's a study investigating this molecule in combination with nivolumab, as was alluded to earlier, and a randomized phase 3 design, where that combination is compared with a physician's choice, essentially a chemotherapy-based option. In that study, it will be 400 patients with stage 3B through stage 4; patients will have progressed on anti PD-1, either as a combination or in sequence, and then come on the study to be randomized to either vusolimogene oderparepvec plus nivolumab versus that physician's choice. And the physician's choice includes chemotherapy agents, but also nivolumab plus relatlimab as another option, or an anti PD-1 monotherapy, if that's deemed to be a reasonable option by the treating investigator. And the primary endpoint of that study is overall survival. And unfortunately, in this highly refractory patient population, that's something that may not take long to identify with key secondary endpoints of progression free survival, as well as overall response rate. I'm quite enthusiastic about this study, given these data, which have now been centrally confirmed as you alluded to before. I think this is a very exciting area of investigation and really crossing my fingers that this may be perhaps the first locally administered therapy which does appear to have a systemic impact that can hold up in phase 3. Dr. Diwakar Davar: Very, very, very exciting results. And I guess it's worthwhile pointing out that this company also has got, I think, multiple studies planned with both RP1 and cutaneous squamous cell carcinoma in a solid organ transplant patient population where single agent activity has already been reported by Dr. Migden at prior meetings, as well as a novel trial of potentially RP2 metastatic uveal melanoma. So we'll now pivot to Abstract 6014. So, 6014 is a drug by a company known as Merus. Essentially, it's a very novel agent. Merus essentially is a company that is specialized in making bicyclics and tricyclics. And these are not bicycles or tricycles, but rather drugs that essentially are bispecific antibodies. And Merus essentially has come up with petosemtamab. I think we're going to have to figure out better names for all of these drugs at some point. But petosemtamab, or MCLA-158, essentially is a bicyclic, targeting both EGFR as well as LGR-5. So EGR-5, of course, is a known oncogenic driver in multiple tumor types, squamous, including non small cell lung cancer, cutaneous squamous cell carcinoma, but also head and neck squamous cell carcinoma. And LGR-5 essentially is leucine-rich repeat-containing G-protein coupled receptor 5, but it's a receptor in cancer stem cells and certainly highly expressed in head neck squam. And MCLA-158, or petosemtamab is a IgG one bispecific with ADCC-activity because of IgG1 backbone co-targeting EGFR and LGR5. Merus had earlier results that evaluated petosemtamab monotherapy. They defined the RP2D and second- and third-line head and neck blastoma patients with a respectable response rate of 37% investigator-assessed ORR with six months median DoR, and this was published by Ezra Cohen about a year or so ago. In this abstract, Dr. Fayette and colleagues report on the results of the MCLA-158-CL01 trial, which is a trial of pembrolizumab plus petosemtamab in one front line head and neck squamous cell population. So maybe let's start with the description of the cohort. And it is a small trial, but we'll be able, I think, to dig into a little bit about why this might be exciting. Dr. Jason Luke: Yes. So, as alluded to, it's not the biggest trial as yet, but there were 26 patients with anti PD-1 treatment naive head and neck squamous cell carcinoma. And all the patients in the study did receive, as you alluded to, pembrolizumab plus petosemtamab. Based on the label for pembrolizumab, all the patients in this study were PDL-1 positive. So that's one point that it's worth pointing out to make sure that that's understood. This is the population of patients who would be expected to benefit from pembrolizumab in the first place. Now, in the abstract, they reported out only 10 response evaluable patients, but they updated that in the actual slides of presentation at the meeting. So among 24 patients that were alluded to, 67% were described as having had a response, although some of those were yet to be confirmed responses. And when it was evaluated by PDL-1 status, there didn't seem to be a clear enrichment of response in the PD-1 positive more than 20% group, as compared to the 1-19% group. That isn't especially surprising because that was a trend that one would see, presumably with pembrolizumab alone. But overall, I think these data are pretty exciting in terms of a preliminary study. Dr. Diwakar Davar: You know, you mentioned that the objective response rate was high, almost 60-something%. The prognosis of these patients is generally poor. The OS is typically thought of as between 6-15 months. And based on KEYNOTE-048, which was led by Dr. Burtness and colleagues, the standard of care in the setting is pembrolizumab +/- platinum based chemotherapy regimens. Allowing for the fact that we only have 10 patients here, how do you think these results stack up against KEYNOTE-048? And you made a very important point earlier, which was, by definition, pembro is on label only for the CPS. So PDL-1 score, at least in head and neck squamous cell carcinoma CPS and not TPS. But in the CPS 1% or greater patient population, where pembro is on label, how do these results stack up against the KEYNOTE-048 results. Dr. Jason Luke: Right. KEYNOTE-048 is considered the seminal study that dictates frontline treatment in head and neck cancer. And before we dive into this too far, we do want to acknowledge that here we're comparing 26 patients versus a phase 3 trial. So, we're not trying to get too far ahead of ourselves, but this is just a preliminary comparison. But in KEYNOTE-048, as you alluded to, two regimens were superior to chemotherapy. One was the pembrolizumab monotherapy, as well as pembrolizumab plus chemotherapy. So again, the study overall survival, of course, was much higher, the PDL-1 positive subgroup, which is what dictated the unlabeled use of this. But response to pembro monotherapy in that population of patients is still modest. We're talking about upwards of 20-30%. So, if you compare that to, again, preliminary evidence here from this trial of only 24 patients, that response rate of 60% seems extremely high. And so even if that were to come down somewhat in a larger data series of patients, that still looks to be quite promising as a treatment regimen, that might eventually even be chemotherapy sparing for this population of patients. I think this raises a lot of eyebrows that perhaps this dual targeting approach, EGFR and LDR-5, may bring something really important to the field that evolves it. Dr. Diwakar Davar: So, what are the next steps for petosemtamab? You mentioned that the activity was interesting. Are we going to see a larger trial? Any thoughts on where things are going to go? Dr. Jason Luke: Well, based on the phase 2 data of petosemtamab alone, even without pembrolizumab, the molecule had already been given fast track designation by FDA, which means allowing for greater communication between the drug sponsor in the FDA and designing a seminal study design. One would assume that this trial will be rapidly expanded quite greatly, perhaps to 100 or 200 patients, to try to flush out what the real response rate is in a more meaningful number of patients. But I think these data will probably also trigger the design and probably near-term evaluation or expedited acceleration of a phase III clinical trial design that would potentially validate this against the current standard of care. So, I'm pretty excited. I think we'll see a lot more about this agent in the relatively near future. Dr. Diwakar Davar: So, finally, we'll pivot to the last abstract that we're going to talk about, which is Abstract 2504. It's a relatively interesting target, CCR8 monoclonal antibody. But this is the efficacy and safety of LM-108, and LM-108 is an anti CCR8 monoclonal antibody that is being developed by LaNova Medicine. And the results that are described, actually a pool set of results of combinations of LM-108 with anti PD-1, two separate anti PD-1, in patients with gastric cancer, mostly done ex-U.S., which is interesting because of this patient population, and it's a pool result of several, 3 phase 1 and 2 studies. LM-108 is an Fc-optimized anti CCR8 monoclonal antibody that selectively depletes tumor infiltrating Tregs. The abstract reported a pooled analysis of three phase 1, 2 trials with 3 different NCT numbers that all evaluated the efficacy of LM-108 and anti PD-1 in patients with gastric cancer. So, let's start with the description of the cohort. Maybe, Jason, you can tell us a little bit about before you start, as you describe the cohort, sort of what we know, editorially speaking, about the difficulty with which Tregs depletion has been tried and obviously failed up until now in the tumor microenvironment. Dr. Jason Luke: Right. I think that's a really interesting comment. And so, for decades, in fact, targeting regulatory T-cell to alleviate immune exclusion in the tumor microenvironment has been of interest in immuno-oncology. And in preclinical mouse models, it seems quite clear that such an approach can deliver therapeutic efficacy. However, by contrast, in human clinical trials, various different Treg depleting strategies have been attempted, and there's really little to no evidence that depleting Tregs from human tumors actually can deliver therapeutic responses. And by that we're referring to CD-25 antibodies. The drug ipilimumab, the CTLA-4 antibody, was punitively described as a Tregs depleter preclinically, but that doesn't seem to be the case in patients. And so, in that background, this is quite an eye raiser that an anti CCR8 antibody could be driving this effect. Now, before we talk about the results of this trial, I will point out, however, that given the Fc-optimization, it's entirely possible that the Tregs are being depleted by this mechanism, but that more could also be going on. Because Fc gamma RII binding by this antibody that could be nonspecific also has the potential to trigger immune responses in the tumor microenvironment, probably mediated by myeloid cells. So I think more to come on this. If this turns out to be the first meaningful Tregs depletor that leads to therapeutic efficacy, that would be very interesting. But it's also possible this drug could have multiple mechanisms. So, having said all of that, in the clinical trial, which was a pooled analysis, like you mentioned, of LM-108 in combination with anti PD-1 of a couple different flavors, there were 48 patients treated either with LM-108, with pembrolizumab, or with toripalimab, which is another anti PD-1 antibody. On the drug combination was, generally speaking, pretty well tolerated, noting grade 3 treatment related adverse events in the range of 38%, which is somewhat expected given combination immunotherapy. We talked about nivolumab and ipilimumab before, which, of course, gives even higher rates of immune-related adverse events, with the most common toxicities being anemia, lipase elevations, rash, ALC decrease; albeit, quite manageable. Dr. Diwakar Davar: So, what about the objective response rate? Can you contextualize the efficacy? And as you do that, maybe we'll think about what you'd expect in the context of, say, gastric cancer, especially in patients who've never really had a prior checkpoint inhibitor before. What do you think about the ORR? What do you think about the relative efficacy of this combination? Dr. Jason Luke: Well, so, in the study, they described overall response rate in the 36 patients as 36% and described immediate progression for survival of about 6.5 months. And so that was among patients who were treatment naive. And in second-line patients, they actually described an even higher response rate, although it was only 11 patients, but they're at 64%. And so, I think those data look to be somewhat interesting. When I was actually scrutinizing the actual data presented, it was of some interest to note that the quality of responses seemed to be about as good on the lower dose of LM-108, so 3 milligrams per kilogram as compared to 10 milligrams per kilogram. I think there's definitely more to learn here to try to optimize the dose and to fully understand what the overall efficacy of this treatment combination would be. I would emphasize that in this disease, I think novel treatment strategies are certainly warranted. While anti PD-1 with chemotherapy has moved the needle in terms of standard of care treatment, it's really only a minor subset of patients who derive durable long-term benefit like we normally associate with immune checkpoint blockade. I think these are preliminary data. They're very intriguing. You alluded to earlier that this population of patients was an Asian data set, and it is well known that the efficacy of chemotherapy and immunotherapy does appear to be somewhat enhanced in Asian populations, and that goes to distributions of metastasis and tumor microenvironment effects, etc. Very difficult to try to tease any of that out in this abstract, other than to look at these data and suggest that this is pretty interesting, both from a novel therapeutic approach, we talked about the Tregs consideration, but also straight up on the efficacy because I think if these data could hold up in a larger number of patients, and particularly in a western population of patients, I think it would be very intriguing. Dr. Diwakar Davar: Certainly, ASCO 2024 had a lot of interesting data, including data from targeted agents, the LAURA trial, ADCs. But just focusing on the immune therapy subset, we certainly saw a lot of great advances in patients who were treated with neoadjuvant as well as relapse refractory disease in the context of RP1 and then a couple of newer agents such as this petosemtamab as well as LM-108. And of course, we cannot forget to highlight the extended DMFS data from the pembro vaccine study from KEYNOTE-942. Jason, as always, thank you for taking a little bit of time out of your extremely busy schedule to come and give us insights as to how these agents are impacting the landscape. We really value your input and so thank you very much. Dr. Jason Luke: Thank you for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for your time today. You will find the links to all the abstracts that we discussed in the transcript of this episode. And finally, if you value the insights that you hear on this podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. So, thank you. Disclaimer: 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. Follow today's speakers: Dr. Diwakar Davar @diwakardavar Dr. Jason Luke @jasonlukemd Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Diwakar Davar: Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences Consulting or Advisory Role: Instil Bio, Vedanta Biosciences Consulting or Advisory Role (Immediate family member): Shionogi Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences Research Funding (Inst.): Zucero Therapeutics Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy Dr. Jason Luke: Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Dr. John Sweetenham shares highlights from Day 4 of the 2024 ASCO Annual Meeting, including exciting new data from the IMROZ trial in multiple myeloma, adjuvant therapy for triple-negative breast cancer in A-BRAVE, and the front-line treatment of advanced renal cell carcinoma in JAVELIN Renal-101. TRANSCRIPT Dr. John Sweetenham: I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast, with my top takeaways on selected abstracts from Day 4 of the 2024 ASCO Annual Meeting. Today's selection features 3 randomized prospective trials in the first-line treatment of multiple myeloma, adjuvant therapy for triple negative breast cancer, and the frontline treatment of advanced renal cell carcinoma, all of which provide important new data. My full disclosures are available in the transcript of this episode. The first of today's abstracts is number 7500. This abstract, presented by Dr. Thierry Facon from the Department of Hematology at the University of Lille in France, describes the results of the IMROZ study. This was a multicenter phase 3 study comparing a current standard first-line regimen for transplant ineligible patients with myeloma VRd with the same combination plus an additional agent, isatuximab. The combination of bortezomib, lenalidomide and dexamethasone, known as VRd, is currently a standard first-line regimen for patients with multiple myeloma, both transplant eligible and ineligible. Previous phase 3 studies have shown that the addition of an anti-CD38 antibody to triplet regimens improves outcomes in newly diagnosed patients. Based on early phase clinical trial data showing promising response rates with isatuximab, the IMROZ study was conducted to compare isatuximab VRd with VRd alone in patients who were either ineligible for transplant or had no immediate indication for transplant. IMROZ was a global study conducted in 21 countries that involved 446 patients randomly assigned 3:2 to induction therapy with Isa-VRd followed by continuous Isa-Rd or induction therapy with VRd followed by Rd alone. The rate of complete response or better was approximately 75% with Isa-VRd compared with 64% with VRd alone. Very good partial response or better was achieved in 89% of patients with Isa-VRd, compared with around 83% of those with VRd alone. With a median follow-up at 5 years, Isa-VRd followed by Isa-Rd had reduced the risk of progression or death by 40.4% compared with VRd alone. The 60-month progression-free survival rate was 63% for Isa-VRd compared with around 45% with VRd alone, and the progression-free survival benefit was maintained in most of the analyzed subgroups. Minimal residual disease negativity was also measured in this study in both the intent to treat population and those patients who achieved a complete response. For example, in the intent to treat population, the MRD negative rate was 58% with Isa-VRd compared with around 43% with VRd alone. There were also higher rates of sustained MRD negativity for 12 months or longer among patients assigned to Isa-VRd compared with VRd alone, reflecting deeper responses in the Isa-VRd arm. Although overall survival data is still immature, data from an interim analysis showed a favorable trend in the Isa-VRd arm with 22.4% risk reduction compared with VRd alone. There was little additional toxicity from the inclusion of isatuximab with the VRd regimen and the quality-of-life data were comparable and stable in both arms of the study. The investigators concluded that although overall survival data are immature, there is a trend in favor of Isa-VRd and this, combined with the favorable response, toxicity and progression-free survival data, establish isatuximab VRd as a potential new standard of care for newly diagnosed multiple myeloma patients not eligible for transplant. There was some discussion regarding the potential use of this regimen in patients over 80 years of age since the upper age limit was capped in IMROZ at 80 years. Although there are concerns for tolerance of the 4-drug regimen in the older patient group, it seems likely that this will be adopted, especially for those with good performance status and without major comorbidities. Next up is LBA500. This abstract reports results of the A-BRAVE trial. This trial, presented by Dr. Pier Franco Conte from the University of Padova, Italy, was a phase 3 randomized trial to assess the efficacy of the immune checkpoint inhibitor avelumab in 2 groups of patients: those with early triple negative breast cancer, with residual disease after neoadjuvant chemotherapy; and those at high risk after primary surgery and adjuvant chemotherapy. As Dr. Conte explained in the introduction to this trial, there is a fairly compelling rationale for the use of checkpoint inhibitors in triple negative breast cancer. The disease has been shown to be more immunogenic than the other breast cancer types with immune biomarkers such as TILs and PDL-1 expression associated with better prognosis, added to which, data in metastatic breast cancer show a correlation between PDL-1 expression and checkpoint inhibitor response. In the A-BRAVE study, 477 high risk patients who had completed local, regional, and systemic treatment with curative intent were stratified according to adjuvant or post neoadjuvant status and randomized 1:1 to receive avelumab at 2-week intervals for 52 weeks or to observation only. Results of the study showed a non-statistically significant improvement in three-year disease-free survival in the overall intent to treat population at 5.1% and in the post neoadjuvant patients at 6.2%. Overall survival was a secondary endpoint in this trial. The results show a significant improvement in overall survival of 8.1% in the intent-to-treat population and a very similar improvement in the post-neoadjuvant patients. The authors reported good tolerance of avelumab, although in total almost 30% discontinued treatment at some point. In their conclusion, the investigators state that the 34% reduction in the risk of death suggests a potential role for avelumab in early triple negative breast cancer patients at high risk after primary surgery or with invasive disease after neoadjuvant chemotherapy. Correlative studies are planned on tumor plasma and feces in this study. These are interesting and somewhat tantalizing results, suggesting a real effect from avelumab. Although confounded somewhat by the sample size, it will be important to see how these results mature with further follow-up. Today's third selected abstract is number 4508 reporting the final analysis of the JAVELIN Renal 101 phase 3 trial in patients with advanced renal cell carcinoma. This study compared the combination of axitinib plus avelumab with sunitinib in this patient group. The trial included 886 patients, of whom around 61% of those in the combination group and around 65% of those in the monotherapy group were PDL-1 positive. In the initial analysis from the JAVELIN Renal 101 study, after at least 6 months of follow-up, avelumab and axitinib significantly improved progression-free survival over sunitinib in patients with PDL-1 positive tumors and in the overall population with advanced renal cell carcinoma. In the fall cohort, the median progression-free survival with the combination was 13.8 months compared with only 8.4 months with sunitinib, and based on those results, the combination received FDA approval as a first-line treatment for patients with advanced renal cell carcinoma in May of 2019. The progression-free survival observed in the initial analysis was confirmed with a new long-term analysis in the overall population. Median progression-free survival with avelumab and axitinib was 13.9 months compared with only 8.5 months with sunitinib and the median duration of response with the combination was 19.4 months versus 14.5 months with sunitinib. However, no difference in overall survival was seen. At 60 months, the overall survival in the combination group was 38.8% and 36.2% with sunitinib. In patients who were PDL-1 positive at 60 months, overall survival with a combination was 37.1% compared with 33.4% with sunitinib. Despite the sustained difference in progression-free survival seen with this combination, the discussant at this session pointed out that most oncologists are unlikely to recommend a combination which has not been shown to improve overall survival when published studies have reported on 4 combinations which do positively impact overall survival in this patient group. Despite the good tolerance of this regimen, it seems unlikely to be a preferred frontline regimen in advanced renal carcinoma moving forward. That concludes today's report. Thanks for listening and we hope you have enjoyed listening to our top takeaways from ASCO24. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review and subscribe wherever you get your podcasts. Disclaimer: 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. Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness