Podcasts about janssen oncology

Host Dr. Nate Pennell and his guest, Dr. Chloe Atreya, discuss the ASCO Educational Book article, “Integrative Oncology: Incorporating Evidence-Based Approaches to Patients With GI Cancers,” highlighting the use of mind-body approaches, exercise, nutrition, acupuncture/acupressure, and natural products. Transcript Dr. Nate Pennell: Welcome to ASCO Education: By the Book, our new monthly podcast series that will feature engaging discussions between editors and authors from the ASCO Educational Book. We'll be bringing you compelling insights on key topics featured in Education Sessions at ASCO meetings and some deep dives on the approaches shaping modern oncology.  I'm Dr. Nate Pennell, director of the Cleveland Clinic Lung Cancer Medical Oncology Program as well as vice chair of clinical research for the Taussig Cancer Institute. Today, I'm delighted to welcome Dr. Chloe Atreya, a professor of Medicine in the GI Oncology Group at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, and the UCSF Osher Center for Integrative Health, to discuss her article titled, “Integrative Oncology Incorporating Evidence-Based Approaches to Patients With GI Cancers”, which was recently published in the ASCO Educational Book. Our full disclosures are available in the transcript of this episode.  Dr. Atreya, it's great to have you on the podcast today. Thanks for joining me. Dr. Chloe Atreya: Thanks Dr. Pennell. It's a pleasure to be here. Dr. Nate Pennell: Dr. Atreya, you co-direct the UCSF Integrative Oncology Program with a goal to really help patients with cancer live as well as possible. And before we dive into the review article and guidelines, I'd love to just know a little bit about what inspired you to go into this field? Dr. Chloe Atreya: Yeah, thank you for asking. I've had a long-standing interest in different approaches to medicine from global traditions and I have a degree in pharmacology, and I continue to work on new drug therapies for patients with colorectal cancer. And one thing that I found is that developing new drugs is a long-term process and often we're not able to get the drugs to the patients in front of us. And so early on as a new faculty member at UCSF, I was trying to figure out what I could do for the patient in front of me if those new drug therapies may not be available in their lifetime. And one thing I recognized was that in some conversations the patient and their family members, even if the patient had metastatic disease, they were able to stay very present and to live well without being sidelined by what might happen in the future. And then in other encounters, people were so afraid of what might be happening in the future, or they may have regrets maybe about not getting that colonoscopy and that was eroding their ability to live well in the present.  So, I started asking the patients and family members who were able to stay present, “What's your secret? How do you do this?” And people would tell me, “It's my meditation practice,” or “It's my yoga practice.” And so, I became interested in this. And an entry point for me, and an entry point to the Osher Center at UCSF was that I took the Mindfulness-Based Stress Reduction Program to try to understand experientially the evidence for this and became very interested in it. I never thought I would be facilitating meditation for patients, but it became a growing interest. And as people are living longer with cancer and are being diagnosed at younger ages, often with young families, how one lives with cancer is becoming increasingly important.   Dr. Nate Pennell: I've always been very aware that it seemed like the patients that I treated who had the best quality of life during their life with cancer, however that ended up going, were those who were able to sort of compartmentalize it, where, when it was time to focus on discussing treatment or their scans, they were, you know, of course, had anxiety and other things that went along with that. But when they weren't in that, they were able to go back to their lives and kind of not think about cancer all the time. Whereas other people sort of adopt that as their identity almost is that they are living with cancer and that kind of consumes all of their time in between visits and really impacts how they're able to enjoy the rest of their lives. And so, I was really interested when I was reading your paper about how mindfulness seemed to be sort of like a formal way to help patients achieve that split. I'm really happy that we're able to talk about that. Dr. Chloe Atreya: Yeah, I think that's absolutely right. So, each of our patients is more than their cancer diagnosis. And the other thing I would say is that sometimes patients can use the cancer diagnosis to get to, “What is it that I really care about in life?” And that can actually heighten an experience of appreciation for the small things in life, appreciation for the people that they love, and that can have an impact beyond their lifetime. Dr. Nate Pennell: Just in general, I feel like integrative medicine has come a long way, especially over the last decade or so. So, there's now mature data supporting the incorporation of elements of integrative oncology into comprehensive cancer care. We've got collaborations with ASCO. They've published clinical practice guidelines around diet, around exercise, and around the use of cannabinoids. ASCO has worked with the Society for Integrative Oncology to address management of pain, anxiety, depression, fatigue – lots of different evidence bases now to try to help guide people, because this is certainly something our patients are incredibly interested in learning about. Can you get our listeners up to speed a little bit on the updated guidelines and resources supporting integrative oncology? Dr. Chloe Atreya: Sure. I can give a summary of some of the key findings. And these are rigorous guidelines that came together by consensus from expert panels. I had the honor of serving on the anxiety and depression panel. So, these panels will rate the quality of the evidence available to come up with a strength of recommendation. I think that people are at least superficially aware of the importance of diet and physical activity and that cannabis and cannabinoids have evidence of benefit for nausea and vomiting. They may not be aware of some of the evidence supporting these other modalities. So, for anxiety and depression, mindfulness-based interventions, which include meditation and meditative movement, have the strongest level of evidence. And the clinical practice guidelines indicate that they should be offered to any adult patient during or after treatment who is experiencing symptoms of anxiety or depression. Other modalities that can help with anxiety and depression include yoga and Tai Chi or Qigong. And with the fatigue guidelines, mindfulness-based interventions are also strongly recommended, along with exercise and cognitive behavioral therapy, Tai Chi and Qigong during treatment, yoga after treatment.  And some of these recommendations also will depend on where the evidence is. So, yoga is an example of an intervention that I think can be helpful during treatment, but most of our evidence is on patients who are post-treatment. So, most of our guidelines separate out during treatment and the post-treatment phase because the quality of evidence may be different for these different phases of treatment.  With the pain guidelines, the strongest recommendation is for acupuncture, specifically for people with breast cancer who may be experiencing joint pain related to aromatase inhibitors. However, acupuncture and other therapies, including massage, can be helpful with pain as well. So those are a few of the highlights. Dr. Nate Pennell: Yeah, I was surprised at the really good level of evidence for the mindfulness-based practices because I don't think that's the first thing that jumps to mind when I think about integrative oncology. I tend to think more about physical interventions like acupuncture or supplements or whatnot. So, I think this is really fantastic that we're highlighting this.  And a lot of these interventions like the Qigong, Tai Chi, yoga, is it the physical practice of those that benefits them or is it that it gives them something to focus on, to be mindful of? Is that the most important intervention? It doesn't really matter what you're doing as long as you have something that kind of takes you out of your experience and allows you to focus on the moment. Dr. Chloe Atreya: I do think it is a mind, body and spirit integration, so that all aspects are important. We also say that the best practice is the one that you actually practice. So, part of the reason that it's important to have these different modalities is that not everybody is going to take up meditation. And there may be people for whom stationary meditation, sitting and meditating, works well, and other people for whom meditative movement practices may be what they gravitate to. And so, I think that it's important to have a variety of options. And one thing that's distinct from some of our pharmacologic therapies is that the safety of these is, you know, quite good. So, it becomes less important to say, “Overall, is Tai Chi better or is yoga better?” for instance. It really depends on what it is that someone is going to take up. Dr. Nate Pennell: And of course, something that's been really nice evidence-based for a long time, even back when I was in my training in the 2000s with Jennifer Temel at Massachusetts General Hospital, was the impact of physical activity and exercise on patients with cancer. It seems like that is pretty much a universally good recommendation for patients. Dr. Chloe Atreya: Yes, that's absolutely right. Physical activity has been associated with improved survival after a cancer diagnosis. And that's both cancer specific survival and overall survival.  The other thing I'll say about physical activity, especially the mindful movement practices like Tai Chi and Qigong and yoga, is that they induce physiologic shifts in the body that can promote relaxation, so they can dampen that stress response in a physiologic way. And these movement practices are also the best way to reduce cancer-associated fatigue. Dr. Nate Pennell: One of the things that patients are always very curious about when they talk to me, and I never really feel like I'm as well qualified as I'd like to be to advise them around dietary changes in nutrition. And can you take me a little bit through some of the evidence base for what works and what doesn't work? Dr. Chloe Atreya: Sure. I do think that it needs to be tailored to the patient's needs. Overall, a diet that is plant-based and includes whole grains is really important. And I often tell patients to eat the rainbow because all of those different phytochemicals that cause the different colors in our fruits and vegetables are supporting different gut microbiota. So that is a basis for a healthy gut microbiome. That said, you know, if someone is experiencing symptoms related to cancer or cancer therapy, it is important to tailor dietary approaches. This is where some of the mindful eating practices can help. So, sometimes actually not just focusing on what we eat, but how we eat can help with symptoms that are associated with eating. So, some of our patients have loss of appetite, and shifting one's relationship to food can help with nutrition. Sometimes ‘slow it down' practices can help both with appetite and with digestion. Dr. Nate Pennell: One of the things that you said both in the paper and just now on our podcast, talking about how individualized and personalized this is. And I really liked the emphasis that you had on flexibility and self-compassion over rigid discipline and prescriptive recommendations here. And this is perhaps one of the real benefits of having an integrative oncology team that can work with patients as opposed to them just trying to find things online. Dr. Chloe Atreya: Yes, particularly during treatment, I think that's really important. And that was borne out by our early studies we called “Being Present.” So, after I was observing the benefits anecdotally among my patients of the ability to be present, we designed these pilot studies to teach meditation and meditative practices to patients. And in these pilot studies, the original ones were pretty prescriptive in a way that mindfulness-based stress reduction is fairly prescriptive in terms of like, “This is what we're asking you to do. Just stick with the program.” And there can be benefits if you can stick with the program. It's really hard though if someone is going through treatment and with GI cancers, it may be that they're getting chemotherapy every two weeks and they have one week where they're feeling really crummy and another week where they're trying to get things done. And we realized that sometimes people were getting overwhelmed and feeling like the mindfulness practice was another thing on their to-do list and that they were failing if they didn't do this thing that was important for them. And so, we've really kind of changed our emphasis. And part of our emphasis now is on incorporating mindfulness practices into daily life. Any activity that doesn't require a lot of executive function can be done mindfully, meaning with full attention. And so, especially for some of our very busy patients, that can be a way of, again, shifting how I'm doing things rather than adding a new thing to do. Dr. Nate Pennell: And then another part I know that patients are always very curious about that I'm really happy to see that we're starting to build an evidence base for is the use of supplements and natural products. So, can you take us a little bit through where we stand in terms of evidence behind, say, cannabis and some of the other available products out there? Dr. Chloe Atreya: Yeah, I would say that is an area that requires a lot more study. It's pretty complicated because unlike mindfulness practices where there are few interactions with other treatments, there is the potential for interactions, particularly with the supplements. And the quality of the supplements matters. And then there tends to be a lot of heterogeneity among the studies both in the patients and what other treatments they may be receiving, as well as the doses of the supplements that they're receiving.  One of my earliest mentors at Yale is someone named Dr. Tommy Chang, who has applied the same rigor that that we apply to testing of biomedical compounds to traditional Chinese medicine formulas. And so, ensuring that the formulation is stable and then formally testing these formulations along with chemotherapy. And we need more funding for that type of research in order to really elevate our knowledge of these natural products. We often will direct patients to the Memorial Sloan Kettering ‘About Herbs, Botanicals, and Other Products' database as one accessible source to learn more about the supplements. We also work with our pharmacists who can provide the data that exists, but we do need to take it with a grain of salt because of the heterogeneity in the data. And then it's really important if people are going to take supplements, for them to take supplements that are of high quality. And that's something in the article that we list all of the things that one should look for on the label of a supplement to ensure that it is what it's billed to be. Dr. Nate Pennell: So, most of what we've been talking about so far has really been applying to all patients with cancer, but you of course are a GI medical oncologist, and this is a publication in the Educational Book from the ASCO GI Symposium. GI cancers obviously have an incredibly high and rising incidence rate among people under 50, representing a quarter of all cancer incidence worldwide, a third of cancer related deaths worldwide. Is there something specific that GI oncologists and patients with GI cancers can take home from your paper or is this applicable to pretty much everyone? Dr. Chloe Atreya: Yeah, so the evidence that we review is specifically for GI cancers. So, it shows both its strengths and also some of the limitations. So many of the studies have focused on other cancers, especially breast cancer. In the integrative oncology field, there are definitely gaps in studying GI cancers. At the same time, I would say that GI cancers are very much linked to lifestyle in ways that are complicated, and we don't fully understand. However, the best ways that we can protect against development of GI cancers, acknowledging that no one is to blame for developing a GI cancer and no one is fully protected, but the best things that we can do for overall health and to prevent GI cancers are a diet that is plant-based, has whole grains. There's some data about fish that especially the deep-water fish, may be protective and then engaging in physical activity.  One thing I would like for people to take away is that these things that we know that are preventative against developing cancer are also important after development of a GI cancer. Most of the data comes from studies of patients with colorectal cancer and that again, both cancer specific and overall mortality is improved with better diet and with physical activity. So, this is even after a cancer diagnosis. And I also think that, and this is hard to really prove, but we're in a pretty inflammatory environment right now. So, the things that we can do to decrease stress, improve sleep, decrease inflammation in the body, and we do know that inflammation is a risk factor for developing GI cancers. So, I think that all of the integrative modalities are important both for prevention and after diagnosis. Dr. Nate Pennell: And one of the things you just mentioned is that most of the studies looking at integrative oncology and GI cancers have focused on colorectal cancer, which of course, is the most common GI cancer. But you also have pointed out that there are gaps in research and what's going on and what needs to be done in order to broaden some of this experience to other GI cancers. Dr. Chloe Atreya: Yeah, and I will say that there are gaps even for colorectal cancer. So right now, some of the authors on the article are collaborating on a textbook chapter for the Society for Integrative Oncology. And so, we're again examining the evidence specifically for colorectal cancer and are in agreement that the level of evidence specific to colorectal cancer is not as high as it is for all patients with adult cancers. And so even colorectal cancer we need to study more.  Just as there are different phases of cancer where treatments may need to be tailored, we also may need to tailor our treatments for different cancer types. And that includes what symptoms the patients are commonly experiencing and how intense the treatment is, and also the duration of treatment. Those are factors that can influence which modalities may be most important or most applicable to a given individual. Dr. Nate Pennell: So, a lot of this sounds fantastic. It sounds like things that a lot of patients would really appreciate working into their care. Your article focused a little bit on some of the logistics of providing this type of care, including group medical visits, multidisciplinary clinics staffed by multiple types of clinicians, including APPs and psychologists, and talked about the sustainability of this in terms of increasing the uptake of guideline-based integrative oncology. Talk a little bit more about both at your institution, I guess, and the overall health system and how this might be both sustainable and perhaps how we broaden this out to patients outside of places like UCSF. Dr. Chloe Atreya: Yes, that's a major focus of our research effort. A lot of comprehensive cancer centers and other places where patients are receiving care, people may have access to dietitians, which is really important and nutritionists. In the article we also provide resources for working with exercise therapists and those are people who may be working remotely and can help people, for instance, who may be in, in rural areas. And then our focus with the mind-body practices in particular has been on group medical visits. And this grew out of, again, my ‘being present' pilot studies where we were showing some benefit. But then when the grant ends, there isn't a way to continue to deliver this care. And so, we were asking ourselves, you know, is there a way to make this sustainable? And group medical visits have been used in other settings, and they've been working really well at our institution and other institutions are now taking them up as well. And this is a way that in this case it's me and many of my colleagues who are delivering these, where I can see eight or ten patients at once. In my case, it's a series of four two-hour sessions delivered by telehealth. So, we're able to focus on the integrative practices in a way that's experiential. So, in the clinic I may be able to mention, you know, after we go over the CT scans, after we go over the labs and the molecular profiling, you know, may be able to say, “Hey, you know, meditation may be helpful for your anxiety,” but in the group medical visits we can actually practice meditation, we can practice chair yoga. And that's where people have that experience in their bodies of these different modalities. And the feedback that we're receiving is that that sticks much more to experience it then you have resources to continue it. And then the group is helpful both in terms of delivery, so timely and efficient care for patients. It's also building community and reducing the social isolation that many of our patients undergoing treatment for cancer experience. Dr. Nate Pennell: I think that makes perfect sense, and I'm glad you brought up telehealth as an option. I don't know how many trained integrative oncologists there are out there, but I'm going to guess this is not a huge number out there. And much like other specialties that really can improve patients' quality of life, like palliative medicine, for example, not everyone has access to a trained expert in their cancer center, and things like telemedicine and telehealth can really potentially broaden that. How do you think telehealth could help broaden the exposure of cancer patients and even practitioners of oncology to integrative medicine? Dr. Chloe Atreya: Yes, I think that telehealth is crucial for all patients with cancer to be able to receive comprehensive cancer care, no matter where they're receiving their chemotherapy or other cancer-directed treatments. So, we will routinely be including patients who live outside of San Francisco. Most of our patients live outside of San Francisco. There's no way that they could participate if they had to drive into the city again to access this. And in the group setting, it's not even safe for people who are receiving chemotherapy to meet in a group most times. And with symptoms, often people aren't feeling so well and they're able to join us on Zoom in a way that they wouldn't be able to make the visit if it was in person. And so, this has really allowed us to expand our catchment area and to include patients, in our case, in all of California. You also mentioned training, and that's also important. So, as someone who's involved in the [UCSF] Osher Collaborative, there are faculty scholars who are at universities all over the US, so I've been able to start training some of those physicians to deliver group medical visits at their sites as well via telehealth. Dr. Nate Pennell: I'm glad we were able to make a plug for that. We need our political leadership to continue to support reimbursement for telehealth because it really does bring access to so many important elements of health care to patients who really struggle to travel to tertiary care centers. And their local cancer center can be quite a distance away.  So, sticking to the theme of training, clinician education and resources are really crucial to continue to support the uptake of integrative oncology in comprehensive cancer care. Where do you think things stand today in terms of clinician education and professional development in integrative oncology. Dr. Chloe Atreya: It's growing. Our medical students now are receiving training in integrative medicine, and making a plug for the Educational Book, I was really happy that ASCO let us have a table that's full of hyperlinks. So that's not typical for an article. Usually, you have to go to the reference list, but I really wanted to make it practical and accessible to people, both the resources that can be shared with patients that are curated and selected that we thought were of high-quality examples for patients. At the bottom of that table also are training resources for clinicians, and some of those include: The Center for Mind-Body Medicine, where people can receive training in how to teach these mind-body practices; The Integrated Center for Group Medical Visits, where people can learn how to develop their own group medical visits; of course, there's the Society for Integrative Oncology; and then I had just mentioned the Osher Collaborative Faculty Fellowship. Dr. Nate Pennell: Oh, that is fantastic. And just looking through, I mean, this article is really a fantastic resource both of the evidence base behind all of the elements that we've discussed today. Actually, the table that you mentioned with all of the direct hyperlinks to the resources is fantastic. Even recommendations for specific dietary changes after GI cancer diagnosis. So, I highly recommend everyone read the full paper after they have listened to the podcast today.  Before we wrap up, is there anything that we didn't get a chance to discuss that you wanted to make sure our listeners are aware of? Dr. Chloe Atreya: One thing that I did want to bring up is the disparities that exist in access to high quality symptom management care. So, patients who are racial and ethnic minorities, particularly our black and Latinx patients, the evidence shows that they aren't receiving the same degree of symptom management care as non-Hispanic White patients. And that is part of what may be leading to some of the disparities in cancer outcomes. So, if symptoms are poorly managed, it's harder for patients to stay with the treatment, and integrative oncology is one way to try to, especially with telehealth, this is a way to try to improve symptom management for all of our patients to help improve both their quality of life and their cancer outcomes. Dr. Nate Pennell: Well, Dr. Atreya, it's been great speaking with you today and thank you for joining me on the ASCO Education: By the Book Podcast and thank you for all of your work in advancing integrative oncology for GI cancers and beyond. Dr. Chloe Atreya: Thank you, Dr. Pennell. It's been a pleasure speaking with you. Dr. Nate Pennell: And thank you to all of our listeners who joined us today. You'll find a link to the article discussed today in the transcript of the episode. We hope you'll join us again for more insightful views on topics you'll be hearing at the Education Sessions from ASCO meetings throughout the year and our deep dives on approaches that are shaping modern oncology. Disclaimer: The purpose of this podcast is to educate, 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. Nathan Pennell   @n8pennell  @n8pennell.bsky.social  Dr. Chloe Atreya  Follow ASCO on social media:    @ASCO on X (formerly Twitter)    ASCO on Bluesky   ASCO on Facebook    ASCO on LinkedIn    Disclosures:   Dr. Nate 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 (Institution): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi   Dr. Chloe Atreya: Consulting or Advisory Role: Roche Genentech, Agenus Research Funding (Institution): Novartis, Merck, Bristol-Myers Squibb, Guardant Health, Gossamer Bio, Erasca, Inc.

On the inaugural episode of ASCO Education: By the Book, Dr. Nathan Pennell and Dr. Don Dizon share reflections on the evolution of the ASCO Educational Book, its global reach, and the role of its new companion podcast to further shine a spotlight on the issues shaping the future of modern oncology. TRANSCRIPT Dr. Nathan Pennell: Hello, I'm Dr. Nate Pennell, welcoming you to the first episode of our new podcast, ASCO Education: By the Book. The podcast will feature engaging discussions between editors and authors from the ASCO Educational Book. Each month, you'll hear nuanced views on key topics in oncology featured in Education Sessions at ASCO meetings, as well as some deep dives on the advances shaping modern oncology. Although I am honored to serve as the editor-in-chief (EIC) of the ASCO Educational Book, in my day job, I am the co-director of the Cleveland Clinic Lung Cancer Program and vice chair for clinical research for the Taussig Cancer Center here in Cleveland. I'm delighted to kick off our new podcast with a discussion featuring the Ed Book's previous editor-in-chief. Dr. Don Dizon is a professor of medicine and surgery at Brown University and works as a medical oncologist specializing in breast and pelvic malignancies at Lifespan Cancer Institute in Rhode Island. Dr. Dizon also serves as the vice chair for membership and accrual at the SWOG Cancer Research Network. Don, it's great to have you here for our first episode of ASCO Education: By the Book. Dr. Don Dizon: Really nice to be here and to see you again, my friend. Dr. Nathan Pennell: This was the first thing I thought of when we were kicking off a podcast that I thought we would set the stage for our hopefully many, many listeners to learn a little bit about what the Ed Book used to be like, how it has evolved over the last 14 years or so since we both started here and where it's going. You started as editor-in-chief in 2012, is that right? Dr. Don Dizon: Oh, boy. I believe that is correct, yes. I did two 5-year stints as EIC of the Educational Book, so that sounds about right. Although you're aging me very clearly on this podcast. Dr. Nathan Pennell: I had to go back in my emails to see if I could figure out when we started on this because we've been working on it for some time. Start out a little bit by telling me what do you remember about the Ed Book from back in the day when you were applying to be editor-in-chief and thinking about the Ed Book. What was it like at that time? Dr. Don Dizon: You know, it's so interesting to think about it.  Ten years ago, we were both in a very different place in our careers, and I remember when the Ed Book position came up, I had been writing a column for ASCO. I had done some editorial activities with other journals for sure, but what always struck me was it was very unclear how one was chosen to be a part of the education program at ASCO. And then it was very unclear how those faculty were then selected to write a paper for the Educational Book. And it was back in the day when the Educational Book was completely printed. So, there was this book that was cherished among American fellows in oncology. And it was one that, when I was newly attending, and certainly two or three years before the editor's position came up, it was one that I referenced all the time. So, it was a known commodity for many of us. And there was a certain sense of selectivity about who was invited to write in it. And it wasn't terribly transparent either. So, when the opportunity to apply for editor-in-chief of the Educational Book came up, I had already been doing so much work for ASCO. I had been on the planning committees and served in many roles across the organization, and editing was something I found I enjoyed in other work. So, I decided to put my name in the ring with the intention of sort of bringing the book forward, getting it indexed, for example, so that there was this credit that was more than just societal credit at ASCO. This ended up being something that was referenced and acknowledged as an important paper through PubMed indexing. And then also to provide it as a space where we could be more transparent about who was being invited and broadening the tent as to who could participate as an author in the Ed Book. Dr. Nathan Pennell: It's going to be surprising to many of our younger listeners to learn that the Educational Book used to be just this giant, almost like a brick. I mean, it was this huge tome of articles from the Education Sessions that you got when you got your meeting abstracts book at the annual meeting. And you can always see people on the plane on the way out of Chicago with their giant books. Dr. Don Dizon: Yes. Dr. Nathan Pennell: That added lots of additional weight to the plane, I'm sure, on the way out. Dr. Don Dizon: And it was not uncommon for us to be sitting at an airport, and people would be reading those books with highlighters. Dr. Nathan Pennell: I fondly remember being a fellow and coming up and the Ed Book was always really important to me, so I was excited. We'll also let the listeners in on that. I also applied to be the original editor-in-chief of the Ed Book back in 2012, although I was very junior and did not have any real editorial experience. I think I may have been section editor for The Oncologist at that point. And I had spoken to Dr. Ramaswamy Govindan at WashU who had been the previous editor-in-chief about applying and he was like, “Oh yeah. You should absolutely try that out.” And then when Dr. Dizon was chosen, I was like, “Oh, well. I guess I didn't get it.” And then out of the blue I got a call asking me to join as the associate editor, which I was really always very thankful for that opportunity. Dr. Don Dizon: Well, it was a highly fruitful collaboration, I think, between you and I when we first started. I do remember taking on the reins and sort of saying, “You know, this is our vision of what we want to do.” But then just working with the authors, which we did, about how to construct their papers and what we were looking for, all of that is something I look back really fondly on. Dr. Nathan Pennell: I think it was interesting too because neither one of us had really a lot of transparency into how things worked when we started. We kind of made it up a little bit as we went along. We wanted to get all of the faculty, or at least as many of them as possible contributing to these. And we would go to the ASCO Education Committee meeting and kind of talk about the Ed Book, and we were thinking about, you know, how could we get people to submit. So, at the time it wasn't PubMed indexed. Most people, I think, submitted individual manuscripts just from their talk, which could be anywhere from full length review articles to very brief manuscripts. Dr. Don Dizon: Sometimes it was their slides with like a couple of comments on it. Dr. Nathan Pennell: And some of them were almost like a summary of the talk. Yeah, exactly. And so sort of making that a little more uniform. There was originally an honorarium attached, which went away, but I think PubMed indexing was probably the biggest incentive for people to join. I remember that was one of the first things you really wanted to get. Dr. Don Dizon Yeah. And, you know, it was fortuitous. I'd like to take all the credit for it, but ASCO was very forward thinking with Dr. Ramaswamy and the conversations about going to PubMed with this had preceded my coming in. We knew what we needed to do to get this acknowledged, which was really strengthening the peer review so that these papers could meet the bar to get on PubMed. But you know, within the first, what, two or three years, Nate, of us doing this, we were able to get this accepted. And now it is. If you look at what PubMed did for us, it not only increased the potential of who was going to access it, but for, I think the oncology community, it allowed people access to papers by key opinion leaders that was not blocked by a paywall. And I thought that was just super important at the time. Social media was something, but it wasn't what it is now. But anybody could access these manuscripts and it's still the case today. Dr. Nathan Pennell: I think it's hard to overstate how important that was. People don't realize this, but the Ed Book is really widely accessed, especially outside the US as well. And a lot of people who can't attend the meeting to get the print, well, the once print, book could actually get access to essentially the education session from the annual meeting without having to fly all the way to the US to attend. Now, you know, we have much better virtual meeting offerings now and whatnot. But at the time it was pretty revolutionary to be able to do that. Dr. Don Dizon: Yeah, and you know, it's so interesting when I think back to, you know, this sort of evolution to a fully online publication of the Ed Book. It was really some requests from international participants of the annual meeting who really wanted to continue to see this in print. At that time, it was important to recognize that access to information was not uniform across the world. And people really wanted that print edition, maybe not for themselves, but so that access in more rural areas or where access in the broadband networks were not established that they still could access the book. I think things have changed now. We were able, I think, in your tenure, to see it fully go online. But even I just remember that being a concern as we went forward. Dr. Nathan Pennell: Yeah, we continued with the print book that was available if people asked for it, but apparently few enough people asked for it that it moved fully online. One of the major advantages of being fully online now is of course, it does allow us to publish kind of in real time as the manuscripts come out in the months leading up to the meeting, which has been, I think, a huge boon because it can build momentum for the Education Sessions coming in. People, you know, really look forward to it. Dr. Don Dizon: Yeah, that was actually a concern, you know, when we were phasing out Ed Book and going to this continuous publication model where authors actually had the ability to sort of revise their manuscript and that would be automatically uploaded. You had a static manuscript that was fully printed, and it was no longer an accurate one. And we did have the ability to fix it. And it just goes to show exactly what you're saying. This idea that these are living papers was really an important thing that ASCO embraced quite early, I think. Dr. Nathan Pennell: And with the onset of PubMed indexing, the participation from faculty skyrocketed and almost within a couple of years was up to the vast majority of sessions and faculty participating. Now I think people really understand that this is part of the whole process. But at the time I remember writing out on my slides in all caps, “THIS IS AN EXPECTATION.” And that's about the best word I could give because I asked if we could make people do it, and they were like, no, you can't make people do it. Dr. Don Dizon: So right.  Actually, I don't think people are aware of the work on the back end every year when I was on as EIC, Nate and myself, and then subsequently Dr. Hope Rugo would have these informational sessions with the education faculty and we would tout the Ed Book, tout the expectation, tout it was PubMed indexed and tout multidisciplinary participation. So, we were not seeing four manuscripts reflecting one session. You know, this encouragement to really embrace multidisciplinary care was something that very early on we introduced and really encouraged people not to submit perspective manuscripts, but to really get them in and then harmonize the paper so that it felt like it was, you know, one voice. Dr. Nathan Pennell: I consider that after PubMed indexing, the next major change to the Ed Book, that really made it a better product and that was moving from, you know, just these short individual single author manuscripts to single session combined manuscript that had multiple perspectives and topics, really much more comprehensive review articles. And I don't even remember what the impetus was for that, but it was really a success. Dr. Don Dizon: Yeah, I mean, I think in the beginning it was more of a challenge, I think, because people were really not given guidance on what these papers were supposed to look like. So, we were seeing individual manuscripts come forward. Looking back, it really foreshadowed the importance of multidisciplinary management. But at the time, it was really more about ensuring that people were leaving the session with a singular message of what to do when you're in clinic again. And the goal was to have the manuscripts reflect that sort of consensus view of a topic that was coming in. There were certain things that people still argued would not fit in a multidisciplinary manuscript. You know, if you have someone who's writing and whose entire talk was on the pathology of thyroid cancer. Another topic was on survivorship after thyroid cancer. It was hard to sort of get those two to interact and cover what was being covered. So, we were still getting that. But you're right, at the end of my tenure and into yours, there were far fewer of those individual manuscripts. Dr. Nathan Pennell: And I think it's even made it easier to write because now, you know, you just have to write a section of a manuscript and not put together an entire review. So, it has helped with getting people on board. Dr. Don Dizon: Well, the other thing I thought was really interesting about the process is when you're invited to do an Education Session at ASCO, you're either invited as a faculty speaker or as the chair of the session. And the responsibility of the chair is to ensure that it flows well and that the talks are succinct based on what the agenda or the objectives were as defined by the education committee for that specific group. But that was it. So really being named “Chair” was sort of an honor, an honorific. It really didn't come with responsibility. So, we use the Ed Book as a way to say, “As chair of the session, it is your responsibility to ensure A, a manuscript comes to me, but B, that the content of that paper harmonizes and is accurate.” And it was very rare, but Nate, I think we got dragged into a couple of times where the accuracy of the manuscript was really called into question by the chair. And those were always very, very tricky discussions because everyone that gets invited to ASCO is a recognized leader in their field. Some of us, especially, I would probably say, dating back 10 years from today, the data behind Standards of Care were not necessarily evidence-based. So, there were a lot of opinion-based therapies. You know, maybe not so much in the medical side, but certainly some of it. But when you went to, you know, surgical treatments and maybe even radiotherapy treatments, it was really based on, “My experience at my center is this and this is why I do what I do.” But those kinds of things ended up being some of the more challenging things to handle as an editor. Dr. Nathan Pennell: And those are the– I'll use “fun” in a broad sense. You know, every once in a while, you get an article where it really does take a lot of hands-on work from the editor to work with the author to try to revise it and make it a suitable academic manuscript. But you know what? I can't think, at least in recent years, of any manuscripts that we turned down. They just sometimes needed a little TLC. Dr. Don Dizon: Yeah. And I think the other important thing it reminds me of is how great it was that I wasn't doing this by myself. Because it was so great to be able to reach out to you and say, “Can you give me your take on this paper?” Or, “Can you help me just join a conference call with the authors to make sure that we're on the same page?” And then on the rare example where we were going to reject a paper, it was really important that we, as the editorial team, and I include our ASCO shepherder, through the whole process. We had to all agree that this was not salvageable. Fortunately, it happened very rarely. But I've got to say, not doing this job alone was one of the more important facets of being the EIC of ASCO's Educational Book. Dr. Nathan Pennell: Well, it's nice to hear you say that. I definitely felt that this was a partnership, you know, it was a labor of love. So, I want to go to what I consider sort of the third major pillar of the changes to the Ed Book during your tenure, and that was the introduction of a whole new kind of manuscript. So up to, I don't know, maybe seven or eight years ago, all the articles were authored just by people who were presenting at the Annual Meeting. And then you had an idea to introduce invited manuscripts. So take me through that. Dr. Don Dizon: Yeah, well, you know, again, it went to this sort of, what can people who are being asked to sort of lead ASCO for that year, what can they demonstrate as sort of a more tangible contribution to the Society and to oncology in general? And I think that was the impetus to use the Ed Book for everyone who was in a leadership position to make their mark. That said, I was here, and I was either president of the society or I was Education Program Chair or Scientific Program Chair, and they got to select an article type that was not being covered in the annual meeting and suggest the authors and work with those authors to construct a manuscript. Never did any one of those folks suggest themselves, which I thought was fascinating. They didn't say, “I want to be the one to write this piece,” because this was never meant to be a presidential speech or a commemorative speech or opportunity for them as leaders. But we wanted to ensure that whatever passion they had within oncology was represented in the book. And again, it was this sort of sense of, I want everyone to look at the Ed Book and see themselves in it and see what they contributed. And that was really important for those who were really shepherding each Annual Meeting each year for ASCO that they had the opportunity to do that. And I was really pleased that leadership really took to that idea and were very excited about bringing ideas and also author groups into the Educational Book who would not have had the opportunity otherwise. I thought that was just really nice. It was about inclusiveness and just making sure that people had the opportunity to say, “If you want to participate, we want you to participate.” Dr. Nathan Pennell: Yeah, I agree. I think the ASCO leadership jumped on this and continues to still really appreciate the opportunity to be able to kind of invite someone on a topic that's meaningful to them. I think we've tried to work in things that incorporate the presidential theme each year in our invited manuscript, so it really allows them to put kind of a stamp on the flavor of each edition. And the numbers reflect that these tend to be among our more highly read articles as well. Dr. Don Dizon: You know, looking back on what we did together, that was something I'm really, really quite proud of, that we were able to sort of help the Educational Book evolve that way. Dr. Nathan Pennell: I agree. You brought up briefly a few minutes ago about social media and its role over time. I think when we started in 2012, I had just joined Twitter now X in 2011, and I think we were both sort of early adopters in the social media. Do you feel like social media has had a role in the growth of the Ed Book or is this something that you think we can develop further? Dr. Don Dizon: When we were doing Ed Book together, professional social media was actually a quite identified space. You know, we were all on the same platform. We analyzed what the outcomes were on that platform and our communities gathered on that platform. So, it was a really good place to highlight what we were publishing, especially as we went to continuous publishing.  I don't remember if it was you or me, but we even started asking our authors for a tweet and those tweets needed work. It was you. It was you or I would actually lay in these tweets to say, “Yeah, we need to just, you know, work on this.” But I think it's harder today. There's no one preferred platform. Alternate platforms are still evolving. So, I think there are opportunities there. The question is: Is that opportunity meaningful enough for the Ed Book to demonstrate its return on an investment, for example? What I always thought about social media, and it's still true today, is that it will get eyes on whatever you're looking at far beyond who you intended to see it. So, you know, your tweets regarding a phase 3 clinical trial in lung cancer, which were so informative, were reaching me, who was not a lung oncologist who doesn't even see lung cancer and getting me more interested in finding that article and more and more pointing to the Educational Book content that speaks to that piece, you know. And I think coupling an impression of the data, associating that with something that is freely accessed is, I think, a golden opportunity not only for our colleagues, but also for anyone who's interested in a topic. Whether you are diagnosed with that cancer or you are taking care of someone with that cancer, or you heard about that cancer, there are people who would like to see information that is relevant and embedded and delivered by people who know what they're talking about. And I think our voices on social media are important because of it. And I think that's where the contribution is. So, if we had to see what the metric was for any social media efforts, it has to be more of the click rates, not just by ASCO members, but the click rates across societies and across countries. Dr. Nathan Pennell: Yeah, social media is, I mean, obviously evolving quite a bit in the last couple of years. But I do know that in terms the alt metrics for the track access through social media and online, the ones that are shared online by the authors, by the Ed Book team, do seem to get more attention. I think a lot of people don't like to just sit with a print journal anymore or an email table of contents for specific journals. People find these articles that are meaningful to them through their network and oftentimes that is online on social media. Dr. Don Dizon: Yes, 100%. And you know what I think we should encourage people to do is look at the source. And if the Ed Book becomes a source of information, I think that will be a plus to the conversations in our world. We're still dealing with a place where, depending on who sponsored the trial, whether it was an industry-sponsored trial, whether it was NCI sponsored or sponsored by the National Institutes of Health, for example, access to the primary data sets may or may not be available across the world, but the Ed Book is. And if the Ed Book can summarize that data and use terms and words that are accessible no matter what your grade level of education is. If we can explain the graphs and the figures in a way that people can actually easily more understand it. If there's a way that we structure our conversations in the Ed Book so that the plethora of inclusion/exclusion criteria are summarized and simplified, then I think we can achieve a place where good information becomes more accessible, and we can point to a summary of the source data in places where the source is not available. Dr. Nathan Pennell: One of the other things that I continue to be surprised at how popular these podcasts are. And that gives you an opportunity pretty much the opposite. Instead of sort of a nugget that directs you to the source material, you've got a more in-depth discussion of the manuscript. And so, I'm delighted that we have our own podcast. For many years, the Ed Book would sort of do a sort of a “Weird Al takeover” of the ASCO Daily News Podcast for a couple of episodes around the Annual Meeting, and I think those were always really popular enough that we were able to argue that we deserved our own podcast. And I'm really looking forward to having these in-depth discussions with authors. Dr. Don Dizon: It's an amazing evolution of where the Ed Book has gone, right? We took it from print only, societally only, to something that is now accessed worldwide via PubMed. We took it from book to fully online print. And now I think making the content live is a natural next step. So, I applaud you for doing the podcast and giving people an opportunity actually to discuss what their article discusses. And if there's a controversial point, giving them the freedom and the opportunity to sort of give more nuanced views on what may not be something that there's 100% consensus over. Dr. Nathan Pennell: Yes. Well, I hope other people enjoy these as well. Just want to highlight a few of the things that have happened just in the couple years since you stepped down as editor-in-chief. One of them, and I don't know if you noticed, but last year we started adding manuscripts from the ASCO thematic meetings, so ASCO GI and ASCO GU, something we had certainly talked about in the past, but had lacked bandwidth to really do. And they seem to be pretty widely accessed. Dr. Don Dizon: That's fantastic. Yes, I do remember talking about the coverage of the thematic meetings and you're right, this takes a long time to sort of concentrate on the Annual Meeting. It may seem like everything happens in the span of like eight weeks. Dr. Nathan Pennell: It does feel like that sometimes. Dr. Don Dizon: Right? But this is actually something that starts a year before, once the education program is set. We're in the room when they set it. But then it's really chasing down manuscripts and then making sure that they're peer reviewed because the peer review is still really important, and then making sure that any revisions are made before it's finalized and goes to press. That is a many months process. So, when we're trying to introduce, “Oh, we should also do ASCO GU or-,” the question was, how do you want to do that given this very, very involved process going forward? So, I'm glad you were able to figure it out. Dr. Nathan Pennell: Well, it's challenging. I don't think people realize quite the compressed timeline for these. You know, the Education Session and authors and invited faculty are picked in the fall, and then basically you have to start turning in your manuscripts in February, March of the following year. And so, it's a really tight turnaround for this. When we talk about the ASCO thematic meetings, it's an even tighter window. Dr. Don Dizon: Right, exactly. Dr. Nathan Pennell: And so, it's challenging to get that moving, but I was really, really proud that we were able to pull that off. Dr. Don Dizon: Well, congratulations again. And I think that is a necessary step, because so much of what's going on in the various disease management sites is only covered cursorily through the Annual Meeting itself. I mean, there's just so much science breaking at any one time that I think if we want to comprehensively catalog the Year in Review in oncology, it kind of behooves us to do that. Dr. Nathan Pennell: Some other things that are coming up because we now have manuscripts that are going to be coming in year-round, and just to kind of make it easier on the editorial staff, we're going to be forming an editorial board. And in addition to our pool of reviewers who get ASCO points, please feel free to go online to the ASCO volunteer portal and sign up if you are interested in participating. So, moving forward, I'm really excited to see where things are going to go. Dr. Don Dizon: Well, that's great. That's great. And I do remember talking about whether or not we needed to have an editorial board. At least when I was there, having this carried by three people was always better than having it carried by one person. And I think as you expand the potential for submissions, it will be very helpful to have that input for sure. And then it gives another opportunity for more members to get involved in ASCO as well. Dr. Nathan Pennell: Absolutely. People want involvement, and so happy to provide that. Dr. Don Dizon: Yes. Dr. Nathan Pennell: Is there anything we didn't cover that you would like to mention before we wrap up? Dr. Don Dizon: Well, I will say this, that ASCO and through its publications not only has had this real emphasis on multidisciplinary management of cancers, especially where it was relevant, but it also always had a stand to ensure representation was front and center and who wrote for us. And I think every president, every chair that I've worked with naturally embraced that idea of representation. And I think it has been a distinct honor to say that during my tenure as EIC, we have always had a plethora of voices, of authors from different countries, of genders, that have participated in the construction of those books. And it stands as a testament that we are a global community and we will always be one. Dr. Nathan Pennell: Well, thank you for that. And I'm happy to continue that as we move forward. Well, Don, thank you. It's been great speaking with you. You played such a pivotal role in the Ed Book's evolution and I'm so glad you were able to join me for our inaugural episode. Dr. Don Dizon: Well, I'm just tickled that you asked me to be your first guest. Thank you so much, Nate. Dr. Nathan Pennell: And I also want to thank our listeners for joining us today. We hope you'll join us again for more insightful views on topics you'll be hearing at the Education Sessions from ASCO meetings throughout the year, as well as our periodic deep dives on advances that are shaping modern oncology. Have a great day. 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. Nathan Pennell  @n8pennell @n8pennell.bsky.social   Dr. Don Dizon @drdondizon.bsky.social  Follow ASCO on social media:   @ASCO on X (formerly Twitter)   ASCO on Bluesky  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. Don Dizon: Stock and Other Ownership Interests: Midi, Doximity Honoraria: UpToDate, American Cancer Society Consulting or Advisory Role: AstraZeneca, Clovis Oncology, Kronos Bio, Immunogen Research Funding (Institution): Bristol-Myers Squibb          

Dr. Vamsi Velcheti and Dr. Charu Aggarwal discuss the evolution of ctDNA as a critical tool in precision oncology and its implications for lung cancer management, including its potential role in the early-stage setting. TRANSCRIPT Dr. Vamsi Velcheti: Hello. I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I am a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health.  The management of small cell lung cancer has rapidly evolved over the past few decades, and today, molecular testing and biomarker testing for lung cancer are absolutely critical in terms of designing treatment options for our patients with metastatic non-small cell lung cancer. Today, I'm delighted to be joined by Dr. Charu Aggarwal for a discussion on ctDNA (circulating tumor DNA) and the role of ctDNA in lung cancer management. Dr. Aggarwal is the Leslye Heisler Professor of Lung Cancer Excellence and section chief of thoracic and head and neck oncology at University of Pennsylvania Abramson Cancer Center.  You'll find our full disclosures in the transcript of that episode.  Dr. Agrawal, it's great to have you on the podcast today. Thank you for being here. Dr. Charu Aggarwal: Thank you for having me. Dr. Vamsi Velcheti: Let's start off with setting the stage for ctDNA technology. These technologies have rapidly evolved from experimental conceptual stage to essential clinical tools for day-to-day clinical practice. Could you briefly discuss how recent advancements in ctDNA technologies are shaping our approach to precision medicine, especially in lung cancer? Dr. Charu Aggarwal: Absolutely. And you know, I think we need to just level set a little bit. What exactly is circulating tumor DNA? This is a way to assess exactly that. Every tumor sheds little pieces of tumor-derived DNA into the bloodstream, and this occurs in a variety of solid tumors. But now we have the technology to be able to derive this DNA that's actually being shed from the tumor into the bloodstream, these minute fragments of DNA, take them out, amplify them and sequence them with a variety of different mechanisms. They can be DNA sequencing alone, they can be DNA and RNA sequencing, they can be whole transcriptome sequencing. The technology, as you rightly pointed out, Dr. Velcheti, has significantly improved from just being able to look at circulating tumor DNA to now being able to amplify it, sequence it, and use it to offer personalized therapy. I think lung cancer is definitely the poster child for such an approach as we have a lot of data that has shown clinical utility and validity of being able to use circulating tumor DNA next-generation gene sequencing to guide therapy. Dr. Vamsi Velcheti: There have been so many technological leaps. It's really impressive how far we've come to advance these sequencing platforms. Recent advances with AI and machine learning are also playing important roles in interpreting ctDNA data. How are these computational advances really enhancing clinical decision-making in day-to-day clinical practice? Dr. Charu Aggarwal: I think while we have firmly established the role of ctDNA in the management of patients with metastatic lung cancer, some of the approaches that you talked about are still experimental. So let me backtrack a little bit and set the stage for how we use ctDNA in clinical practice right now. I think most patients, when they come in with a new diagnosis of stage IV lung cancer, we want to test for biomarkers. And this should actually be the established standard. Now included in the NCCN guidelines and actually also international guidelines, is to consider using blood-based testing or plasma-based testing to look for biomarkers, not just tissue-based testing which had been our historical standard, but to use these plasma guided approaches to identify the seven to nine biomarkers that may be truly implicated in either first- or second-line therapy that are called as your immediately actionable mutations.  What you're talking about is AI computational methods. I think there's a lot of excitement about how we can use genomic signatures that are derived from either tissue or ctDNA-based biomarker testing, combine it with radiomic features, combine it with histologic features, look at H & E patterns, use AI algorithmic learning to be able to actually predict recurrence scores, or can we actually come up with predictive signatures that may be extremely helpful?  So, I think some of the techniques and technologies that you're talking about are incoming. They are provocative. I think they're very exciting, but very early. Dr. Vamsi Velcheti: I think it's really amazing how many advances we have with these platforms. You know, the challenge really is the significant gap in terms of uptake of molecular testing. Even today, in 2025, there are significant gaps in terms of all metastatic lung cancer patients being tested for all biomarkers.  So, why do you think there's such a challenge in testing patients with lung cancer? In most academic practices, we try to achieve 100% testing for all our patients, but we know from recent studies that that's not the case across the country. What do you think the gaps are? Dr. Charu Aggarwal: Biomarker testing is so essential, like you pointed out, for us to be able to guide the right therapy for our patients. And we see this in our practice every day as you and I see patients with lung cancer, that a large proportion of our patients either don't get tested or they start therapy before their test results come back. So, I think this is a real problem.  However, to add some optimism to this problem, I do think that we are making a move in the right direction. So, four or five years ago, there was a lot of data being presented at national meetings, including ones from the American Society of Clinical Oncology, where we saw that, nationally, the rates of biomarker testing were probably in the rate of 40 to 50%. However, now with the availability of both tissue and plasma, I do think that the rates of biomarker testing are increasing. And if you were to survey a sample or even perform retrospective data research, I believe that the number is closer to 70% of all patients with metastatic non-small cell lung cancer.  And you know, you asked why is it not 100%? I think there are many reasons. I think the number one reason is tissue availability. Many times, the biopsies are small, or the tumor is very necrotic. So, either the tissue quantity itself is small, or the tissue quantity is insufficient to perform gene sequencing. And that's exactly where plasma comes in. When you don't have tissue availability, we have shown, as have others, that you can use plasma effectively to increase the proportion of patients who are not only tested but also receive the right therapy. I think there are also other barriers, including inertia. You know, I think this is both patient and physician inertia, where patients want to get started quickly, they don't want to wait. Physicians are very busy and sometimes want to be able to deliver treatment as soon as possible. We have seen there are some institutional barriers. Not every institution has in-house gene sequencing testing. So how do you really operationalize, send out these tests in a fast, efficient manner so that you get results back? Is it a pathologist who sends out the test? Is it the medical oncologist? Is it the pulmonologist or the interventionalist? I think there is this need to develop reflex testing mechanisms which some institutions do really well and some don't. And then finally, there are financial implications as well. How do we do this in a most cost-efficient fashion?  So there are many barriers, but I'm happy to say that we are making a move in the right direction as we are understanding that it's important to do it, it's easy to do it maybe with a value add of plasma, and finally, as you said, you know, as these technologies become more available, they're actually getting more cost-effective. Dr. Vamsi Velcheti: Dr. Aggarwal, you've been at the cutting edge of these advanced platforms and testing. So, what do you do in UPenn? How do you handle all these barriers and what is your workflow for patients in University of Pennsylvania? Dr. Charu Aggarwal: One of the things that I mentioned to you was there may be institutional barriers when it comes to gene sequencing. So, we actually, several years ago now, instituted a very robust reflex testing paradigm where almost all of our patients, regardless of stage, with a non-squamous non-small cell lung cancer diagnosis, would automatically be reflexively sent to our molecular pathology lab where they would get gene sequencing both for the DNA as well as with an RNA fusion-based platform. And the reason we did this was because we wanted to expedite and reduce the turnaround time. We also wanted to ensure that we were not just doing DNA testing, which I think is really important for our listeners here. There are many fusions as well as certain skipping mutations like MET exon 14 that may be missed on DNA testing alone. So, it's really incredibly important to run both DNA and RNA samples.  So, we do this routinely, and based on our research and others, what we also do routinely is that we send concurrent tissue and liquid biopsies or plasma MGS testing upon initial diagnosis. For example, if a patient comes in with a diagnosis of stage IV non-small cell lung cancer, their tissue might already be at my molecular pathology lab based on the reflex mechanism that I just described to you. But upon their initial meeting with me, we will send off plasma. And I will tell you this, that Penn is not just one institution, right? We have a large network of sites. And as part of my research, one of the things that we wanted to do was implement wide scale means to improve biomarker testing. And we have done this with the use of technology like you mentioned, Dr. Velcheti: How can we actually use AI? How can we leverage our electronic medical record to identify these patients? So, we have a nudge-based mechanism which actually facilitates the pending of orders for biomarker testing for patients with new diagnosis of metastatic non-small cell lung cancer. And we are looking at our rates of biomarker testing but also rates of completion of biomarker testing before first-line therapy started. So many of our participating sites are clusters for our randomized control trial to increase molecular testing. And I'm really excited about the fact that we're able to implement it not just at our main satellite, downtown Penn Hospital, but also across our community. Dr. Vamsi Velcheti: I think that's great. Thank you so much for those insights, Dr. Aggarwal. I think it's so important because having the best technology is just not enough. I think implementation science is actually a real thing. And I think we need to all learn from each other, advance these things.  So, I want to ask you about the new emerging paradigm in terms of using ctDNA. Of course, in the metastatic setting, we've been using ctDNA for molecular profiling for a while now. But the recent data around monitoring early-stage disease, especially post-operative monitoring, is an exciting area. There are a lot of opportunities there. Could you please talk us through the emerging data in lung cancer and how do we incorporate ctDNA-based monitoring MRD or should we even do that right now? Is the data ripe enough for us to kind of deploy this in a clinical setting? Dr. Charu Aggarwal: I think using ctDNA in the early-stage setting is our next frontier in lung cancer. I think naturally we have been able to successfully deploy this in the stage 4 setting. It made a meaningful difference in the lives of our patients, and we are a little bit behind the A ball in terms of how MRD is used in lung cancer. Because, you know, colorectal cancer has already done large-randomized trials based on ctDNA and MRD. It's routinely used in hematological malignancy. So, it makes sense that we should start to use it.  However, when I say this, I say this with excitement, but also a little bit of gentle caution saying that we actually don't quite have the prospective randomized data just yet on how to deploy. Yes, intuitively we would say that if you detect ctDNA and MRD, that patient is at higher risk. So, we identify that, but we actually don't know what to do with the second part of that information once you identify a patient with high risk. Are there other techniques that we can then come in with or other drugs that we can come in with to modify that risk? And that's the thing that I think we don't have right now. The other thing that we don't have right now is the timing of the assay, when to use it. Is it to be tested in the pre-op setting? Is the post-op test the best timing, or is it monitoring and dynamics of ctDNA that are most important? And the third thing I will say in terms of precautionary cause is that we don't know which test just yet. There are actually a few commercially available tests out in the market right now. We know about them and I'm sure our community colleagues know about them. Some of them even have Medicare approval. However, many of these tests are currently tissue informed. We don't have tissue uninformed tests. And what does that mean? Tissue uninformed means that you actually take a piece of tumor tissue, you sequence that tumor and based on the gene profile of that tumor, you actually design a panel that can then be used to track the mutations in the blood-based pack. This requires, as the name implies, a tumor. So can this be used in the pre-op setting is a large question. Because coming back to the idea of tissue availability, you and I both know that when we get FNAS and we use it for PDL-1 testing and we use it for gene sequencing, there often isn't enough tissue left for us to then either do whole genome sequencing or even whole transcriptome sequencing, which may be required to build some of these assays.  I think the future lies in this idea of tumor uninformed assays because if we could go to a blood only or a plasma only approach using novel signatures like proteomics or methylation, I think that's where the future is. But we're still a little bit early in the discovery stages of those, as well as to come are the validation stages so that we can be confident that these blood-only assays may actually give us an answer.  So, with those three cautionary notes, I would say that optimism is still very high. I think ctDNA MRD is the right place to think about. We need to do this for our patients to better identify high-risk patients and to think about means to escalate treatment for them. Dr. Vamsi Velcheti: Yeah, I completely agree, and I think with all the changes and evolution of treatments in the management of early-stage lung cancer now with neoadjuvant and adjuvant, there's really a need for an escalation and de-escalation of therapies post-operatively. And I think it's a huge opportunity. I think we all could learn from our colorectal colleagues. I think they've done a really good job at actually doing prospective trials in this setting. I think we're kind of a little behind here.  Dr. Charu Aggarwal: I think in the metastatic setting there are ongoing trials to look at this exact question. How do you choose an appropriate first-line therapy, a monitor ctDNA at the six-week trial? It's being evaluated in a trial called the “Shedders” trial, where if patients are still ctDNA positive at six weeks, then you can escalate treatment because they haven't “cleared” their ctDNA. There has been a lot of research that has shown that lack of ctDNA clearance in the metastatic setting may be a poor prognostic factor. We and others have shown that if you do clear your ctDNA or if you have a reduction in ctDNA load overall, that that is directly related to both an improved progression-free survival and overall survival. This has been shown with both tissue informed and uninformed assays. So I think it's very clear that yes, you can track it. I think the question is: Can you apply that data to the early-stage setting? And that's an open research question. A lot of groups are looking at that and I think it's completely reasonable, especially to determine duration of therapy, to determine optimal timing, optimal timing of scans even. And I think these are just such interesting questions that will be answered in the future. Dr. Vamsi Velcheti: And also like a kind of early detection of resistance patterns that might inform early initiation of combination strategies. And I think it's a lot of opportunities I think yet to be explored. A lot of exciting things to come and I'm sure we'll kind of see more and more data in the next few years.  Dr. Aggarwal, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been a pleasure to have you on the podcast today. Hope to see you at ASCO. Dr. Charu Aggarwal: Thank you so much. This was great and I remain so excited by all of the possibilities to improve outcomes for our patients. Dr. Vamsi Velcheti: Thank you to all the listeners for your time today. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much. 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. Vamsidhar Velcheti  @VamsiVelcheti  @vamsivelcheti.bsky.social Dr. Charu Aggarwal @CharuAggarwalMD   Follow ASCO on social media:  @ASCO on X (formerly Twitter)  ASCO on Bluesky ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. Vamsidhar Velcheti:  Honoraria: Glavanize Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, AstraZeneca/MedImmune, GSK, Amgen, Taiho Oncology, Novocure, Takeda, Janssen Oncology, Picture Health, Regeneron Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  Dr. Charu Aggarwal: Consulting or Advisory Role: AstraZeneca, Daiichi Sankyo/AstraZeneca, Regeneron/Sanofi, Pfizer, Boehringer Ingelheim, Takeda, Arcus Biosciences, Gilead Sciences, Novocure, Abbvie Speakers' Bureau: AstraZeneca (an immediate family member) Research Funding (Inst): Merck Sharp & Dohme, AstraZeneca/MedImmune, Daiichi Sankyo/AstraZeneca, Lilly@Loxo, Candel Therapeutics  

Dr. Neeraj Agarwal and Dr. Peter Hoskin discuss key abstracts in GU cancers from the 2025 ASCO Genitourinary Cancers Symposium, including novel therapies in prostate, bladder, and kidney cancer and the impact of combination therapies on patient outcomes. TRANSCSRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program and professor of medicine at the Huntsman Cancer Institute at the University of Utah, and editor-in-chief of ASCO Daily News. Today, we'll be discussing practice-informing abstracts and other key advances in GU oncology featured at the 2025 ASCO Genitourinary Cancers Symposium. Joining me for this discussion is Dr. Peter Hoskin, the chair of this year's ASCO GU Symposium. Dr. Hoskin is a professor in clinical oncology in the University of Manchester and honorary consultant in clinical oncology at the Christie Hospital, Manchester, and University College Hospital London, in the United Kingdom. Our full disclosures are available in the transcript of this episode. Peter, thank you for joining us today. Dr. Peter Hoskin: Thank you so much, Neeraj. I am very pleased to be here. Dr. Neeraj Agarwal: The GU meeting highlighted remarkable advancements across the spectrum of GU malignancies. What stood out to you as the most exciting developments at the ASCO GU Symposium?  Dr. Peter Hoskin: The theme of this year's meeting was "Driving Innovation, Improving Patient Care," and this reflected ASCO GU's incredible milestone in GU cancer research over the years. We were thrilled to welcome almost 6,000 attendees on this occasion from over 70 countries, and most of them were attending in person and not online, although this was a hybrid meeting. Furthermore, we had more than 1,000 abstract submissions. You can imagine then that it fostered fantastic networking opportunities and facilitated valuable knowledge and idea exchanges among experts, trainees, and mentees. So, to start I'd like to come back to you for a second because the first day started with a focus on prostate cancer and some of the key clinical trials. And congratulations to you, Neeraj, on sharing the data from the TALAPRO-2 trial, which we were eagerly awaiting. I'd love to get your thoughts on the data that you presented. Could you tell us more about that trial, Abstract LBA18?  Dr. Neeraj Agarwal: Yes, Peter, I agree with you. It was such an exciting conference overall and thank you for your leadership of this conference. So, let's talk about the TALAPRO-2 trial. First of all, I would like to remind our audience that the combination of talazoparib plus enzalutamide was approved by the U.S. FDA in June 2023 in patients with metastatic castration-resistant prostate cancer harboring HRR gene alterations, after this combination improved the primary endpoint of radiographic progression-free survival compared to enzalutamide alone in the randomized, double-blind, placebo-controlled, multi-cohort phase 3 TALAPRO-2 trial. In the abstract I presented at ASCO GU 2025, we reported the final overall survival data, which was a key alpha-protected secondary endpoint in cohort 1, which enrolled an all-comer population of patients with mCRPC. So, at a median follow-up of around 53 months, in the intention-to-treat population, the combination of talazoparib plus enzalutamide significantly reduced the risk of death by 20% compared to enzalutamide alone, with a median OS of 45.8 months in the experimental arm versus 37 months in the control arm, which was an active control arm of enzalutamide. This improvement was consistent in patients with HRR alterations with a hazard ratio of 0.54 and in those with non-deficient or unknown HRR status, with a hazard ratio of 0.87. In a post hoc analysis, the hazard ratio for OS was 0.78 favoring the combination in those patients who did not have any HRR gene alteration in their tumors by both tissue and ctDNA testing. Consistent with the primary analysis, the updated rPFS data also favored the experimental arm with a median rPFS of 33.1 compared to 19.5 months in the control arm, and a hazard ratio of 0.667. No new safety signals were identified with extended follow-up. Thus, TALAPRO-2 is the first PARP inhibitor plus ARPI study to show a statistically significant and a clinically meaningful improvement in OS compared to standard-of-care enzalutamide as first-line treatment in patients with mCRPC unselected for HRR gene alterations. Dr. Peter Hoskin: Thank you, Neeraj. That's a great summary of the data presented and very important data indeed. There was another abstract also featured in the same session, Abstract 20, titled “Which patients with metastatic hormone-sensitive prostate cancer benefit more from androgen receptor pathway inhibitors? STOPCAP meta-analyses of individual participant data.” Neeraj, could you tell us more about this abstract? Dr. Neeraj Agarwal: Absolutely, I would be delighted to. So, in this meta-analysis, Dr. David Fischer and colleagues pooled individual participant data from different randomized phase 3 trials in the mHSPC setting to assess the potential ARPI effect modifiers and determine who benefits more from an ARPI plus ADT doublet. The primary outcome was OS for main effects and PFS for subgroup analyses. Prostate cancer specific survival was a sensitivity outcome. The investigators pooled data from 11 ARPI trials and more than 11,000 patients. Overall, there was a clear benefit of adding an ARPI on both OS and PFS, with hazard ratios of 0.66 and 0.51, respectively, representing a 13% and 21% absolute improvement at 5 years, respectively, with no clear difference by the class of agent. When stratifying the patients by age group, the effects of adding an ARPI on OS and PFS were slightly smaller in patients older than 75, than in those younger than 65, or aged between 65 and 75 years. Notably, in the trials assessing the use of abiraterone, we saw very little OS effects in the group of patients older than 75, however there was some benefit maintained in prostate-cancer specific survival, suggesting that other causes of death may be having an impact. The effects of the other ARPIs, or ‘lutamides' as I would call them, were similar across all three age subgroups on both OS and PFS. Therefore, the majority of patients with mHSPC benefit from the addition of ARPIs, and the benefits/risks of abiraterone and other ‘amides' must be considered in older patients.  Dr. Peter Hoskin: Thanks, Neeraj. Another great summary relevant to our day-to-day practice. Of course, there's ongoing collection of individual patient data from other key trials, which will allow robust comparison of ARPI doublet with triplet therapy (including docetaxel), guiding more personalized treatment.   Dr. Neeraj Agarwal: I agree with you, Peter, we need more data to help guide personalized treatment for patients with mHSPC and potentially guide de-escalation versus escalation strategies. Now, moving on to a different setting in prostate cancer, would you like to mention Abstract 17 titled, “Overall survival and quality of life with Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in poor-risk, metastatic, castration-resistant prostate cancer in ENZA-p (ANZUP 1901),” presented by Dr. Louise Emmett? Dr. Peter Hoskin: Of course I will. So, ENZA-p was a multicenter, open-label, randomized, phase 2 trial conducted in Australia. It randomized 163 patients into adaptive doses (2 or 4 cycles) of Lu-PSMA-617 plus enzalutamide versus enzalutamide alone as first-line treatment in PSMA-PET-CT-positive, poor-risk, mCRPC. The interim analysis of ENZA-p with median follow-up 20 months showed improved PSA-progression-free survival with the addition of Lu-PSMA-617 to enzalutamide. Here, the investigators reported the secondary outcomes, overall survival, and health-related quality of life (HRQOL). After a median follow up of 34 months, overall survival was longer in the combination arm compared to the enzalutamide arm, with a median OS of 34 months compared to 26 months; with an HR of 0.55. Moreover, the combination improved both deterioration-free survival and health-related quality of life indicators for pain, fatigue, physical function, and overall health and quality of life compared to the control arm. Consistent with the primary analysis, the rPFS also favored the experimental arm with a median rPFS of 17 months compared to 14 months with a HR of 0.61. So, the addition of LuPSMA improved overall survival, and HRQOL in patients with high-risk mCRPC. Dr. Neeraj Agarwal: Thank you, Peter. Great summary, and promising results with Lu-177 and ARPI combination in first line treatment for mCRPC among patients who had two or more high risk features associated with early enzalutamide failure. Before we move on to bladder cancer, would you like to tell us about Abstract 15 titled, “World-wide oligometastatic prostate cancer (omPC) meta-analysis leveraging individual patient data (IPD) from randomized trials (WOLVERINE): An analysis from the X-MET collaboration,” presented by Dr. Chad Tang?  Dr. Peter Hoskin: Sure. So, with metastatic-directed therapy (MDT), we have a number of phase 2 studies making up the database, and the X-MET collaboration aimed to consolidate all randomized data on oligometastatic solid tumors. This abstract presented pooled individual patient data from all the published trials involving patients with oligometastatic prostate cancer who received MDT alongside standard of care (SOC) against SOC alone. The analysis included data from five trials, encompassing 472 patients with oligometastatic prostate cancer, and followed for a median of 41 months. Patients were randomly assigned in a 1:1 ratio to receive either MDT plus SOC or SOC alone. The addition of MDT significantly improved PFS. The median PFS was 32 months with MDT compared to 14.9 months with SOC alone, with an HR of 0.45. Subgroup analyses further confirmed the consistent benefits of MDT across different patient groups. Regardless of factors like castration status, receipt of prior primary treatment, stage, or number of metastases, MDT consistently improved PFS. In patients with mHSPC, MDT significantly delayed the time to castration resistance by nine months, extending it to a median of 72 months compared to 63 months in the SOC group with an HR of 0.58. In terms of OS, the addition of MDT improved the 48-month survival rate by 12%, with OS rates of 87% in the MDT+SOC group compared to 75% in the SOC alone group. Dr. Neeraj Agarwal: Thank you, Peter. These data demonstrate that adding MDT to systemic therapy significantly improves PFS, rPFS, and castration resistance-free survival, reinforcing its potential role in the treatment of oligometastatic prostate cancer. So, let's switch gears to bladder cancer and start with Abstract 658 reporting the OS analysis of the CheckMate-274 trial. Would you like to tell us about this abstract?  Dr. Peter Hoskin: Yes, sure, Neeraj. This was presented by Dr. Matt Milowsky, and it was additional efficacy outcomes, including overall survival, from the CheckMate-274 trial which evaluated adjuvant nivolumab versus placebo in patients with high-risk muscle-invasive bladder cancer after radical surgery. The phase 3 trial previously demonstrated a significant improvement in disease-free survival with nivolumab. With a median follow-up of 36.1 months, disease-free survival was longer with nivolumab compared to placebo across all patients with muscle-invasive bladder cancer, reducing the risk of disease recurrence or death by 37%. Among patients who had received prior neoadjuvant cisplatin-based chemotherapy, nivolumab reduced this risk by 42%, whilst in those who had not received chemotherapy, the risk was reduced by 31%. Overall survival also favored nivolumab over placebo, reducing the risk of death by 30% in all patients with muscle-invasive bladder cancer and by 52% in those with tumors expressing PD-L1 at 1% or higher. Among patients who had received prior neoadjuvant chemotherapy, nivolumab reduced the risk of death by 26%, whilst in those who had not received chemotherapy, the risk was reduced by 33%. Alongside this, the safety profile remained consistent with previous findings. Dr. Neeraj Agarwal: Thank you, Peter, for such a nice overview of this abstract. These results reinforce adjuvant nivolumab as a standard of care for high-risk muscle-invasive bladder cancer, offering the potential for a curative outcome for our patients. Dr. Peter Hoskin: I agree with you Neeraj. Perhaps you would like to mention Abstract 659 titled, “Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA.” Dr. Neeraj Agarwal: Of course. Dr. Galsky presented additional outcomes from the phase 3 NIAGARA study, which evaluated perioperative durvalumab combined with neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer. The study previously demonstrated a significant improvement in event-free survival and overall survival with durvalumab compared to chemotherapy alone, with a manageable safety profile and no negative impact on the ability to undergo radical cystectomy. Among the 1,063 randomized patients, those who received durvalumab had a 33% reduction in the risk of developing distant metastases or death and a 31% reduction in the risk of dying from bladder cancer compared to those who received chemotherapy alone. More patients who received durvalumab achieved a pathological complete response at the time of surgery with 37% compared to 28% in the chemotherapy-alone group. Patients who achieved a pathological complete response had better event-free survival and overall survival compared to those who did not. In both groups, durvalumab provided additional survival benefits, reducing the risk of disease progression or death by 42% and the risk of death by 28% in patients with a pathological complete response, while in those patients without a pathological complete response, the risk of disease progression or death was reduced by 23% and the risk of death by 16% when durvalumab was added to the chemotherapy. Immune-mediated adverse events occurred in 21% of patients in the durvalumab group compared to 3% in the chemotherapy-alone group, with grade 3 or higher events occurring in 3% compared to 0.2%. The most common immune-related adverse events included hypothyroidism in 10% of patients treated with durvalumab compared to 1% in the chemotherapy-alone group, and hyperthyroidism in 3% versus 0.8%. At the time of the data cutoff, these adverse events had resolved in 41% of affected patients in the durvalumab group and 44% in the chemotherapy-alone group. Dr. Peter Hoskin: Thank you, Neeraj, for the great summary. These findings further support the role of perioperative durvalumab as a potential standard of care for patients with muscle-invasive bladder cancer. Dr. Neeraj Agarwal: I concur with your thoughts, Peter. Before wrapping up the bladder cancer section, would you like to mention Abstract 664 reporting updated results from the EV-302 trial, which evaluated enfortumab vedotin in combination with pembrolizumab compared to chemotherapy as first-line treatment for patients with previously untreated locally advanced or metastatic urothelial carcinoma? Dr. Peter Hoskin: Yes, of course. Dr. Tom Powles presented updated findings from the EV-302 study, and in this abstract presented 12 months of additional follow-up for EV-302 (>2 y of median follow-up) and an exploratory analysis of patients with confirmed complete response (cCR). The study had a median follow-up of 29.1 months and previously demonstrated significant improvements in progression-free survival and overall survival with enfortumab vedotin and pembrolizumab. This is now the standard of care in global treatment guidelines. Among the 886 randomized patients, enfortumab vedotin and pembrolizumab reduced the risk of disease progression or death by 52% and the risk of death by 49% compared to chemotherapy. The survival benefit was consistent regardless of cisplatin eligibility or the presence of liver metastases. The confirmed objective response rate was higher with enfortumab vedotin and pembrolizumab at 67.5% compared to 44.2% with chemotherapy. The median duration of response was 23.3 months with enfortumab vedotin and pembrolizumab compared to 7.0 months with chemotherapy. A complete response was achieved in 30.4% of patients in the enfortumab vedotin and pembrolizumab group compared to 14.5% in the chemotherapy group, with the median duration of complete response not yet reached in the enfortumab vedotin and pembrolizumab group compared to 15.2 months in the chemotherapy group. Severe treatment-related adverse events occurred in 57.3% of patients treated with enfortumab vedotin and pembrolizumab compared to 69.5% in the chemotherapy group, while in patients who achieved a complete response, severe adverse events occurred in 61.7% of those treated with enfortumab vedotin and pembrolizumab compared to 71.9% with chemotherapy. Treatment-related deaths were reported in 1.1% of patients treated with enfortumab vedotin and pembrolizumab compared to 0.9% with chemotherapy, with no treatment-related deaths occurring in those who achieved a complete response. These findings clearly confirm the durable efficacy of enfortumab vedotin and pembrolizumab, reinforcing its role as the standard of care for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma, and no new safety concerns have been identified. Dr. Neeraj Agarwal: Thank you for this great summary. Moving on to kidney cancer, let's talk about Abstract 439 titled, “Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Final follow-up results from the CheckMate-9ER trial.” Dr. Peter Hoskin: Sure. Dr. Motzer presented the final results from the phase 3 CheckMate-9ER trial, which compared the combination of cabozantinib and nivolumab against sunitinib in previously untreated advanced renal cell carcinoma. The data after more than five years follow-up show that the combination therapy provided sustained superior efficacy compared to sunitinib. In terms of overall survival, we see an 11-month improvement in median OS, 46.5 months for the cabo-nivo versus 35.5 months for sunitinib and a 42% reduction in the risk of disease progression or death, with median progression-free survival nearly doubling – that's 16.4 months in the combination group and 8.3 months with sunitinib. Importantly, the safety profile was consistent with the known safety profiles of the individual medicines, with no new safety concerns identified. Dr. Neeraj Agarwal: Great summary, Peter. These data further support the efficacy of cabo-nivo combination therapy in advanced renal cell carcinoma, which is showing a 11-month difference in overall survival. Dr. Peter Hoskin: Neeraj, before wrapping up this podcast, would you like to tell us about Abstract 618? This is titled “Prospective COTRIMS (Cologne trial of retroperitoneal lymphadenectomy in metastatic seminoma) trial: Final results.” Dr. Neeraj Agarwal: Sure, Peter. I would be delighted to. Dr Heidenrich from the University of Cologne in Germany presented the COTRIMS data evaluating retroperitoneal LN dissection in patients with clinical stage 2A/B seminomas. Seminomas are classified as 2A or B when the disease spreads to the retroperitoneal lymph nodes of up to 2 cm (CS IIA) or of more than 2 cm to up to 5 cm (CS 2B) in maximum diameter, respectively. They account for 10-15% of seminomas and they are usually treated with radiation and chemotherapy. However, radiation and chemo can be associated with long-term toxicities such as cardiovascular toxicities, diabetes, solid cancers, leukemia, particularly for younger patients. From this standpoint, Dr Heidenrich and colleagues evaluated unilateral, modified template, nerve-sparing retroperitoneal lymph node dissection as a less toxic alternative compared to chemo and radiation. They included 34 patients with negative AFP, beta-HCG, and clinical stage 2A/B seminomas. At a median follow-up of 43.2 months, the trial demonstrated great outcomes: a 99.3% treatment-free survival rate and 100% overall survival, with only four relapses. Antegrade ejaculation was preserved in 88% of patients, and severe complications such as grade 3 and 4 were observed in 12% of patients. Pathological analysis revealed metastatic seminoma in 85% of cases, with miR371 being true positive in 23 out of 24 cases and true negative in 100% of cases. It appears to be a valid biomarker for predicting the presence of lymph node metastases. These findings highlight retroperitoneal lymph node dissection is feasible; it has low morbidity, and excellent oncologic outcomes, avoiding overtreatment in 80% of patients and sparing unnecessary chemotherapy or radiotherapy in 10-15% of cases. Dr. Peter Hoskin: Great summary and important data on retroperitoneal lymphadenectomy in metastatic seminoma. These findings will help shape clinical practice. Any final remarks before we conclude today's podcast? Dr. Neeraj Agarwal: Before wrapping up this podcast, I would like to say that we have reviewed several abstracts addressing prostate, bladder, kidney cancers, and seminoma, which are impacting our medical practices now and in the near future. Peter, thank you for sharing your insights with us today. These updates are undoubtedly exciting for the entire GU oncology community, and we greatly appreciate your valuable contribution to the discussion and your leadership of the conference. Many thanks. Dr. Peter Hoskin: Thank you, Neeraj. Thank you for the opportunity to share this information more widely. I'm aware that whilst we have nearly 6,000 delegates, there are many other tens of thousands of colleagues around the world who need to have access to this information. And it was a great privilege to chair this ASCO GU25. So, thank you once again, Neeraj, for this opportunity to share more of this information that we discussed over those few days. Dr. Neeraj Agarwal: Thank you, Peter. 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. 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. Neeraj Agarwal    @neerajaiims    Dr. Peter Hoskin Follow ASCO on social media:      @ASCO on Twitter      ASCO on Bluesky  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. Peter Hoskin: Research Funding (Institution): Varian Medical Systems, Astellas Pharma, Bayer, Roche, Pfizer, Elekta, Bristol Myers  

Host Dr. Shannon Westin and guests Dr. Bill Aronson discuss the article "High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial" and how Omega-6 are predominant in the American diet while the study significantly lowered the intake of Omega- 6 fats. TRANSCRIPT  Dr. Shannon Westin: Hello everyone and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, GYN Oncologist by trade and one of the grateful Social Media Editors of the JCO. And I am very excited to welcome a special guest today, Dr. William Aronson. He is professor of Urology in the UCLA Department of Urology, the Chief of Urology at Olive View UCLA Medical Center, and Chief of Urologic Oncology at the Veterans Administration West Los Angeles. Welcome, Dr. Aronson. Dr. William Aronson: Thank you, Shannon, and delighted to be here. Dr. Shannon Westin: We are so excited to have you discussing your manuscript, “High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial,” which was published in the Journal of Clinical Oncology on December 13, 2024. So let's get right to it. First of all, you know we have a very mixed audience, so can you just level set for us and speak about the population you studied in this important trial - that low risk, favorable, intermediate risk prostate cancer. How common is that? How is it defined? That would really help. Dr. William Aronson: I would say about 50% of the patients that we diagnose with prostate cancer either have low risk disease or what we call favorable intermediate risk disease. So when the pathologists look at the cancer under the microscope, they assign what's called a Gleason grade. Grade 3 is the slower growing type of prostate cancer, grade 5 is the fastest growing type, and grade 4 is somewhere in between. So a low risk group would be only the grade 3, the slower growing type. And the favorable intermediate risk group would actually be the grade 3+4, which means they mostly see the low risk type in there, but they also see the slightly faster growing type, grade 4. So this is what we typically see. We see these patients on a very regular basis when they're newly diagnosed with prostate cancer. Dr. Shannon Westin: Okay, got it. And then can you walk us through just what the management options are typically for this patient population? Dr. William Aronson: So typically for what we call the low risk group, the patients with a low PSA and only that grade 3 type, slower growing type of prostate cancer, the standard recommendations are active surveillance. So typically, we'll periodically monitor these patients with PSA blood testing and periodically do prostate biopsies depending upon the patient's other medical problems. Dr. Shannon Westin: So I think it would also be really helpful just to understand what your typical management options are for this patient population. Dr. William Aronson: So for patients with low risk prostate cancer, they only have the Gleason Grade 3+3 with a low PSA. The standard practice is observation. And so these men will periodically see them and measure their PSA values. And periodically, they'll undergo prostate biopsy to make sure they're not getting progression of their disease. For men with favorable intermediate risk prostate cancer, that's a little different. In some practices, the patient and the urologist will decide to do active surveillance. In other scenarios, these patients will definitely elect treatment, either with radical prostatectomy or radiation therapy or other treatments that are available. Dr. Shannon Westin: So your manuscript notes that there was a high level of interest in dietary supplements and approaches among patients with prostate cancer that do elect for active surveillance. Prior to the results of CAPFISH-3, did we have any data to support those types of recommendations? Dr. William Aronson: We actually don't have any long term prospective randomized trials that support that recommendation. There have been a number of very interesting epidemiologic studies, for example, suggesting maybe a plant-based diet might be helpful. Or a number of other studies suggesting maybe more tomato-based products like tomato sauces or tomato paste may be helpful. But no prospective longer term randomized trials that were positive. Dr. Shannon Westin: Okay, that makes sense. So what led you all to explore the high omega-3, low omega-6 fatty acid diet in this trial? Dr. William Aronson: After our initial omega-6 studies, we subsequently did some studies where we raised the omega-3 from fish oil and lowered the 6, looking at a more favorable ratio of the omega-3 to omega-6. And once again, we found that in our animal models, there was a significant delay in progression of prostate cancer. That then led us to perform a clinical trial. It was a short term trial in men prior to undergoing radical prostatectomy. And in these men, they were randomly assigned to one of two groups, either a western high fat diet or a low fat diet with fish oil. And we found after just four to six weeks, a significant change in the Ki67 level in their radical prostatectomy tissue. And Ki67 is actually a strong indicator of prostate cancer progression, spread, or even death from prostate cancer. Dr. Shannon Westin: Well, and I think that leads us really nicely into the design of the current study. So why don't you walk us through how CAPFISH-3 was designed. And you've already spoken a little bit about your primary endpoint. Dr. William Aronson: Based on the results of what we saw in the lab and what we saw in our short term clinical trial, we decided to perform a one year trial, a longer term trial in men on active surveillance. And these men were randomly assigned to either a diet with slight reduction in dietary fat, specifically reduction in the omega-6 intake as well as increase in foods with omega-3 and fish oil capsules. The other group, we asked the men to just not take fish oil capsules, but they could eat whatever else they wanted during the course of the study. Men in the diet where we lowered the omega-6 and raised the omega-3, they were seen by a dietitian once a month to really ensure that they were compliant with that intervention, which they were. The other intriguing part of our study, which I think is super important, is the precision that was used when these men underwent prostate biopsy. So, at baseline and at one year, when these men underwent prostate biopsy, they had the same site within the prostate biopsied. That's important because it's not so easy to find the same site within the prostate because of heterogeneity throughout the prostate. And so we were able to obtain that high level of precision as they were in an active surveillance program at UCLA with Dr. Leonard Marks. Dr. Shannon Westin: So we spoke a little bit about what's important about the Ki67 index as your primary endpoint. Can you talk a little bit about what the study found with your intervention? Dr. William Aronson: So we found that the Ki67 index increased by 24% in the control group and decreased by 15% in the low omega-6, high omega-3 group with fish oil capsules. So that ended up resulting in a statistically significant change between the groups favoring the low omega-6, high omega-3 group. Dr. Shannon Westin: And then what were the secondary endpoints that CAPFISH-3 explored? Anything of note that you want to review for the listeners? Dr. William Aronson: So a number of positive secondary endpoints from the trial. Firstly, we saw that the triglyceride levels were lower, which is what can typically be seen with omega-3 intake. We also saw reduced levels of a cytokine, a circulating factor in the bloodstream called ‘macrophage colony stimulating factor'. And that's particularly interesting because there's a certain type of macrophage which is well known to be involved in prostate cancer progression in men with more advanced prostate cancer, and we've been able to inhibit that in our animal models and in our tissue culture studies. And it was especially interesting to see that we did have an effect on this particular cytokine in this prospective randomized trial. We did not see changes in a number of other measures, including Gleason grade or PSA. These are measures that we use in clinical practice. To see an effect on those would have required a longer term and larger study to be performed. Dr. Shannon Westin: That makes sense. I think it's always great to try to get as much of these types of translational data as we can. But sometimes you just have to do what is reasonable and you get what you get. It looks to me like this regimen was fairly well tolerated. Did you obtain any patient reported outcomes or feedback on the trial? Dr. William Aronson: So, there were four patients in the fish oil group that did have some side effects, and we withdrew them from the study. They did have some effects on their upset stomach, and a number of men also had some diarrhea as well. And so for those four patients, we did withdraw them from the study. Dr. Shannon Westin: And then I guess the last question I have is really, what's next for this intervention? Are we ready to move this to the clinic or what do you see as next steps? Dr. William Aronson: Well, this next step that we're working on right now is to better understand exactly what happened in these patients. So we have blood, we have tissue, we're doing genetic studies on these patients. So that's really the first step, in our mind, to better understand what happened before moving to the next step. I'm particularly intrigued about trying this intervention in men with more advanced prostate cancer, specifically because of what we see, this particular diet and how it's affecting the patient's immune system and how that may favorably affect their course of their prostate cancer. Dr. Shannon Westin: Well, great. Well, thank you so much for taking the time to chat with us about such an important clinical trial, and I really appreciate all the work you're doing and hope to get to see you soon. Dr. William Aronson: Well, thanks for having me, Shannon. It's really an exciting finding and I think it's something that clinicians and patients are going to be super interested in. Dr. Shannon Westin: We love straightforward interventions that actually make a difference, so you guys are to be congratulated for that. And I just want to thank all of you for listening. Thanks again, and I hope you enjoyed this episode of JCO After Hours. Be sure to check out our other podcast offerings wherever you get your podcasts. Have an awesome day.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Aronson Disclosures: Stock and Other Ownership Interests Johnson and Johnson Speakers' Bureau Company name: Janssen Oncology, Bayer, Blue Earth Diagnostics, AstraZeneca, Pfizer/Astellas Research Funding: Lantheus Medical Imaging UCLA Health Article Video

Dr. Nathan Pennell and Dr. John Sweetenham discuss the evolving landscape of oncology in 2025 and the challenges oncologists will be facing, including the impact of Medicare drug price negotiations, ongoing drug shortages, and the promising role of AI and telehealth in improving patient outcomes and access to clinical trials. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. 2025 promises to be a year of continued progress in drug development, patient care, and technological innovations that will shape the future of cancer care. Oncologists will also be grappling with some familiar challenges in oncology practice and probably face a few new ones as well. I'm delighted to be joined today by Dr. Nathan Pennell to discuss some of these challenges. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research at the Taussig Cancer Center. He also serves as the editor-in-chief of the ASCO Educational Book.  You'll find our full disclosures in the transcript of this episode.  Nate, it's great to have you on the podcast today. Dr. Nathan Pennell: Thanks for inviting me, John. I'm excited to be here. Dr. John Sweetenham: Thanks. So, Nate, we've been hearing a lot recently about implementation science in oncology particularly. This has been the case, I would say, over the past decade and of course the goal is to how do we figure out the best way to integrate evidence-based practice into oncology care? There's been a lot of very good guidance from organizations like ASCO and every year we're reminded of the need for clinical decision support for practicing oncologists at the point of care. Although I think we all agree it is the right thing to do, and this has been a matter of discussion for probably more than 10 years, for the most part, I don't think we've really got there. Some big practices probably have a truly well-integrated clinical decision support tool, but for many of us this is still lacking in the field. I wonder whether we do need some kind of global clinical decision support tool. What do you think about the future of clinical decision support at the point of care? And do you think this is going to continue to be a need? Dr. Nathan Pennell: I think that's a fantastic question and it absolutely is something we're going to continue to work towards. We're in an incredibly exciting time in oncology. We've got all these exciting predictive biomarkers, effective treatments that are working better than anything we've had in our careers up to this point. But when we actually look to see who is benefiting from them, what we find is that outside of clinical trial populations, many of our patients aren't actually accessing these. And so publications that look at real-world use of these, one that jumps to mind for me is a publication looking at biomarker testing for driver oncogenes in lung cancer showed that while everyone who treats lung cancer says, “Absolutely, we need to test for biomarkers such as EGFR mutations,” in the real world, probably only slightly over a third of people ever access these drugs because there are so many different gaps in care that fall through the cracks. And so decision support is absolutely critical.  You mentioned this has been going on for a decade. Actually, the Institute of Medicine in 2013 recommended that with the uptake of electronic medical records, that we move forward with building these true learning health care systems that would improve quality and use every patient's information to help inform their care. And in 2023, as a representative of ASCO, I was able to look back at the last decade, and the uniform conclusion was that we had failed to build this learning health care system. So, what can we do going forward? The good news is there are improvements in technology. There are, for better or for worse, some consolidation of electronic medical records that has allowed larger numbers of patients to sort of have data sets shared. ASCO started CancerLinQ to try to improve quality, which is now part of OpenAI, and is still working on technology solutions to help provide decision support as we are better able to access patient data. And I think we're going to talk a little bit later about some of the technological advances that are going on in artificial intelligence that are really going to help improve this. So I think this is very close to impacting patient care and improving quality of care. I think for, as you'd mentioned, large health care systems and users of the major EMRs, this is going to be extremely close. Dr. John Sweetenham: Thanks, Nate. And just to extend the conversation into another area, one of the constant, I think, pain points for practicing oncologists has been the issue of prior authorization and the amount of time and energy it takes to deal with insurance denials in cancer care. And I think in a way, these two things are linked in as much as if we had clinical decision support tools at the point of care which were truly functional, then hopefully there would be a more facile way for an oncologist to be able to determine whether the patient in front of him or her is actually covered for the treatment that the oncologist wants to prescribe. But nevertheless, we're really not there yet, although, I think we're on the way to being there. But it does remain, like I said, a real pain point for oncologists.  I wonder if you have any thoughts on the issue of prior authorization and whether you see in the coming year anything which is going to help practicing oncologists to overcome the time and effort that they spend in this space. Dr. Nathan Pennell: I think many oncologists would have to list this among, if not the least favorite aspects of our job these days is dealing with insurance, dealing with prior authorizations. We understand that health care is incredibly expensive. We understand that oncology drugs and tests are even more expensive, probably among, if not the most rapidly growing costs to the health care system in the U.S., which is already at about 20% of our GDP every year. And so I understand the concern that costs are potentially unsustainable in the long term. Unfortunately, the major efforts to contain these costs seem to have fallen on the group that we would least like to be in charge of that, which are the payers and insurance companies, through use of prior authorization. And this is good in concept, utilization review, making sure that things are appropriate, not overutilizing our expensive treatments, that makes perfect sense. Unfortunately, it's moved beyond expensive treatments that have limited utility to more or less everything, no matter how inexpensive or standard. And there's now multiple publications suggesting that this is taking on massive amounts of time. Some even estimated that for each physician it's a full 40-hour work week per physician from someone to manage prior authorizations, which costs billions of dollars for practices every year. And so this is definitely a major pain point.  It is, however, an area where I'm kind of optimistic, maybe not necessarily in 2025, but in the coming several years with some of the technology solutions that are coming out, as we've talked about, with things like clinical pathways and whatnot, where the insurance company approvals can be tied directly to some of these guideline concordance pathway tools. So the recent publication at the ASCO Quality [Care] Symposium looking at a radiation oncology practice that had a guideline concordant prior auth tool that showed there was massive decrease in denials by using this. And as this gets rolled out more broadly, I think that this can increase the concept of gold carding, where if practices follow these clinical guidelines to a certain extent, they may be even exempt from prior authorization. I think I can envision that this is very close to potentially removing this as a major problem. I know that ASCO certainly has advocated on the national level for changes to this through, for example, advocating for the Improving Seniors Timely Access to Care Act. But I think, unfortunately, the recent election, I'm not sure how much progress will be made on the national level for progress in this. So I think that the market solutions with some of the technology interventions may be the best hope. Dr. John Sweetenham: Yeah, thanks. You raised a couple of other important points in that answer, Nate, which I'll pick up on now. You mentioned drug prices, and of course, during 2025, we're going to see Medicare negotiating drug prices. And we've already seen, I think, early effects from that. But I think it's going to be really interesting to see how this rolls out for our cancer patients in 2025. And of course, the thing that we can't really tell at the moment that you've alluded to is how all this is going to evolve with the new administration of President Trump. I understand, of course, that none of us really knows at this point; it's too early to know what the new administration will do. But would you care to comment on this in any way and about your concerns and hopes for Medicare specifically and what the administration will do to cancer care in general? Dr. Nathan Pennell: I think all of us are naturally a little bit anxious about what's going to happen under the new administration. The good news, if there's good news, is that under the first Trump administration, the National Cancer Institute and cancer care in general was pretty broadly supported both in Congress and by the administration. And if we look at specifically negotiating drug prices by Medicare, you can envision that having a businessman president who prides himself in negotiations might be something that would be supported and perhaps even expanded under the incoming Trump administration. So I think that's not too hard to imagine, although we don't really know. On the other hand, there are very valid concerns about what's going to happen with the Affordable Care Act, with Medicaid expansion, with protections for preexisting conditions, which impact our patients with cancer. And obviously there are potential people in the new administration who perhaps lack trust in traditional evidence-based medicine, vaccines, things like that, which we're not sure where they're going to fall in terms of the health care landscape, but certainly something we'll have to watch out for. Dr. John Sweetenham: Yeah. Certainly, when we regroup to record next year's podcast, we may have a clearer picture of how that's going to play out. Dr. Nathan Pennell: I mean, if there's anything good from this, it's that cancer has always been a bipartisan issue that people support. And so I don't want to be too negative about this. I do think that public support for cancer is likely to continue. And so overall, I think we'll probably be okay. Dr. John Sweetenham: Yeah, I agree with that. And I think one of the things that's important to remember, I do remember that one of the institutions I've worked at previously that there from time to time was some discussion about politics and cancer care. And the quote that I always remember is “We all belong to the cancer party,” and that's what's really important. So let's just keep our eye on the board. I hope that we can do that.  I'm going to switch gears just a little bit now because another issue which has been quite prominent in 2024 and in a few years before that has been supply chain issues and drug shortages. We've seen this over many years now, but obviously the problems have apparently been exacerbated in recent years, particularly by climate events. But certainly ASCO has published some recommendations in terms of quality care delivery for patients with cancer. Can you tell us a little bit about how you think this will go in the coming year and what we can do to address some of the concerns that are there over drug shortages? Dr. Nathan Pennell: Yeah. This continues to be, I think, a surprising issue for many oncologists because it has been going on for a long time, but really hasn't been in the public eye. The general problem is that once drugs go off patent and become generic, they often have limited manufacturers that are often outside the U.S. sometimes even a single manufacturer, which leaves them extremely vulnerable to supply chain disruption issues or regulatory issues. So situations where the FDA inspects and decides that they're not manufacturing things up to snuff and suddenly the only manufacturer is temporarily shut down. And then as you mentioned, things like extreme weather events where we had Hurricane Maria hit Puerto Rico and suddenly we have no bags of saline for several months. And so these are major issues which I think have benefited from being in the public eye.  ASCO, on the one hand, has, I think, done an excellent job leading on what to do in scenarios where there are shortages. But I think more importantly, we need more attention on a national level to policy changes that would help prevent this in the future. Some suggestions have been to increase some of the oversight of the FDA into supply chain issues and generic drugs, perhaps forming more of an early warning system to anticipate shortages so that we can find workarounds, find alternative suppliers that perhaps aren't currently being widely utilized. We can advocate for our legislators to pass legislation to support drug production for vital agents through things like long term contracts or even guaranteed pricing that might also even encourage U.S. manufacturers to take back up generic drugs if they were able to make it profitable. And then finally, I think just more of a national coordinated approach rather than the piecemeal approach we've done in the past. I remember when we had a platinum [drug] shortage last year. Our institution, with massive resources in our pharmacy, really did an excellent job of making sure that we always had enough supply. We never actually saw that shortage in real time, but I know a lot of places did not have those resources and therefore were really struggling. And so I think more of a coordinated approach with communication and awareness so that we can try to prevent this from happening. Dr. John Sweetenham: Thanks, Nate. And you raised the issue of major weather events, and I'd like to pick up on that for just a moment to talk about climate change. We now know that there is a growing body of evidence showing that climate change impacts cancer care. And it does it in a lot of ways. I mean, the most obvious is disrupting care delivery during one of these major events. But there are also issues about increased exposure to carcinogens, reduced access to food, reduced access to cancer screenings during these major disasters. And the recent hurricanes, of course, have highlighted the need for cancer centers to have robust disaster preparedness plans. In addition to that, obviously there are questions about greenhouse gas emissions and how cancer centers and health care organizations handle that.  But what do you see for 2025 in this regard? And what's your thinking about how well we're prepared as deliverers of cancer care to deal with these climate change issues? Dr. Nathan Pennell: Yeah, that is sobering to look at some of the things that have happened with climate change in recent years. I would love to say that I think that from a national level, we will see these changes and proactively work to reduce greenhouse emissions so that we can reduce these issues in the future. I'm not sure what we're going to see from the incoming administration and current government in terms of national policy on changes for fossil fuel use and climate change. I worry that there's a chance that we may see less done on the national level. I know the NCI certainly has policies in place to try to study climate change impact on cancer. It's possible that even that policy could be impacted by the incoming administration. So we'll have to see.  So, unfortunately, I worry that we may be still dealing in a reactive way to the impacts of this. So, obviously, wildfires causing carcinogens, pollution leading to increased cancer incidence, obviously, major weather events leading to physical disruptions, where cancer centers definitely have to have plans in place to help people maintain their treatment during those periods. As an individual, we can certainly make our impact on climate change. There are certainly organizations like Oncologists United for Climate and Health, or so-called OUCH, led by Dr. Joan Schiller, a friend of mine in the lung cancer world, where oncologists are advocating for policies to reduce use of fossil fuels. But I don't know, John, I don't know if I'm hopeful that there's going to be major policy changes on this in the coming year. Dr. John Sweetenham: I suspect you're right about that, although I think on the positive side, I think the issue as a whole is getting a lot more attention than it was maybe even two or three years ago. So that has to be a good thing that there's more advocacy and more attention out there now.  Nate, before we go on to the last question, because I do want to finish on a positive note, I just wanted to mention briefly that there are a couple of ongoing issues which, when we do this podcast each year, we normally address, and they certainly haven't gone away. But we know that burnout and workforce issues in oncology will continue to be a big challenge. The workforce issues may or may not be exacerbated by whatever the new administration's approach to immigration is going to be, because that could easily significantly affect the workforce in oncology. So that's one issue around workforce and burnout that we are not addressing in detail this year. But I wanted to raise it just because it certainly hasn't gone away and is going to continue to challenge us in 2025.  And then the other one, which I kind of put in the same category, is that of disparities. We continue to see ethnic and racial disparities of care. We continue to see disparities in rural areas. And I certainly wouldn't want to minimize the challenges that these are likely to continue to present in 2025. I wonder if you just have any brief comments you'd like to make and whether you think we're headed in the right direction with those issues. Dr. Nathan Pennell: Well, I'm somewhat optimistic in some ways about burnout. And I think when we get to our final topic, I think some of that may help. There may be some technology changes that may help reduce some of the influences of burnout. Disparities in care, obviously, I think similarly to some of the other issues we talked about have really benefited from just a lot of attention being cast on that. But again, I actually am optimistic that there are some technology changes that are going to help reduce some disparities in care. Dr. John Sweetenham: It's always great to finish one of these conversations on a positive note, and I think there is a lot to be very positive about. As you mentioned right at the beginning of the podcast, we continue to see quite extraordinary advances, remarkable advances in all fields of oncology in the therapeutic area, with just a massive expansion in not only our understanding, but also resulting from that improved understanding of the biology of the disease, the treatment advances that have come along. And so I think undoubtedly, we're going to see continued progress during 2025. And I know that there are technology solutions that you've mentioned already that you're very excited about. So, I'd really like to finish today by asking you if you could tell us a little about those and in particular what you're excited about for 2025. Dr. Nathan Pennell: Yeah. It's always dangerous to ask me to nerd out a little bit about some of these technology things, but I don't think that we can end any conversation about technology and not discuss the potential for artificial intelligence (AI) in health care and oncology. AI is sort of everywhere in the media and sort of already worked its way into our lives in our phones and apps that we're using and whatnot. But some of what I am seeing in tools that are probably going to be here very soon and, in some cases, already arriving, are pretty remarkable.  So some of the advances in natural language processing, or NLP, which in the past has been a barrier to really mining the vast amounts of patient information in the electronic medical record, is so much better now. So now, we can actually use technology to read doctor's notes, to read through scanned PDFs in our EMRs. And we can imagine that it's going to become very soon, much harder to miss abnormal labs, going to be much harder to miss findings on scans such as pulmonary nodules that get picked up incidentally. It's going to be much easier to keep up with new developments as clinical guidelines get worked in and decision support tools start reminding patients and physicians about evidence-based, high-quality recommendations. Being able to identify patients who are eligible for clinical trials is going to become much more easy.  And that leads me to the second thing, which is, throughout the pandemic we have greatly increased our use of telehealth, and this really has the potential to reduce disparities in care by reaching patients basically wherever they are. This is going to disproportionately allow us to access rural patients, patients that are currently underrepresented in clinical trials and whatnot, being able to present patients for clinical trials. In the recent “State of Cancer Care in America” report from ASCO, more than 60% of patients in the U.S. did not have access to clinical trials. And now we have the technology to screen them, identify them and reach out to and potentially enroll them in trials through use of decentralized elements for clinical trials. And so I'm very optimistic that not just good quality standard cancer care, but also clinical research is going to be greatly expanded with the use of AI and telehealth. Dr. John Sweetenham: Really encouraging to hear that. Nate, it's been a real pleasure speaking with you today and I want to thank you for taking the time to share your insights with us on the ASCO Daily News Podcast.  Dr. Nathan Pennell: Thanks, John. Dr. John Sweetenham: I also want to say thank you to our listeners for your time today. 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 speakers: Dr. Nathan Pennell @n8pennell   Dr. John Sweetenham   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. 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. 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

Jonas ist 35, als er die Diagnose Darmkrebs erhält und plötzlich muss er sein ganzes Leben neu ordnen – Familienplanung, Beruf, Hobbies. Wie er diese Herausforderungen gemeistert und ob er trotz Krebs zum Vaterglück gefunden hat, erzählt uns Jonas in dieser Folge. Link zum Vlog von Jonas: https://shorturl.at/GMkJALink zur Peer Plattform der Krebsliga: https://peerplattform.krebsliga.chPodcast MySurvivalStory mit Martin Inderbitzin: https://open.spotify.com/show/7F8kAJ8u15MFwQ8dNge4jg?si=a08f193e47b14236Diese Folge wird unterstützt durch Janssen Oncology. Die Mitarbeitenden bei Janssen arbeiten daran, Krebserkrankungen durch Prävention, Behandlung und Heilung vollständig zu eliminieren und den Betroffenen so mehr Zeit und Lebensqualität zu schenken.Mehr Infos zum Engagement von Janssen: www.Janssen.comWir freuen uns sehr über Rückmeldungen, Ideen und Themenvorschläge für unseren Podcast. Schreib uns gerne auf Instagram (@lebenmitkrebs_ch), Facebook (@LebenmitKrebsSchweiz) oder via E-Mail auf info@lebenmitkrebs.ch. Alles Liebe Nadine & Sandra Disclaimer:Gekennzeichnete Folgen wurden mit finanzieller Unterstützung der jeweiligen Unternehmen erstellt. Die Unternehmen haben keinen Einfluss auf den finalen Inhalt der Folgen. Die Unternehmen sowie die Produzentin übernehmen keine Verantwortung für wiedergegebenen Meinungen und Aussagen von Interviewpartnern in den jeweiligen Folgen. Die unterstützenden Unternehmen und die Redaktion geben ebenso wenig individuelle Empfehlungen in Bezug auf die Diagnose oder den Behandlungsplan von Patienten und Patientinnen. Diese Fragen sind mit den behandelnden Ärzt*innen zu besprechen.

While molecularly targeted therapies based on actionable biomarkers are improving outcomes for patients with lung cancer, access to biomarker testing continues to hinder equitable and comprehensive care for underserved patients. In this episode, CANCER BUZZ TV speaks with Tom Lycan, DO, MHS, assistant professor of Hematology & Oncology at the Wake Forest School of Medicine, about a practical tool that can provide a care plan roadmap for providers and patients to mitigate precision medicine disparities.  “[The 4R Care Sequences pathway] gives an overarching view of what they [patients] are looking for in the immediate future and also down the road, and it can be a very helpful thing for patients and navigators, and honestly for clinicians...when I'm meeting with patients in-clinic, it helps me to just point to this and go through and review their pathway with the patient, so that I also can reframe everything in how we're coming up with a [treatment] plan together.”—Tom Lycan, DO, MHS Tom Lycan, DO, MHS Assistant Professor, Hematology & Oncology, Department of Internal Medicine Wake Forest School of Medicine Winston-Salem, NC   This episode was developed in connection with the ACCC education program Eliminating Precision Medicine Disparities, in partnership with the LUNGevity Foundation, and is supported by Janssen Oncology and Pfizer. Resources: Eliminating Precision Medicine Disparities - ACCC  LUNGevity Patient Resources  Care Action Plans for People with Cancer - ACCC  Fostering a High-Functioning Team in Cancer Care Using the 4R Oncology Model: Assessment in a Large Health System and a Blueprint for Other Institutions  

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

Inkontinenz und Erektionsstörungen als Folge einer Prostatakrebs-Operation sind immer noch Tabuthemen bei vielen Männern. Einer, der das ändern will, ist Prof. André Reitz, leitender Arzt am KontinenzZentrum der Klinik Hirslanden Zürich. Mit ihm sprechen wir über konventionelle und invasive Methoden zur Bewältigung dieser häufig auftretenden Probleme sowie über sein eigens entwickeltes Reha-Programm.Weiterführende Infos zur Postatakrebs-Reha im Kontinzzentrum der Klinik Hirslanden Zürich: www.kontinenzzentrum.ch/reha-nach-prostatakrebs und www.klinik-hirslanden.ch/kontinenzzentrumDiese Folge wird unterstützt durch Janssen Oncology. Die Mitarbeitenden bei Janssen arbeiten daran, Krebserkrankungen durch Prävention, Behandlung und Heilung vollständig zu eliminieren und den Betroffenen so mehr Zeit und Lebensqualität zu schenken.Mehr Infos zum Engagement von Janssen: www.Janssen.comWir freuen uns sehr über Rückmeldungen, Ideen und Themenvorschläge für unseren Podcast. Schreib uns gerne auf Instagram (@lebenmitkrebs_ch), Facebook (@LebenmitKrebsSchweiz) oder via E-Mail auf info@lebenmitkrebs.ch. Alles Liebe Nadine & Sandra Disclaimer:Gekennzeichnete Folgen wurden mit finanzieller Unterstützung der jeweiligen Unternehmen erstellt. Die Unternehmen haben keinen Einfluss auf den finalen Inhalt der Folgen. Die Unternehmen sowie die Produzentin übernehmen keine Verantwortung für wiedergegebenen Meinungen und Aussagen von Interviewpartnern in den jeweiligen Folgen. Die unterstützenden Unternehmen und die Redaktion geben ebenso wenig individuelle Empfehlungen in Bezug auf die Diagnose oder den Behandlungsplan von Patienten und Patientinnen. Diese Fragen sind mit den behandelnden Ärzt*innen zu besprechen.

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. Vamsi Velcheti and Nathan Pennell discuss novel approaches and key studies in lung cancer that were showcased at the 2024 ASCO Annual Meeting, including the Plenary abstracts LAURA and ADRIATIC.   TRANSCRIPT Dr. Vamsi Velcheti: Hello, I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. Today, I'm joined by Dr. Nate Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and the vice chair of clinical research at the Taussig Cancer Center in Cleveland Clinic. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Today, we will be discussing practice-changing abstracts and the exciting advances in lung cancer that were featured at the ASCO 2024 Annual Meeting. You'll find our full disclosures in the transcript of the episode. Nate, we're delighted to have you back on the podcast today. Thanks for being here. It was an exciting Annual Meeting with a lot of important updates in lung cancer. Dr. Nate Pennell: Thanks, Vamsi. I'm glad to be back. And yes, it was a huge year for lung. So I'm glad that we got a chance to discuss all of these late-breaking abstracts that we didn't get to talk about during the prelim podcast. Dr. Vamsi Velcheti: Let's dive in. Nate, it was wonderful to see all the exciting data, and one of the abstracts in the Plenary Session caught my attention, LBA3. In this study, the investigators did a comparative large-scale effectiveness trial of early palliative care delivered via telehealth versus in-person among patients with advanced non-small cell lung cancer. And the study is very promising. Could you tell us a little bit more about the study and your take-home messages? Dr. Nate Pennell: Yes, I think this was a very important study. So just to put things in perspective, it's now been more than a decade since Dr. Jennifer Temel and her group at Massachusetts General Hospital did a randomized study that showed that early interventions with palliative medicine consultation in patients with advanced non-small cell lung cancer significantly improves quality of life and in her initial study, perhaps even overall survival. And since then, there have been numerous studies that have basically reproduced this effect, showing that getting palliative medicine involved in people with advanced cancer, multiple different cancer types, really, has benefits.  The difficulty in applying this has been that palliative care-trained specialists are few and far between, and many people simply don't have easy access to palliative medicine-trained physicians and providers. So with that in mind, Dr. Temel and her group designed a randomized study called the REACH PC trial, where 1,250 patients were randomized with advanced non-small cell lung cancer to either in-person palliative medicine visits which is sort of the standard, or one in-person assessment followed by monthly telemedicine video visits with palliative medicine. Primary endpoint was essentially to show that it was equivalent in terms of quality of life and patient satisfaction. And what was exciting about this was that it absolutely was. I mean, pretty much across the board in all the metrics that were measured, the quality-of-life, the patient satisfaction, the anxiety and depression scores, all were equivalent between doing telemedicine visits and in-person visits. And this hopefully will now extend the ability to get this kind of benefit to a much larger group of people who don't have to geographically be located near a palliative medicine program. Dr. Vamsi Velcheti: Yeah, I think it's a great abstract, Nate and I actually was very impressed by the ASCO committee for selecting this for the Plenary. We typically don't see supportive care studies highlighted in such a way at ASCO. This really highlights the need for true interdisciplinary care for our patients. And as you said, this study will clearly address that unmet need in terms of providing access to palliative care for a lot of patients who otherwise wouldn't have access. I'm really glad to see those results. Dr. Nate Pennell: It was. And that really went along with Dr. Schuchter's theme this year of bringing care to patients incorporating supportive care. So I agree with you.  Now, moving to some of the other exciting abstracts in the Plenary Session. So we were talking about how this was a big year for lung cancer. There were actually 3 lung cancer studies in the Plenary Session at the Annual Meeting. And let's move on to the second one, LBA4, the LAURA study. This was the first phase 3 study to assess osimertinib, an EGFR tyrosine kinase inhibitor, in patients with EGFR mutant, unresectable stage III non-small cell lung cancer. What are your takeaways from this study?  Dr. Vamsi Velcheti: This is certainly an exciting study, and all of us in the lung community have been kind of eagerly awaiting the results of the study. As you know, for stage III non-small cell lung cancer patients who are unresectable, the standard of care has been really established by the PACIFIC study with the consolidation durvalumab after definitive concurrent chemoradiation. The problem with that study is it doesn't really answer the question of the role of immunotherapy in patients who are never-smokers, and especially in patients who are EGFR positive tumors, where the role of immunotherapy in a metastatic setting has always been questioned. And in fact, there have been several studies as you know, in patients with EGFR mutation positive metastatic lung cancer where immunotherapy has not been that effective. In fact, in the subgroup analysis in the PACIFIC study, patients with EGFR mutation did not really benefit from adding immunotherapy.  So this is an interesting study where they looked at patients with locally advanced, unresectable stage III patients and they randomized the patients 2:1 to osimertinib versus placebo following concurrent or sequential tumor radiation. The primary endpoint for the study was progression free survival, and a total of 216 patients were enrolled and 143 patients received a study treatment, which is osimertinib, and 73 received placebo. And 80% of the patients on the placebo arm crossed over to getting treatment at the time of progression.  So most of us in the lung cancer community were kind of suspecting this would be a positive trial for PFS. But however, I think the magnitude of the difference was truly remarkable. The median PFS in the osimertinib arm was 39.1 months and placebo was 5.6 months and the hazard ratio of 0.16. So it was a pretty striking difference in terms of DFS benefit with the osimertinib consolidation following chemoradiation. So it was truly a positive study for the primary endpoint and the benefit was seen across all the subgroups and the safety was no unexpected safety signals other than a slight increase in the radiation pneumonitis rates in patients receiving osimertinib and other GI and skin tox were kind of as expected. In my opinion, it's truly practice changing and I think patients with EGFR mutation should not be getting immunotherapy consolidation post chemoradiation. Dr. Nate Pennell: I completely agree with you. I think that this really just continues the understanding of the use of osimertinib in EGFR-mutant lung cancer in earlier stages of disease. We know from the ADAURA trial, presented twice in the Plenary at the ASCO Annual Meeting, that for IB, stage II and resectable IIIA, that you prolong progression free or disease free survival. So this is a very similar, comparable situation, but at an even higher risk population or the unresectable stage III patients. I think that the most discussion about this was the fact that the osimertinib is indefinite and that it is distinct from the adjuvant setting where it's being given for three years and then stopped. But I think all of us had some pause when we saw that after three years, especially in the stage III patients from ADAURA, that there were clearly an increase in recurrences after stopping the drug, suggesting that there are patients who are not cured with a time limited treatment, or at least with 3 years of treatment.  The other thing that is sobering from the study, and was pointed out by the discussant, Dr. Lecia Sequist, is if you look at the two-year disease-free survival in the placebo arm, it was only 13%, meaning almost no one was really cured with chemo radiation alone. And that really suggests that this is not that different from a very early stage IV population where indefinite treatment really is the standard of care. I wonder whether you think that's a reasonable approach. Dr. Vamsi Velcheti: I completely agree with you, Nate, and I don't think we cure a majority of our patients with stage III, and less so in patients who have EGFR-mutant, stage III locally advanced. As you just pointed out, I think very few patients actually make it that far along. And I think there's a very high rate of CNS micrometastatic disease or just systemic micrometastatic disease in this population that an effective systemic therapy of osimertinib can potentially have long term outcomes. But again, we perhaps don't cure a vast majority of them. I think that the next wave of studies should incorporate ctDNA and MRD-based assays to potentially identify those patients who could potentially go off osimertinib at some point. But, again, outside of a trial, I would not be doing that. But I think it's definitely an important question to ask to identify de-escalation strategies with osimertinib. And even immunotherapy for that matter, I think we all know that not all patients really require years and years of immunotherapy. They're still trying to figure out how to use immunotherapy in these post-surgical settings, using the MRD to de-escalate adjuvant therapies. So I think we have to have some sort of strategy here. But outside of a clinical trial, I will not be using those assays here to cite treatments, but certainly an important question to ask.  Moving on to the other exciting late-breaking abstracts, LBA5, the ADRIATIC study. This is another study which was also in the plenary session. This study was designed to address this question of consolidation immunotherapy, post chemo radiation for limited-stage small cell cancer, the treatment arms being durvalumab tremelimumab, and durvalumab observation. So what do you think about the study? This study also received a lot of applause and a lot of attention at the ASCO meeting. Dr. Nate Pennell: It was. It was remarkable to be there and actually watch this study as well as the LAURA study live, because when the disease free survival curves and in the ADRIATIC study, the overall survival curves were shown, the speakers were both interrupted by standing ovation of applause just because there was a recognition that the treatment was changing kind of before our eyes. I thought that was really neat. So in this case, I think this is truly a historic study, not necessarily because it's going to necessarily be an earth shakingly positive study. I mean, it was clearly a positive study, but more simply because of the disease in which it was done, and that is limited-stage small cell lung cancer. We really have not had a change in the way we've treated limited-stage small cell lung cancer, probably 25 years. Maybe the last significant advances in that were the advent of concurrent chemotherapy and radiation and then the use of PCI with a very modest improvement in survival. Both of those, I would say, are still relatively modest advances.  In this case, the addition of immunotherapy, which we know helps patients with small cell lung cancer - it's of course the standard of care in combination chemotherapy for extensive stage small cell lung cancer - in this case, patients who completed concurrent chemo radiation were then randomized to either placebo or durvalumab, as well as the third arm of durvalumab tremelimumab, which is not yet been recorded, and co primary endpoints were overall survival and progression free survival. And extraordinarily, there was an improvement in overall survival seen at the first analysis, with a median overall survival of 55.9 months compared to 33.4 months, hazard ratio of 0.73. So highly clinically and statistically significant, that translates at three years to a difference in overall survival of 56.5%, compared to 47.6%, or almost 10% improvement in survival at three years.  There was also a nearly identical improvement in progression-free survival, also with a hazard ratio of 0.76, suggesting that there's a modest number of patients who benefit. But it seems to be a clear improvement with the curves plateauing out. In my opinion, this is very comparable to what we saw with the PACIFIC study in stage III, unresectable non-small cell lung cancer, which immediately changed practice back when that first was reported. And I expect that this will change practice pretty much immediately for small cell as well. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think it's an exciting advance in patients with limited-stage small cell lung cancer. For sure, it's practice-changing, and I think the results were exciting.  So one thing that really intrigued me was in the extensive-stage setting, the benefit was very mediocre with one-to-two month overall survival benefit in both the PACIFIC and in IMpower trial. Here we are seeing almost two-year of median OS benefit. I was kind of puzzled by that, and I thought it may have to do with patients receiving radiation. And we've seen that with the PACIFIC, and makes you wonder if both the CASPIAN and the IMpower studies actually did not allow consolidation thoracic radiation. Hypothetically, if they had allowed consolidation thoracic radiation, perhaps we would have seen better outcomes. Any thoughts on that? Dr. Nate Pennell: We've been trying to prove that radiation and immunotherapy somehow go together better for a long time. Going back to the first description of the abscopal effect, and I'm not sure if I necessarily believe that to be the case, but in this setting where we truly are trying to cure people rather than merely prolong their survival, maybe this is the situation where it truly is more beneficial. I think what we're seeing is something very similar to what we're seen in PACIFIC, where in the stage IV setting, some people have long term survival with immunotherapy, but it's relatively modest. But perhaps in the curative setting, you're seeing more of an impact. Certainly, looking at these curves, we'll have to see with another couple of years to follow up. But a three-year survival of 56% is pretty extraordinary, and I look forward to seeing if this really maintains over the next couple of years follow up.  Moving beyond the Plenary, there were actually lots of really exciting presentations, even outside the Plenary section. One that I think probably got at least as much attention as the ones that we've already discussed today was actually an update of an old trial that's been presented for several prior years. And I'm curious to get your take on why you thought this was such a remarkable study. And we're talking about the LBA8503, which was the 5-year update from the CROWN study, which looked at previously untreated ALK-positive advanced non-small cell in cancer patients randomly assigned to lorlatinib, the third generation ALK inhibitor, versus crizotinib, the first generation ALK inhibitor. What was so exciting about this study, and why were people talking about it?  Dr. Vamsi Velcheti: Yeah, I agree, Nate. We've seen the data in the past, right? Like on the CROWN data, just first like a quick recap. This is the CROWN study, like the phase 3 study of third generation ALK inhibitor lorlatinib. So global randomized phase 3 study in patients with metastatic disease randomized to lorlatinib versus crizotinib, which is a controller. So the primary endpoint was PFS, and we've seen the results in the past of the CROWN readout quoted, with a positive study and the lorlatinib received FDA approval in the frontline setting. But the current study that was presented at the ASCO annual meeting is a kind of a postdoc analysis of five years. The endpoint for the study with central review stopped at three years, and this is actually a follow up beyond that last readout. Interestingly, in this study, when they looked at the median PFS at five years, the lorlatinib arm did not reach a median PFS even at five years and the hazard ratio is 0.19, which is kind of phenomenal in some ways. At 5 years, the majority of the patients were still on the drug. So that's quite incredible. And the benefit was more profound in patients with brain mets with a hazard ratio of 0.08. And again, speaking to the importance of brain penetrant, small molecule inhibitors, and target therapy, the safety profile, there were no additional safety signals noted in the study. We kind of know about the side effects of lorlatinib already from previous studies readouts. No unusual long-term toxicities.  I should note though, about 40% of patients did have CNS, AEs grade 1, 2 CNS toxicities on the  lorlatinib arm. And the other interesting thing that was also reported in the trial was dose reduction of lorlatinib did not have an impact on the PFS, which is interesting in my opinion. They also did some subgroup analysis, biomarker testing, biomarker populations. Patients who had P53 cooperation did much better with lorlatinib versus crizotinib. So overall, the other thing that they also had shown on the trial was the resistance mechanisms that were seen with lorlatinib were very different than what we are used to seeing with the earlier generation ALK inhibitors. The majority of the patients who develop resistance have bypass mechanisms and alterations in MAP kinase pathway PI3K/MTOR/PTEN pathway, suggesting that lorlatinib is a very potent ALK inhibitor and on target ALK mutations don't happen as frequently as we see with the earlier generation ALK inhibitors.  So I think this really begs the question, should we offer lorlatinib to all our patients with metastatic ALK-positive tumors? I think looking at the long-term data, it's quite tempting to say ‘yes', but I think at the same time we have to take into consideration patient safety tolerability. And again, the competitor arm here is crizotinib. So lorlatinib suddenly seems to be, again, cross trial comparisons, but I think the long-term outcomes here are really phenomenal. But at the same time, I think we've got to kind of think about patient because these patients are on these drugs for years, they have to live with all the toxicities. And I think the patient preferences and safety profile matters in terms of what drug we recommend to patients. Dr. Nate Pennell: I completely agree with you. I think the right answer, is that this has to be an individual discussion with patients. The results are incredibly exciting. I mean, the two-year progression free survival was 70%, and the five-year, three years later is still 60%. Only 10% of people are failing over the subsequent three years. And the line is pretty flat. And as you said, even with brain metastases, the median survival is in reach. It's really extraordinary. Moreover, while we do talk about the significant toxicities of lorlatinib, I thought it was really interesting that only 5% of people were supposedly discontinued the drug because of treatment related AEs, which meant that with dose reduction and management, it seems as though most patients were able to continue on the drug, even though they, as you mentioned, were taking it for several years.  That being said, all of us who've had experience with the second-generation drugs like alectinib and brigatinib, compared to the third-generation drug lorlatinib, can speak to the challenges of some of the unique toxicities that go along with it. I don't think this is going to be a drug for everyone, but I do think it is now worth bringing it up and discussing it with the patients most of the time now. And I do think that there will be many people for whom this is going to be a good choice, which is exciting. Dr. Vamsi Velcheti: Absolutely, completely agree. And I think there are newer ALK inhibitors in clinical development which have cleaner and better safety profiles. So we'll have to kind of wait and see how those pan out.  Moving on to the other exciting abstract, LBA8509, the KRYSTAL-12 study. LBA8509 is a phase 3 study looking at adagrasib versus docetaxel in patients with previously treated advanced metastatic non-small cell cancer with KRASG12C mutation. Nate, there's been a lot of hype around this trial. You've seen the data. Do you think it's practice-changing? How does it differentiate with the other drug that's already FDA approved, sotorasib?  Dr. Nate Pennell: Yeah, this is an interesting one. I think we've all been very excited in recent years about the identification of KRASG12C mutations as targetable mutations. We know that this represents about half of KRAS mutations in patients with non-small cell lung cancer, adenocarcinoma, and there are two FDA-approved drugs. Sotorasib was the first and adagrasib shortly thereafter. We already had seen the CodeBreaK 200 study, which was a phase 3 study of sotorasib versus docetaxel that did modestly prolong progression free survival compared to docetaxel, although did not seem to necessarily translate to an improvement in overall survival. And so now, coming on the heels of that study, the KRYSTAL-12 study compared adagrasib, also the KRASG12C  inhibitor versus docetaxel and those with previously treated non-small cell with KRASG12C. And it did significantly improve progression free survival with a hazard ratio of 0.58. Although when you look at the median numbers, the median PFS was only 5.5 months with the adagrasib arm compared to 3.8 months with docetaxel. So while it is a significant and potentially clinically significant difference, it is still, I would say a modest improvement.   And there were some pretty broad improvements across all the different subgroups, including those with brain metastases. It did improve response rate significantly. So 32% response rate without adagrasib, compared to only 9% with docetaxel. It's about what you would expect with chemotherapy. And very importantly, in this patient population, there was activity in the brain with an intracranial overall response rate among those who had measurable brain metastases of 40%. So certainly important and probably that would distinguish it from drugs like docetaxel, which we don't expect to have a lot of intracranial toxicity. There is certainly a pattern of side effects that go along with that adagrasib, so it does cause especially GI toxicity, like diarrhea, nausea, vomiting, transaminitis. All of these were actually, at least numerically, somewhat higher in the adagrasib arm than in docetaxel, a lot more hematologic toxicity with the docetaxel. But overall, the number of serious adverse events were actually pretty well matched between the two groups. So it wasn't really a home run in terms of favorable toxicity with that adagrasib.  So the question is: “In the absence of any data yet on overall survival, should this change practice?” And I'm not sure it's going to change practice, because I do think that based on the accelerated approval, most physicians are already offering the G12C inhibitors like sotorasib and adagrasib, probably more often than chemotherapy, I think based on perceived improvement in side effects and higher response rates, modestly longer progression-free survival, so I think most people think that represents a modest improvement over chemotherapy. And so I think that will continue. It will be very interesting, however, when the overall survival report is out, if it is not significantly better, what the FDA is going to do when they look at these drugs.  Dr. Vamsi Velcheti: Thanks so much. Very well summarized. And I do agree they look more similar than dissimilar. I think CodeBreaK-200 and the KRYSTAL-12, they kind of are very identical. I should say, though I was a little surprised with the toxicity profile of adagrasib. It seemed, I mean, not significantly, but definitely seemed worse than the earlier readouts that we've seen. The GI tox especially seems much worse on this trial. I'm kind of curious why, but if I recall correctly, I think 5% of the patients had grade 3 diarrhea. A significant proportion of patients had grade 3 nausea and vomiting. And the other complicating thing here is you can't use a lot of the antiemetics because of the QT issues. So that's another problem. But I think it's more comparable to sotorasib, in my opinion.  Dr. Nate Pennell: While this is exciting, I like to think of this as the early days of EGFR, when we were using gefitinib and erlotinib. They were certainly advances, but we now have drugs that are much more effective and long lasting in these patients. And I think that the first-generation inhibitors like sotorasib and adagrasib, while they certainly benefit patients, now is just the beginning. There's a lot of research going on, and we're not going to talk about some of the other abstracts presented, but some of the next generation G12C inhibitors, for example, olomorasib, which did have also in the same session, a presentation in combination with pembrolizumab that had a very impressive response rate with potentially fewer side effects, may end up replacing the first generation drugs when they get a little bit farther along. And then moving on to another one, which I think potentially could change practice. I am curious to hear your take on it, was the LBA8505, which was the PALOMA-3 study. This was interesting in that it compared two different versions of the same drug. So amivantamab, the bispecific, EGFR and MET, which is already approved for EGFR exon 20 non-small cell lung cancer, in this case, in more typical EGFR-mutated non-small cell lung cancer in combination with osimertinib with the intravenous amivantamab, compared to the subcutaneous formulation of amivantamab. Why would this be an important study? Dr. Vamsi Velcheti: I found this study really interesting as well, Nate. And as you know, amivantamab has been FDA approved for patients with exon 20 mutation. And also, we've had, like two positive readouts in patients with classical EGFR mutations. One, the MARIPOSA study in the frontline setting and the MARIPOSA-2, in the second-line post osimertinib setting. For those studies, the intravenous amivantamab was used as a treatment arm, and the intravenous amivantamab had a lot of baggage to go along with it, like the infusion reactions and VTEs and other classic EGFR related toxicity, skin toxicities. So the idea behind developing the subcutaneous formulation of amivantamab was mainly to reduce the burden of infusion, infusion time and most importantly, the infusion related reactions associated with IV formulation.  In a smaller phase 2 study, the PALOMA study, they had looked at various dosing schemas like, subcutaneous formulation, and they found that the infusion related reactions were very, very low with the subcutaneous formulation. So that led to the design of this current study that was presented, the PALOMA-3 study. This was for patients who had classical EGFR mutations like exon 19, L858R. The patients were randomized 1:1 to subcutaneous amivantamab with lazertinib versus IV amivantamab plus lazertinib. The endpoints for the study, it's a non-inferiority study with co primary endpoints of C trough and C2 AUC, Cycle 2 AUC. They were looking at those pharmacological endpoints to kind of demonstrate comparability to the IV formulation. So in this study, they looked at these pharmacokinetic endpoints and they were essentially identical. Both subcutaneous and IV formulations were compatible. And in terms of clinical efficacy as well, the response rate was identical, no significant differences. Duration of response was also identical. The PFS also was comparable to the IV formulation. In fact, numerically, the subcutaneous arm was a little better, though not significant. But it appears like, you know, the overall clinical and pharmacological profile of the subcutaneous amivantamab was comparable. And most interestingly, the AE profile, the skin toxicity was not much different. However, the infusion reactions were substantially lower, 13% with the subcutaneous amivantamab and 66% with IV amivantamab. And also, interestingly, the VTE rates were lower with the subcutaneous version of amivantamab. There was still a substantial proportion of patients, especially those who didn't have prophylactic anticoagulation. 17% of the patients with the subcutaneous amivantamab had VTE versus 26% with IV amivantamab. With prophylaxis, which is lower in both IV and subcutaneous, but still subcutaneous formulation at a lower 7% versus 12% with the IV amivantamab.  So overall, I think this is an interesting study, and also the authors had actually presented some interesting data on administration time. I've never seen this before. Patients reported convenience using a modified score of patient convenience, essentially like patients having to spend a lot of time in the infusion site and convenience of the patient getting the treatment. And it turns out, and no surprise, that subcutaneous amivantamab was found to be more convenient for patients.  So, Nate, I want to ask you your take on this. In a lot of our busy infusion centers, the time it takes for those patients to get the infusion does matter, right? And I think in our clinic where we are kind of fully booked for the infusion, I think having the patients come in and leave in 15, 20 minutes, I think it adds a lot of value to the cancer center operation.  Dr. Nate Pennell: Oh, I completely agree. I think the efficacy results were reassuring. I think the infusion related reaction difference, I think is a huge difference. I mean, I have given a fair amount of amivantamab, and I would say the published IRR rate of 66%, 67% I would say, is maybe even underestimates how many patients get some kind of reaction from that, although it really is a first dose phenomenon. And I think that taking that down to 13% is a tremendous advance. I think fusion share time is not trivial as we get busier and busier. I know our cancer center is also very full and it becomes challenging to schedule people, and being able to do a five-minute treatment versus a five-hour treatment makes a big difference for patients.  It's interesting, there was one slide that was presented from an efficacy standpoint. I'm curious about your take on this. They showed that the overall survival was actually better in the subcu amivantamab arm, hazard ratio of 0.62. Now, this was only an exploratory endpoint. They sort of talk about perhaps some rationale for why this might be the case. But at the very least, I think we can be reassured that it's not less effective to give it and does seem to be more tolerable and so I would expect that this hopefully will be fairly widely adopted. Dr. Vamsi Velcheti: Yeah, I agree. I think this is a welcome change. Like, I think the infusion reactions and the resources it takes to get patients through treatments. I think it's definitely a win-win for patients and also the providers.  And with that, we come to the conclusion of the podcast. Nate, thank you so much for the fantastic insights today. Our listeners will find all the abstracts discussed today in the transcripts of the episode. Thank you so much for joining us today, Dr. Pennell.  Dr. Nate Pennell: Oh, thanks for inviting me. It's always fun to talk about all these exciting advances for our patients. Dr. Vamsi Velcheti: Thanks to our listeners for your time today. You will find links to all the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.   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. Vamsi Velcheti  @VamsiVelcheti    Dr. Nathan Pennell  @n8pennell    Follow ASCO on social media:      @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:  Dr. Vamsi Velcheti:  Honoraria: ITeos Therapeutics  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus  Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  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

Prostatakrebs ist die häufigste Krebsart bei Männern – mehr als 7'000 Diagnosen werden jährlich neu gestellt. In dieser Folge sprechen wir mit jemandem, der weiss, wie es ist, mit Prostatakrebs zu leben. Marcus teilt mit uns seine persönlichen Erfahrungen und erzählt, was die Diagnose Prostatakrebs für einen Mann bedeuten kann. Link zur Peer Plattform der Krebsliga: https://peerplattform.krebsliga.chDiese Folge wird unterstützt durch Janssen Oncology. Die Mitarbeitenden bei Janssen arbeiten daran, Krebserkrankungen durch Prävention, Behandlung und Heilung vollständig zu eliminieren und den Betroffenen so mehr Zeit und Lebensqualität zu schenken.Mehr Infos zum Engagement von Janssen: www.Janssen.comWir freuen uns sehr über Rückmeldungen, Ideen und Themenvorschläge für unseren Podcast. Schreib uns gerne auf Instagram (@lebenmitkrebs_ch), Facebook (@LebenmitKrebsSchweiz) oder via E-Mail auf info@lebenmitkrebs.ch. Alles Liebe Nadine & Sandra Disclaimer:Gekennzeichnete Folgen wurden mit finanzieller Unterstützung der jeweiligen Unternehmen erstellt. Die Unternehmen haben keinen Einfluss auf den finalen Inhalt der Folgen. Die Unternehmen sowie die Produzentin übernehmen keine Verantwortung für wiedergegebenen Meinungen und Aussagen von Interviewpartnern in den jeweiligen Folgen. Die unterstützenden Unternehmen und die Redaktion geben ebenso wenig individuelle Empfehlungen in Bezug auf die Diagnose oder den Behandlungsplan von Patienten und Patientinnen. Diese Fragen sind mit den behandelnden Ärzt*innen zu besprechen.

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss promising combination therapies and other compelling advances in genitourinary cancers in advance of the 2024 ASCO Annual Meeting. 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'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of genitourinary cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode. Jeanny, it's great to have you on the podcast. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal. It's a pleasure to be here. Dr. Neeraj Agarwal: So, Jeanny, let's start with some bladder cancer abstracts. Could you tell us about the Abstract 4509 titled, “Characterization of Complete Responders to Nivolumab plus Gemcitabine Cisplatin versus Gemcitabine Cisplatin Alone in Patients with Lymph Node Only Metastatic Urothelial Carcinoma from the CheckMate 901 Trial.”  Dr. Jeanny Aragon-Ching: Of course, Neeraj, I would be delighted to. First, I would like to remind our listeners that the CheckMate 901 trial was a randomized, open-label, phase 3 study, in which this particular sub-study looked at cisplatin-eligible patients with previously untreated, unresectable, or metastatic urothelial carcinoma who were assigned to receive the combination of gemcitabine and cisplatin, followed by up to 2 years of nivolumab or placebo. Based on the data presented at ESMO 2023 and subsequently published in the New England Journal of Medicine, which shows significantly improved progression-free survival and overall survival in patients receiving the combination of gemcitabine, cisplatin, and nivolumab, this regimen was approved in March 2024 as a first-line therapy for patients with unresectable or metastatic urothelial carcinoma.  In the abstract that will be featured at ASCO this year, Dr. Matt Galsky and colleagues present a post-hoc analysis that aims to characterize a subset of patients with complete response as well as those with lymph node-only metastatic disease. In patients receiving the experimental treatment, 21.7% achieved a complete response, while 11.8% of the patients in the control arm achieved a complete response.  Among these complete responders, around 52% had lymph- node-only disease in both arms. Furthermore, when characterizing the subgroup of patients with lymph-node-only disease, those receiving the combination of gemcitabine-cisplatin plus nivolumab had a 62% reduction in the risk of progression or death and a 42% reduction in the risk of death compared to those treated with gemcitabine-cisplatin alone.  The median overall survival in the experimental arm in this subgroup was around 46.3 months, while it was only 24.9 months in the control arm. The ORR in patients with lymph-node-only disease receiving gem-cis plus nivo was about 81.5% compared to 64.3% in those treated with gem-cis alone. Dr. Neeraj Agarwal: Thank you, Jeanny, for the excellent summary of this abstract. We can say that nivolumab plus gemcitabine-cisplatin induced durable disease control and clinically meaningful improvements in OS and PFS compared to gem-cis alone in patients with lymph- node-only metastasis, and deserves to be considered as one of the options for these patients.  In a similar first-line metastatic urothelial carcinoma setting, Abstract 4502, also reported data on a recently approved combination of enfortumab vedotin and pembrolizumab. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, as quick reminder to our audience, this regimen was tested in the EV-302 phase 3 trial, where patients with previously untreated, locally advanced or metastatic urothelial carcinoma were randomized to receive enfortumab vedotin, plus pembrolizumab or gemcitabine plus either cisplatin or carboplatin. These data were also first presented at ESMO 2023 and subsequently published in the New England Journal of Medicine. They showed that this immune based combination significantly improved both progression free survival and overall survival, which were the primary endpoints compared to chemotherapy. In this abstract, Dr. Shilpa Gupta from the Cleveland Clinic and colleagues present the results of patient reported outcomes based on quality-of-life questionnaires in this trial.  Time to pain progression and time to confirm deterioration were numerically longer in patients treated with EV plus pembro, and patients with moderate to severe pain at baseline receiving this combination had a meaningful improvement in the Brief Pain Inventory Short-Form worst pain from week 3 through 26. Dr. Neeraj Agarwal: Thank you, Jeanny. This means that patients treated with EV plus pembro did not only have improved survival compared with platinum-based chemotherapy, but also improvement in their quality-of-life and functioning, further supporting the value of this combination for patients with locally advanced or metastatic urothelial carcinoma. This is terrific news for all of our patients.   Before we wrap up the bladder cancer section, would you like to tell our listeners about Abstract 4565, which provides the data on the efficacy of trastuzumab deruxtecan in patients with bladder cancer? Dr. Jeanny Aragon-Ching: Yes, Neeraj; this is timely given the recent FDA approval, which we will talk about. The abstract is titled, “Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2 Expressing Solid Tumors: Results from the Bladder Cohort of the DESTINY-PanTumor02 Study.” And as a quick reminder, the DESTINY-PanTumor02 was a phase 2 open-label study where trastuzumab deruxtecan, an antibody-drug conjugate targeting HER2 expression on cancer cells, was evaluated in patients with HER2-expressing locally advanced or metastatic disease who previously received systemic treatment or who had no other treatment options. The expression of HER2 was evaluated on immunohistochemistry by local or central testing.   The primary endpoint was confirmed objective response rate by investigator assessment. Secondary endpoints included duration of response, progression free survival, disease control rate, and safety. The primary analysis, which was published in the Journal of Clinical Oncology, showed an ORR of 37.1% and responses across all cohorts and the median duration of response was 11.3 months. Based on these results, fam-trastuzumab deruxtecan-nxki was just granted accelerated FDA approval for unresectable or metastatic HER2-positive solid tumors in April 2024.  So, back to this abstract; Dr. Wysocki and colleagues report the results of the bladder cancer cohort. This study included 41 patients with urothelial cancer and at a median follow up of around 12.6 months, the objective response rate among these patients was 39%, the median PFS was 7 months, and the duration of response median was 8.7 months. The disease control rate at 12 weeks was around 71%. Regarding the safety profile, 41.5% of patients experienced grade ≥3 drug related adverse events and interstitial lung disease or pneumonitis did occur in about 4 patients. Although there was no statistical comparison between different groups, the ORR was numerically highest among the HER2 3+ group with 56.3%.  Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data support consideration of trastuzumab deruxtecan as a salvage therapy option for pre-treated patients with HER2 expressing urothelial cancers and show that we are extending our treatment options to include therapies with novel mechanisms of action. This is definitely exciting news for patients with bladder cancer. Dr. Jeanny Aragon-Ching: Yes, absolutely, Neeraj. Now, let's switch gears a bit to prostate cancer. Could you tell us about Abstract 5005 which is titled, “EMBARK Post Hoc Analysis of Impact of Treatment Suspension on Health Quality-of-Life?” Dr. Neeraj Agarwal: Of course, I'd be happy to. So, enzalutamide was recently granted FDA approval for the treatment of patients with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high-risk of metastasis, based on the results of the EMBARK trial, which was a phase 3 study where patients with high-risk biochemical recurrence were randomized to receive either enzalutamide with leuprolide, enzalutamide monotherapy, or placebo plus leuprolide. The primary endpoint was metastasis-free survival with secondary endpoints including overall survival and safety.  Results showed that patients receiving enzalutamide alone or enzalutamide plus leuprolide had significantly improved metastasis-free survival compared to those treated with leuprolide alone while preserving health-related quality-of-life.   One important aspect in the design of the trial was that patients who achieved undetectable PSA at week 37 underwent treatment suspension. The treatment was resumed if PSA rose to more than 2 ng/ml for patients who underwent radical proctectomy or when PSA rose to more than 5 ng/ml for those who did not undergo surgery.  In this abstract, Dr. Stephen Freedland and colleagues present a post-hoc analysis of health-related quality-of-life outcomes after treatment suspension between weeks 37 and 205. They found that treatment was suspended in 90.9% of patients receiving enzalutamide plus leuprolide, 85.9% of those receiving enzalutamide monotherapy, and 67.8% of those receiving leuprolide monotherapy. Among those patients who stayed on treatment suspension, a trend toward numerical improvement in health-related quality-of-life after week 37 was seen in all 3 arms and this reached clinically meaningful threshold at week 205 in pain questionnaires, physical well-being, urinary and bowel symptoms. For hormonal treatment side effects, all arms reached clinically meaningful improvement at the subsequent assessments of week 49 to week 97. However, patients slowly deteriorated, with clinically meaningful deterioration at week 205 relative to week 37 in patients receiving the combination of enzalutamide and leuprolide and those treated with leuprolide.    Concerning sexual activity, a clinically meaningful improvement was reported only in patients receiving enzalutamide plus leuprolide, possibly because sexual function was better preserved prior to suspension in the enzalutamide monotherapy arm and thus there was less opportunity for “improvement” while on suspension.  Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for this great summary. This analysis confirms that treatment suspension in good responders might lead to a clinically meaningful improvements in health-related quality-of-life.   Now, moving on to patients with metastatic castration-resistant prostate cancer, what can you tell us, about Abstract 5008 titled, “Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore”?  Dr. Neeraj Agarwal: Sure, Jeanny. The PSMAfore trial was a phase 3 study that compared the efficacy of 177Lu-PSMA-617 versus an ARPI switch in patients with mCRPC and prior progression on a first ARPI, and not previously exposed to docetaxel chemotherapy. The primary endpoint was rPFS and OS was an important secondary endpoint. The primary analysis presented at ESMO 2023 showed a significantly prolonged rPFS in patients receiving lutetium. In the abstract that will be featured at the 2024 ASCO Annual Meeting, Dr. Johann De Bono and colleagues present an exploratory analysis regarding the associations between baseline circulating tumor DNA and outcomes.  ctDNA fraction was evaluated in all samples as well as alterations in key prostate cancer drivers prevalent in more than 10% of participants.  The investigators sought to interrogate the association of ctDNA fraction or alterations with rPFS, PSA response, and RECIST response at data cutoff. They showed that median rPFS was significantly shorter in patients with a ctDNA fraction >1% compared to those with a fraction < 1% regardless of the treatment arm. Furthermore, ctDNA fraction >1% was also associated with worst RECIST response and PSA50 response. Regarding prostate cancer drivers, median rPFS was significantly shorter in patients with alterations in the AR, TP53 or PTEN in both treatment arms. There was no significant association between ctDNA alterations and PSA or objective responses. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that the presence of a ctDNA fraction >1% or alterations in AR, P53 and PTEN were all associated with worse outcomes regardless of treatment with lutetium or change in the ARPI. These data are definitely important for counseling and prognostication of patients in the clinic and may guide the design of future clinical trials. Let's move on to kidney cancer. Neeraj, do you have any updates for us?  Dr. Neeraj Agarwal:  Sure. In Abstract 4512 titled, “A Multi-institution Analysis of Outcomes with First-Line Therapy for 99 Patients with Metastatic Chromophobe Renal Cell Carcinoma,” Dr. Sahil Doshi and colleagues present a retrospective, multi-institutional study comparing survival outcomes, including time-to-treatment failure and overall survival, between different first-line treatment options in patients with metastatic chromophobe renal cell carcinoma, where limited clinical trial data exists to guide systemic therapy. They categorized patients into 4 treatment groups: and immune checkpoint inhibitors + targeted therapy doublets (such as ICI VEGF TKI); pure immune checkpoint inhibitor monotherapy and doublets (such as ipilimumab plus nivolumab); targeted therapy doublets (such as lenvatinib plus everolimus), and targeted monotherapy (such as sunitinib).  They identified 99 patients, of whom 54 patients received targeted monotherapy, 17 received ICI VEGF-TKI, 14 received targeted doublet, and 14 patients received only ICI therapies. So the patients treated with any doublet containing a targeted agent had a 52% decrease in the risk of treatment failure and a 44% decrease in the risk of death compared to those treated with targeted monotherapy. The median time to treatment failure was 15 months with IO-targeted doublet, and the median overall survival was 56 months. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that targeted doublet regimens resulted in a longer time to treatment failure and overall survival compared to any monotherapy in patients with chromophobe metastatic RCC and definitely provides valuable insights on treatment selection, albeit I would say there's still a small number of patients that were included in this retrospective analysis. Dr. Neeraj Agarwal: I completely agree this is a relatively small number of patients, but I decided to highlight the abstract given how rare the cancer is, and it is highly unlikely that we'll see large randomized clinical trials in patients with metastatic chromophobe renal cell carcinoma.  So, before we wrap up the podcast, what would you like to tell us about Abstract 5009 which is titled, “A Phase II Trial of Pembrolizumab Platinum Based Chemotherapy as First Line Systemic Therapy in Advanced Penile Cancer: HERCULES (LACOG 0218) Trial.” Dr. Jeanny Aragon-Ching: I'm glad you brought this up, Neeraj. As our listeners may know, advanced penile squamous cell carcinoma has a poor prognosis with limited treatment options. From this perspective, the results of the LACOG 0218 trial are very important. As you mentioned, this was a phase 2 single-arm study evaluating the addition of pembrolizumab to platinum-based chemotherapy as first-line treatment in patients with metastatic or locally advanced penile squamous cell carcinoma not amenable to curative therapy. Patients enrolled received chemotherapy, namely 5-Fluorouracil with cisplatin or carboplatin and pembrolizumab 200 mg IV every 3 weeks for 6 cycles, followed by pembrolizumab 200 mg IV every 3 weeks up to 34 cycles. The primary endpoint was confirmed overall response rate by investigator assessment.  In the 33 patients eligible for the efficacy analysis, the confirmed ORR by investigator assessment was 39.4% and included one complete response and 12 partial responses. The confirmed ORR was 75% in patients with high TMB and 55.6% in patients positive for HPV16, making TMB and HPV16 potential predictive biomarkers for efficacy in this study. Concerning the toxicity profile, any grade treatment-related adverse events were reported in around 92% of patients, and grade 3 or more treatment-related adverse events occurred in 51% of patients. 10.8% of patients discontinued treatment due to adverse events.  Dr. Neeraj Agarwal: Thank you, Jeanny. I would like to add that HERCULES is the first trial to demonstrate the efficacy of an immune checkpoint inhibitor in advanced penile squamous cell carcinoma with a manageable safety profile. Thus, the combination of ICI with platinum-based chemotherapy is a promising treatment for advanced penile squamous cell carcinoma and warrants further investigation.  Dr. Jeanny Aragon-Ching: I agree, Neeraj. Any final remarks before we conclude today's podcast? Dr. Neeraj Agarwal: Jeanny, I really want to thank you for your participation and valuable insights. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. It was a pleasure.  Dr. Neeraj Agarwal:  As we bring this podcast to an end, I would like to acknowledge the significant advances happening in the treatment of patients with genitourinary cancers. During our upcoming 2024 ASCO Annual Meeting, there will be an array of different studies featuring practice-changing data presented by researchers and physicians from around the globe. I urge our listeners to not only participate in this event to celebrate these achievements, but to also play a role in sharing these cutting-edge data with healthcare professionals worldwide. Through our collective efforts, we can surely optimize the benefits of patients on a global scale.   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 podcast. Thank you very much.   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. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    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. Jeanny Aragon-Ching:  Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 

Dr. John Sweetenham and Dr. Marc Braunstein look ahead at key abstracts across the spectrum of hematologic malignancies that will be presented at the 2024 ASCO Annual Meeting, including the OPTIC trial in chronic myeloid leukemia, treatment options for transplant-ineligible patients with multiple myeloma, and the 7-year analysis of the ECHELON-1 trial in classical Hodgkin lymphoma. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and the host of the ASCO Daily News Podcast. I'm delighted to be joined again this year by Dr. Marc Braunstein, a hematologist and oncologist at the NYU Perlmutter Cancer Center in New York. We're going to be discussing some of the key abstracts in hematologic malignancies that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod.  Marc, it's great to have you back on the podcast. Dr. Marc Braunstein: It's a pleasure to be back, John.  Dr. John Sweetenham: There are some exciting abstracts to be presented at this year's meeting, and I would like to begin, if we can, with Abstract 6501. As you know, this reports the four-year results from the OPTIC trial of ponatinib in patients with chronic-phase CML and the T315I mutation. Can you tell us about the trial and about these latest follow-up results? Dr. Marc Braunstein: Sure. Well, we've made tremendous progress in managing patients with CML in the past two decades using these oral tyrosine kinase inhibitors such as ponatinib. Ponatinib is a third-generation TKI that has activity in both Philadelphia-positive ALL as well as CML, and can overcome the resistance mutation you mentioned, called the T315I mutation, which is sometimes found following prior TKI therapy. The OPTIC study is a multicenter phase 2 randomized study of various doses of ponatinib in 283 chronic phase CML patients who had received 2 or more prior lines of therapy or those who had the presence of a T315I mutation, with the current analysis examining the major remission at 48 months, PFS, as well as OS. Of note, in this study, after patients have achieved a major remission with a transcript level of 1% or less, the study allowed for dose reduction of ponatinib from the original dose of either 45 milligrams or 30 milligrams to a reduced dose of 15 milligrams.  So, when we look at the results, we find that the patients who had the highest overall response rates and higher rates of molecular remission were those who received the 45-milligram dose. And remember, these patients were allowed to be dose-reduced to the 15-milligram dose once they achieved a molecular remission of 1% or less. In addition, the rates of overall survival were highest in the 45-milligram dose as well. When looking at the T315I subgroup, the rates of molecular remission, the depth of remission, and the rates of progression-free survival, in general, were lower in that subgroup, but still higher in the 45-milligram dose than the 35- milligram dose.  Furthermore, when looking at the rates of treatment-emergent adverse events leading to discontinuation, they were 8% in the 45-milligram dose compared to 14% in the 30-milligram dose and 5% in the patients who only received the 15-milligram dose. The authors have concluded that the 45-milligram dose, with the potential to be reduced to 15 milligrams after achieving 1% or less of the BCR-ABL transcript level, seems to be the right balance between efficacy and safety.  Dr. John Sweetenham: Thanks, Marc. In the longer term, do you think that this study will, in any way, affect the position of ponatinib in the treatment algorithm for CML? Is it going to remain as a second or third-line option, or do you think there's any chance it will be moved up? Dr. Marc Braunstein: Well, that's a great question. There are other TKIs, such as asciminib, that also target the T315I mutation, and that mutation tends to develop after prior first-line or second-line TKI therapy. But given its activity in both ALL and CML, I think it's certainly reasonable to expect that ponatinib will be used in earlier lines of therapy given its efficacy in later lines. Dr. John Sweetenham: Let's change gears and move the focus to acute myeloid leukemia. There has been a lot of discussion around frailty in many different malignancies, but the impact of frailty on outcomes in AML is maybe something that hasn't been quite so well studied. In Abstract 6506, investigators did a population-based study in Ontario, Canada, that assessed the patient's frailty risk and the impact that might have on outcomes. What are your takeaways from this study, and how do you think these data will help optimize treatment decisions?  Dr. Marc Braunstein: Yeah, I'm glad we're talking about this abstract John, because frailty scores are increasingly being used in hematologic malignancies to help guide goals and intensity of care. And as opposed to using age or performance status alone, these composite frailty assessment tools, such as the MFI tool that they used in this particular study, take into account multiple variables that are both physiologic, such as the patient's comorbidities, as well as social, and what kind of support system do they have, and things of that nature. And that accounts for their overall fitness. So, in this retrospective cohort study that was a population-based study in Ontario between 2006 and 2021, they looked at 5,450 patients retrospectively with acute leukemia and grouped those patients into 3 categories based on this frailty index. Patients who are either fit, somewhere in the middle between fit or frail, which they call pre-frail, or frail. And they looked at outcomes such as overall survival, comparing patients who got intensive chemotherapy regimens for induction or those who got non-intensive therapy for induction. Patients in either group could have been assigned to either fit, pre-frail, or frail although there are much more fit patients than those who got intensive induction.  And so, looking at their findings, it was noted that patients who were in the frail category, not entirely unexpectedly, had lower overall survival when compared to those who were fit or pre-frail. I think the value of a study like this is not just to highlight the benefit of frailty scores to help predict which patients may ultimately have a shorter survival, but also to help potentially guide which patients may be more suitable for intensive versus less intensive induction. I will note that this study was conducted in an era where we didn't have the same sorts of less intensive induction that are very effective in less fit patients, such as the combination of azacytidine and venetoclax, which is commonly used in less fit patients nowadays. So, the study may encompass patients who didn't have access to that therapy because it wasn't available during that time. But I think it still, overall, does highlight the fact that assessing fitness or frailty in acute myeloid leukemia is important for predictive value. Dr. John Sweetenham: I agree. Marc, I don't know what your thoughts are on this, but it goes either way. I mean, I think that, if I remember the numbers correctly, 25% of fit patients received non-intensive therapy. So, is there a missed opportunity there for that group of patients who actually may have tolerated the intensive therapy but it was never offered? Dr. Marc Braunstein: That's an excellent point, John, and I think that highlights the importance of frailty indices because they take into account much more than one particular factor, or even just a subjective assessment of the patient in real time when they're first presenting. And they may have disease-specific features that are decreasing, say one element of their assessment such as their performance status. So, really taking these composite fitness scores into account may actually allow you to escalate therapy in a patient who may actually be fit but maybe perceived as less fit when they present. Dr. John Sweetenham: Yeah. So, I think, as you mentioned, there are better treatment options out there now maybe than there were at the time this study was conducted. Nevertheless, there may still be that opportunity for more intensive therapy for some of these patients when they are more holistically assessed.  Let's move on and switch gears once again and talk about a study in multiple myeloma, the so-called IMROZ study, which is Abstract 7500. So, this is a study looking at treatment options for transplant-ineligible patients with newly diagnosed multiple myeloma. Some of these patients may not have a chance for subsequent therapy if they are not eligible for transplant. What are your thoughts on this study? Do you think we're closer to a new standard of care for patients who are not going to proceed to an autologous stem cell transplant?  Dr. Marc Braunstein: It seems like every year there's a new standard of care for newly diagnosed multiple myeloma because there's so much data emerging, which is just wonderful. So, I think as background, at the 2023 ASH meeting, the IsKia study was presented, which is a randomized phase 3 study in newly diagnosed transplant-eligible patients. And that was using isatuximab with carfilzomib, lenalidomide, and dexamethasone upfront and that study did show a benefit in terms of reducing minimal residual disease compared to carfilzomib, lenalidomide, and dexamethasone alone. But that study was looking at fit newly diagnosed patients who were going on to stem cell transplant. Right now, the standard of care for patients who are not eligible for transplant is generally to use a 2 or 3-drug regimen, such as daratumumab, lenalidomide, and dexamethasone, based on the phase 3 MAYA study. But this study is really unique in that it looks at using a quadruplet regimen in patients who are transplant ineligible or not intended to go for transplant.  So, the phase 3 IMROZ study was a randomized study of 446 patients that compared isatuximab, bortezomib, lenalidomide, and dexamethasone to bortezomib, lenalidomide, and dexamethasone alone. So, a quad versus a triplet regimen. The primary endpoint in this study was progression-free survival, but they also looked at secondary endpoints, such as complete response rate and minimal residual disease negativity.   Just to quickly highlight the results and then discuss the standard of care, the median duration of treatment in this study was 53 months in the quad regimen and 31 months in the control arm. At a median follow-up of about 60 months, the progression-free survival was not reached with the quad regimen versus 54 months in the triplet, and that was a significant difference. In addition, the safety profile was pretty much consistent with the class, there were a bit more grade three or higher treatment-emergent adverse events with the ESA-containing regimen, 92% versus 84%, but no difference in adverse events leading to discontinuation in either arm.   So, this study is certainly compelling in terms of using quadruplet-based regimens that contain an anti-CD38 monoclonal antibody for newly diagnosed patients who are not intended to undergo transplant. I think at the meeting, I will be interested to see the patient population that was included. Patients who are over the age of 80, for example, are excluded. So, I would like to know more about their fitness level and performance status. But I think it's clear, John, that using quad regimens over triplet regimens is just consistently superior in terms of efficacy outcomes. Dr. John Sweetenham: Right. I guess that, even though maybe we can't focus on the specific agents right now, it looks as if quad regimens are going to be the standard of care regimens for the future in this group. Do you think that is fair?  Dr. Marc Braunstein: Very likely. Dr. John Sweetenham: Absolutely. Well, that's a pretty challenging group of patients.   And so to move on again, let's talk about another, perhaps equally challenging group - patients with mantle cell lymphoma, particularly those who carry certain mutations. The so-called SYMPATICO study, which is reported in Abstract 7007, presents data on the efficacy and safety of ibrutinib and venetoclax in patients with mantle cell lymphoma who carry a TP53 mutation. We know that this mutation confers a high risk of early progressive disease and poorer outcomes when these patients are treated with standard chemoimmunotherapy for mantle cell. Trials to date have been limited to small single-arm studies. Can you tell us a little bit about this study and the outcomes and what you think it means for the future?  Dr. Marc Braunstein: As a background, although BTK inhibitors such as ibrutinib have yet to be approved for newly diagnosed mantle cell lymphoma, acalabrutinib and zanubrutinib, which are second-generation BTK inhibitors, are FDA-approved for previously treated mantle cell lymphoma. Ibrutinib was withdrawn from the market. The lead author of this abstract, Dr. Michael Wang, had presented a late-breaking data from the phase 3 SYMPATICO trial at ASH last year, in which 267 patients with relapsed or refractory mantle cell lymphoma after one to five prior lines of therapy were randomized to receive the combination of ibrutinib plus the BCL-2 inhibitor venetoclax or ibrutinib plus placebo. That study showed there was a 32 versus 22-month progression-free survival with a hazard ratio of 0.65 at a median follow-up of 51 months, indicating the PFS benefit of the combination of ibrutinib and venetoclax compared to ibrutinib with placebo.   So that leads us to this subgroup analysis in the current study being presented at ASCO, in which they looked at a subgroup of patients with mantle cell lymphoma who are at very high risk for treatment failure and early relapse - those are patients who have a mutation in TP53, which again is high risk for treatment failure. This abstract examined an open-label cohort of 44 first-line patients, as well as 75 patients who were in the relapse/refractory cohort, and compared to patients who either did or did not have the P53 mutation. When we look at the progression-free survival outcomes, the median progression-free survival in the first-line cohort of patients who did not have a P53 mutation was not reached, whereas those with the P53 mutation had a median progression-free survival of 22 months, which is still meaningful but still less than those who did not have a P53 mutation. Which again is not entirely unexpected. But the overall response rate of the combination of ibrutinib and venetoclax was very high at 90%, and the median duration of response was about 21 months.  Now comparing this to the relapse/refractory cohort, in those without a P53 mutation, the progression-free survival of the combination of ibrutinib and venetoclax was about 47 months versus those who don't have the P53 mutation was about 21 months with an overall response rate of 80%. I think one takeaway looking at this comparison of the first-line and relapse/refractory setting is that patients seem to do very similar in terms of overall response rate and progression-free survival, whether they were in the first line or in the later lines of treatment if they had the P53 mutation, which says that the combination of ibrutinib and venetoclax is effective no matter which phase of the disease the patient might be in, indicating its overall activity and being strong.    Dr. John Sweetenham: Yeah, I thought that was an interesting observation, actually, how similar the outcomes were in those two groups.  Dr. Marc Braunstein: No, I agree. And I think although patients with TP53 mutations did comparatively worse than those without the mutation according to progression-free survival, overall response rate, or complete remission rates, they did seem to be similar whether a patient was in first-line or relapsed refractory if they were P53 mutant and were treated with this combination. So, I think we need further data in the first line, such as the data that's awaiting publication from the TRIANGLE study, which is examining upfront ibrutinib. But certainly, BTK inhibitors have significant activity in either the first line or the relapse setting of mantle cell lymphoma.  Dr. John Sweetenham: Great. Thanks, Marc.  Let's wind up with one more abstract, and this is Abstract 7053. It's a 7-year analysis of the so-called ECHELON-1 study. This was a study comparing the standard of care, ABVD, with the same regimen with bleomycin substituted by brentuximab vedotin for patients with previously untreated advanced-stage classical Hodgkin lymphoma. The study at the time it was originally reported, resulted in a significant practice change in the first-line therapy of Hodgkin's lymphoma. We now have mature follow-up. What are your take-homes from this study? Dr. Marc Braunstein: The ECHELON-1 study has certainly been a practice-changing clinical trial where, as you said, brentuximab with the backbone of AVD was compared to ABVD, which was the prior standard. And this was examined in newly diagnosed patients with classical Hodgkin lymphoma who were at advanced-stage, stage 3 or 4. The publication, first of the progression-free survival, and more recently, in the New England Journal of Medicine in 2022, where we saw the 6-year overall survival was 94% with the brentuximab-containing arm versus 89% in the control arm, established the brentuximab AVD, or otherwise called AAVD, as the standard of care in advanced stage newly diagnosed classical Hodgkin lymphoma. The current study is now reporting 7-year follow-up on about 1,300 randomized patients who were enrolled in this impressive study.   Though at a median follow-up of 89 months now, the 7-year overall survival was quite similar, 94% versus 89%, again favoring the brentuximab-containing arm. In particular, this was driven by patients who had stage 4 disease or those patients who were aged less than 60 in subgroup analyses. So, what I take away from this abstract in the 7-year follow-up of the ECHELON-1 is that brentuximab with AVD remains the standard of care for previously untreated advanced-stage classical Hodgkin lymphoma. It is worth noting that the SWOG S1826 study that was presented at ASCO last year compared nivolumab with AVD compared to brentuximab AVD and did show a slight PFS advantage of 94% versus 86% with nivolumab AVD. Obviously, these were different studies with different patient populations enrolled, so we're really just cross-comparing different studies. But I think brentuximab AVD, given the survival benefit that is retained now at seven years in the current abstract, still remains the standard of care for advanced-stage classical Hodgkin lymphoma. The role of immune checkpoint inhibitors like nivolumab is making headway in terms of treating newly diagnosed patients as well. Dr. John Sweetenham: Yeah, thanks, Marc. I mean, one of the observations that I thought was of interest in this study was the outcome for patients who were PET-2 positive, when you compare AAVD and ABVD. It does seem as if even in those patients who are PET-2 positive, having had AAVD, they still apparently have a better outcome than those who received ABVD in that situation who were PET-2 positive. So, I think that's another interesting observation. I'm not quite sure what it means, except speaking to the overall superior efficacy of that regimen. Dr. Marc Braunstein: You make a great point, John, because it's worth noting that in ECHELON-1, a PET scan was done after cycle 2, but the study was not PET-adapted. So even if you had a positive PET, you continued for the full six cycles of treatment. But PET-2 status is often used in various studies of Hodgkin lymphoma to guide whether to give additional cycles or escalate therapy. So, I think the benefit of presenting those subgroups is that even if you were PET-2 positive, you still did better by continuing on the brentuximab-containing regimen. Dr. John Sweetenham: Yeah, exactly. I mean, the other important takeaway message, I think, is that the outcome for patients with advanced Hodgkin lymphoma seems to continue to steadily improve, which is great news and also really remarkable. And I'm excited to see there may be some additional data presented at one of the late-breaking abstracts in this year's meeting, so it will truly be interesting to see what that shows us as well.  Dr. Marc Braunstein: Incredible. Dr. John Sweetenham: Well, Marc, as always, thank you for sharing your insights with us today on the ASCO Daily News Podcast. We look forward very much to hearing the updated data from these abstracts at the meeting.  Dr. Marc Braunstein: As do I and thank you so much for inviting me again.  Dr. John Sweetenham: And 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 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. Vamsi Velcheti and Nathan Pennell discuss key lung cancer abstracts from the 2024 ASCO Annual Meeting, including data from LUMINOSITY and ADAURA, novel therapies in KRASG12C-mutant advanced NSCLC, and the need for effective adjuvant therapies for patients with rare mutations. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic medical oncology at Perlmutter Cancer Center at NYU Langone Health. Today, I'm delighted to welcome Dr. Nathan Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research at the Taussig Cancer Center. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Dr. Pennell is sharing his valuable insights today on key abstracts in lung cancer that will be presented at the 2024 ASCO Annual Meeting. You'll find our full disclosures in the transcript of the episode.  Nate, it's great to have you here on the podcast. Thank you for being here. Dr. Nathan Pennell: Thanks, Vamsi, for inviting me. I'm always excited for the ASCO Annual Meeting, and we have a tremendous amount of exciting lung cancer abstracts. I know we're not going to discuss all of them on this podcast, but even exciting Plenary presentations coming up.  Dr. Vamsi Velcheti: So, one of the abstracts that caught my attention was Abstract 103, the LUMINOSITY trial, which will be presenting the primary analysis at the meeting. So, there's a lot of buzz and excitement around ADCs. Can you comment on this abstract, Nate, and what are your thoughts on key takeaways from this abstract?  Dr. Nathan Pennell: Absolutely, I agree. This is really an exciting new potential target for lung cancer. So historically, when we think about MET and lung cancer, we think about the MET exon 14 skipping mutations which are present in 3% or 4% of adenocarcinoma patients. And we have approved tyrosine kinase inhibitors, small molecule inhibitors that can be very effective for those. What we're talking about here is actually an antibody drug conjugate or ADC telisotuzumab vedotin, which is targeting the MET protein over expression in non-squamous EGFR wild type advanced non-small cell lung cancer. The LUMINOSITY was a single arm, phase 2 study of teliso, and first of all, I think we have to define the patient population. So, these were MET over expressing non-small cell lung cancer by immunohistochemical staining. So, it included both what they considered MET high expression and MET intermediate expression, both of which had to be 3+ IHC positive on 25% to 50% of cells in the intermediate and 50% or higher in the high expressing group. They were treated with the ADC and had pretty promising results, a response rate of 35% in the MET high group and 23% in the intermediate group. Duration of response at nine months and 7.2 months in those two groups, and the PFS was five and a half and six months. So I would say in a previously treated population, this was relatively promising and potentially defines a completely new and unique subgroup of biomarker defined patients. So, Vamsi, I'm curious, though, if this ends up moving forward to further development, what your thoughts are on adding yet another biomarker in non-small cell lung cancer? Dr. Vamsi Velcheti: Yeah, I think it's certainly exciting. I think for this population, we really don't have a lot of options beyond the second line, and even in the second line, docetaxels are low bar. So,I think having more options for our patients is certainly outcome development. And I think MET IHC is relatively easy to deploy in a clinical setting. I think we already test for MET PD-L1 IHC routinely, and now recently, as you know, HER2 IHC given approval for ADCs, HER2 ADCs there in that space. So, I think from a technical standpoint, I don't see a big barrier in terms of adding an additional IHC marker. And usually, the IHC testing is pretty quick. And I think if you have a therapeutic approval based on IHC positivity, I think certainly from an operational standpoint, it shouldn't be a very complicated issue. Dr. Nathan Pennell: Yeah, I agree. This is cheap. It's something that can be done everywhere in the world. And as you said, in addition to diagnostic IHC, we're already looking at PD-L1, and probably moving towards doing that for HER2. This is really wonderful that we're moving into kind of the era of the ADCs, which is opening up a whole new therapeutic group of options for patients. Dr. Vamsi Velcheti: So, the other abstract that caught my attention was like, the Abstract 8005. This is the molecular residual disease MRD analysis from the ADAURA trial. The ADAURA trial, as you all know, is the trial that led to the FDA approval of adjuvant use of osimertinib in patients with EGFR mutant stage 1B through 3A non-small cell lung cancer. And in this trial, osimertinib demonstrated significant improvements in DFS and OS. And in this particular study, Abstract 8005, the authors looked at the role of MRD in predicting DFS in the study. And after 682 patients who were randomized, 36% of the patients had samples to look at MRD post- surgery. And in the trial the MRD status predicted DFS or event free survival at 36 months with a hazard ratio of 0.23. And the MRD status had a median lead time of 4.7 months across both the arms, both osimertinib and the placebo arm. So, suggesting that MRD could potentially identify high risk subgroups of patients post-surgery to tailor personalized approaches potentially in this population. So, Nate, in your practice, of course, we don't have a clinically validated approach yet to kind of use MRD in this setting, but if we have an option to use an MRD based assay, do you think that would potentially be an opportunity to perhaps escalate or de-escalate adjuvant strategies with TKIs in the adjuvant setting? Do you see value in using MRI assays post- surgery? Dr. Nathan Pennell: Yeah, I think this is a really important study because this is such an important topic around adjuvant targeted treatment. So, of course, ADAURA really changed how we treated people with EGFR mutant lung cancer who underwent surgical resection, because we know that the three years of osimertinib significantly improved disease-free survival and overall survival. But there's still a lot of questions being asked about, is that affordable? Obviously, we're putting a lot of resources into three years of treatment, and not everyone necessarily needs it. There may well be people who are cured with surgery alone and adjuvant chemotherapy. And then what about duration? Is three years enough? Do we need even longer treatment, or do we need shorter treatment? And up to date, we haven't really been able to tell people at risk of recurrence other than the pure odds-based risk based on their stage.   And the assay that was used in the ADAURA study was a personalized tumor informed assay based on the resected tumor. It's unclear to me whether this was just a subgroup of people that had this done or whether they tried to do it in all 600 patients and only, it looks like they were successful in about 32% of people. Maybe about a third were able to successfully have a tumor informed assay. So, the first question is, “Can you use this to help guide who needs treatment or not?” And I think what they showed was only about 4% of people in osimertinib arm in 12% had MRD positive at baseline after surgery. So probably, upfront testing is not really going to be all that helpful at determining who's at high risk and needs to be treated.   Interestingly, of those who were positive, though, most of them, or 80% of them, did go MRD negative on osimertinib. And what I found really interesting is that of those who did have a recurrence, 65% of them did have the MRD test turn positive. And as you mentioned, that was about five months prior to being picked up radiographically, and so you can pick them up sooner. And it also looks like about two thirds of recurrences can be identified with the blood test. So that potentially could identify people who are recurring earlier that might be eligible for a more intensive treatment. The other thing that was really interesting is of those who recurred in the osimertinib arm, 68% of them happened after stopping the osimertinib, suggesting that for the majority of patients, even those not necessarily cured, they seem to have disease control while on the osimertinib, suggesting that maybe a longer duration of treatment for those patients could be helpful. The problem is it still isn't necessarily helpful at identifying who those people are who need the longer duration of treatment. So, definitely an important study. I think it could be useful in practice if this was available clinically, especially at monitoring those after completion of treatment. I think as the sensitivity of these MRD assays gets better, these will become more and more important. Dr. Vamsi Velcheti: I think it's a little bit of a challenge in terms of standardizing these assays, and they're like multiple assays, which are currently commercially available. And I think the field is getting really complicated in terms of how you incorporate different assays and different therapeutics in the adjuvant space, especially if you're kind of looking at de-escalating immunotherapeutic strategies at the adjuvant setting, I think, makes it even more challenging. I think exciting times. We definitely need more thoughtful and better studies to really define the role of MRD in the adjuvant space. So, I guess more to come in this space. Dr. Nathan Pennell: Vamsi, I wanted to ask you about another really interesting Abstract 8011. This is a subgroup of the AEGEAN perioperative study for early-stage resected non-small cell lung cancer. This abstract is specifically looking at baseline N2 lymph node involvement in stage 2A-3B with N2 positive patients in an exploratory subgroup analysis. What are your key takeaways from the study?   Dr. Vamsi Velcheti: I felt this was a very interesting abstract for a couple of reasons. As you know, this is the AEGEAN trial, the phase 3 trial that was reported earlier last year. This is a perioperative study of durvalumab plus new adjuvant chemotherapy versus new adjuvant chemotherapy alone and adjuvant durvalumab plus placebo. The study obviously met its primary endpoint, as we all saw, like the event-free survival. And here in this abstract, the authors present an exploratory subgroup analysis of patients who had N2 lymph node involvement prior to study enrollment. So, in this study, they were focusing on perioperative outcomes. And one of the issues that has come up multiple times, as you know, in a lot of these preoperative studies, is the impact of neoadjuvant chemo immunotherapy on surgery or surgical outcomes. And consistently, across a lot of these trials, including the CheckMate 816, about 20% of patients don't end up making it to surgery. So in that light, I think this study and the findings are very interesting. In this study, they looked at patients who had N2 nodal involvement and of the patients with N2 nodal involvement, the surgical operability or the number of patients who completed surgery was similar in both the groups. So, there was no significant difference between patients who received durva versus chemotherapy and also among patients who had N2 subgroup who had surgery, similar proportions of durvalumab and placebo arms had open versus minimally invasive versus pneumonectomy. So durvalumab didn't have a negative impact on the type of surgery that the patients had at the time of surgery. So overall, the findings were consistent with other trials, perioperative trials that we have seen. So, the surgical outcomes were not negatively impacted by adding immunotherapy in the neoadjuvant perioperative space. So, this is consistent with other trials that we have seen. And also, the other issue, Nate, I'd like to get your opinion on is, across the board, in all the perioperative trials we have seen that about 20% of the patients actually don't end up making it a surgery. And of course, most of these perioperative trials, a lot of these patients are stage 3 patients. And my take on this was that there's probably a little bit of a patient selection issue. We generally tend to err on the side of operability when we have a stage 3 patient discussed in the tumor board, sometimes feel like the patient may downstage and could potentially go to surgery. But even in the real world, in stage 3 operable patients, what proportion of patients do you think don't end up going to surgery? Dr. Nathan Pennell: That is such an important question that I don't think we have the best answer to. You're right. All of these perioperative studies have a relatively high- sort of 20% to 30% of people who enroll on the studies don't necessarily go to surgery. And I don't think that they've done as great a job as they could in all of these trials describing exactly what happens to these patients. So in the real world, obviously not everyone would be fit enough to go to surgery or might progress in the time between when they were diagnosed and the time as planned for surgery. But probably more of them would go to surgery if they weren't getting neoadjuvant treatment, because that would be their initial treatment. The question is, of course, is that the right choice? If someone gets 12 weeks or nine weeks of neoadjuvant treatment and then a restaging scan shows that they've had progression with metastatic disease, are those really the people that would have been optimally treated with surgery upfront, or would they just have had recurrence on their first postoperative scan? So, it's really an important question to answer. I think the bigger one is, is the treatment preventing them through toxicity from going to treatment? And I think the studies have generally felt that few patients are missing out on the option of surgery because of toxicity being caused by the IO. And in the AEGEAN study, for example, in this subgroup, a slightly numerically higher percentage of patients in the durvalumab arm actually underwent surgery compared to those who got neoadjuvant chemo. So, it doesn't seem like we're necessarily harming people with the neoadjuvant treatment. But I know that this is a concern for patients and doctors who are undergoing this approach. Dr. Vamsi Velcheti: Definitely, I think having multiple data sets from perioperative trials, looking at the relative impact of IO on the safety and the nature of the surgery is going to be important, and this is a very important study for that reason. Dr. Nathan Pennell: Can I ask you another thing that I thought really interesting about this particular one is they looked at the difference between those with single station N2 and multi station N2. And I know this is one of those, should we be operating on people who have multi station N2 disease? And the AEGEAN study did include people who had multiple N2 stations where perhaps in the pre-IO era, these would have been treated with definitive chemoradiation and not surgery at all. But the disease-free survival hazard ratio was essentially the same for multi station N2 as it was in the overall population. So, has that changed the way we're approaching these patients in these multidisciplinary discussions? Dr. Vamsi Velcheti: Absolutely, Nate. I think surgical operability is in the eye of the beholder. I think it depends on which surgeon sees the patient or how the discussion goes in the tumor boards, as you know. Certainly, I think with this optionality of having a chemo IO option and potential for downstaging, kind of pushes, at least in our practice, more of these patients who are multistation, who would have otherwise gone down the chemoradiation route are now actually going through neo adjuvant chemo IO and with the hope that they would make it to surgery. So, I think it's an interesting change in paradigm in managing our locally advanced patients. So, I think it's certainly interesting, but I guess to your point, there clearly are some patients who probably should just have chemoradiation upfront, and we may be kind of like delaying that definitive chemoradiation approach for at least a subset of patients. So, at the end of the day, I think it's a lot of clinical decision-making and I think there's going to be a little bit of art to managing these patients and it's going to be really hard to define that population for a clinical trial.  Dr. Nathan Pennell: Yeah, clearly, multidisciplinary discussion, still very important for earliest age non-small cell lung cancer patients. If we move back to metastatic lung cancer, let's talk about Abstract 8510 looking at one of our newer, exciting biomarkers, which are the KRASG12Cmutant non-small cell lung cancer. So this is a study of a second generation KRASG12Cinhibitor, olomorasib, which was combined with pembrolizumab, the anti PD-1 antibody, in patients with advanced KRASG12C mutant non-small cell lung cancer. This is something that has been tried before with first generation G12C inhibitors, with some concerns about how safe it was to do that. So, Vamsi, what did you learn from this abstract? Dr. Vamsi Velcheti: Definitely, I think one of the concerns that we've had in other trials is like the cumulative toxicity of adding checkpoint inhibition to G12C inhibitors, especially the sotorasib CodeBreaK trial, where we see increased rates of grade 3, 4 transaminitis. So, it is encouraging to see that some of the newer agents have less of those issues when it comes to combining the checkpoint inhibition. So especially with KRASG12C, as you know, these are patients who are smokers, and often these are patients who have high PDL-1 could potentially also benefit from immunotherapy. In order for these KRASG12C inhibitors, in order to move these targeted therapy options for these patients to the front line, I do think we need to have substantial comfort in combining the checkpoint inhibitors, which is a standard treatment approach for patients in the frontline setting. I think this is exciting, and I think they're also like, as you know, there are other KRASG12C inhibitors also looking to combine with checkpoint inhibition in the frontline settings. So, we'll have to kind of wait and see how the other agents will perform in the setting. Dr. Nathan Pennell: Yeah, I completely agree. I think this is such an important area to explore specifically because unlike our other targeted oncogenes like EGFR and ALK, we have multiple options for these patients, both immunotherapy and targeted treatments. And if we could think about sequencing them or even combining them and if it could be done safely, I think that would be well worth investigating. There still was significant toxicity in this trial; 30% of people had diarrhea, even at the reduced dose, and there was transaminitis at sort of about 20% or so, although probably at a manageable level. But the response rate was really quite promising. And these are all previously IO and mostly G12C TKI pre-treated patients still had a response rate of 63%. And in those who were naive to IO and TKIs, it was 78% response rate. So, if it could be done safely, I think it's definitely worth pursuing this in further trials. Dr. Vamsi Velcheti: And also, there's some data, preclinical data, like looking at G12C inhibition. And also we have known with MET inhibition for a long time that it could potentially augment immune responses and could be having some synergistic effect with IO. So, we'll have to wait and see, I think. But safety is really the top in mind when it comes to combining these agents with checkpoint inhibitors. So, it's really encouraging to see that some of the newer agents may be more combinable IO. Now moving on to the next abstract, and moving on to, again, the early-stage setting. So, Abstract 8052 from our colleagues in Princess Margaret reported outcomes in early-stage non- small cell lung cancer in patients with rare targetable mutation. This is actually becoming increasingly more relevant because we are seeing at least, like with the ALINA data, with the ALK and EGFR, now with ADAURA, we know that these patients don't benefit with adjuvant immunotherapy, especially some of these rare oncogene living mutations, other than like G12C. So I always struggle with this. When you have early-stage patients, with, let's say, a ROS or a RET, where we just don't have data, and we know that those are poor actors because biologically these are aggressive tumors. So, there's a really odd clinical question to ask in terms of, what is the role of adjuvant immunotherapy? Of course, this trial and this abstract are not really addressing that. But what is your take on this abstract? If you could just summarize the abstract for us. Dr. Nathan Pennell: Sure. Well, I think this is incredibly important, and this is an area near and dear to my own heart. And that is, of course, the whole landscape of how we manage early-stage patients has changed with both ADAURA, because we now have effective treatment in the adjuvant setting for EGFR mutant patients, and now more recently with the ALINA trial for adjuvant alectinib for ALK positive patients now being FDA-approved. So, what that means is we actually have to be testing people at diagnosis even before they would be getting adjuvant treatment, and potentially before even surgery to look for these targets. We need the PD-L1 status, we need EGFR and ALK. And if you're going to be looking at these biomarkers, I think there is a reasonable argument to be made that you should be doing broad testing for all of the targetable oncogenes in these patients. There are some studies suggesting that there's value to this and identifying them for treatment at the time of recurrence. But we also know that these patients are at high risk of recurrence and probably need to be investigated, at least in trials for the adjuvant setting. So, this particular study looked at 201 resected, mostly adenocarcinoma patients, and then they basically sequenced them for all of the targeted oncogenes. And they were quite common, perhaps even more common than you might expect in an advanced population. So, 43% of them had KRASG12C mutations, 13% had EGFR Exon 20 mutation, ERBB2 or HER2 mutations found in 11%, MET mutations in 10%, ALK in 7%, ROS1 in 6%, BRAF in 5%, and RET in 2%. So quite common to find these targetable oncogenes in this particular population, perhaps a somewhat biased population at Princess Margaret Hospital, but very common. And then they looked at the outcomes of these patients without targeted adjuvant treatment. And what they found was there was a very high rate of recurrence. So, relapse-free survival was pretty high in these patients across different stages, and generally their prognosis was worse than the more common KRASG12C patients. Most of these, in particular the HER2 mutant patients, seem to have a significantly worse relapse free survival. Interestingly enough, though, that did not carry over to overall survival. Overall survival was better in those who had targetable oncogenes. And my guess is that that probably had to do with the availability of targeted treatments at the time of recurrence that may have impacted overall survival. But I do think that this particularly highlights the need, the unmet need for effective adjuvant treatment in these patients. And most of them, with the exception of KRAS and perhaps BRAF, perhaps MET unlikely to benefit from adjuvant immunotherapy, as you mentioned. And so, I think we really need to be investing in trials of adjuvant targeted treatments in these populations.  Dr. Vamsi Velcheti: Yeah, this is an area that we really don't have a lot of data. But Nate, a question for you. So tomorrow you have a patient with RET fusion, stage 2, N1 disease. What would you do? Would you offer them an adjuvant RET inhibitor? Dr. Nathan Pennell: I think I would search really hard for a trial to give them access. But if you really want to know what I think, and I'm usually willing to tell people what I think, I think the proof of concept is there. I think we know that in the setting of highly effective and very tolerable adjuvant targeted treatment in the EGFR space with osimertinib, in the ALK space with alectinib, if anything, drugs like selpercatinib and pralsetinib in RET fusion positive lung cancer in the advanced setting are just as well tolerated and easily as effective and long lasting. And so, I think if you did a trial and they are doing trials looking at these drugs in the adjuvant space, almost certainly you're going to see the same really dramatic disease-free survival benefit from these treatments, which, at least in the EGFR space, seems to have translated into an improvement in overall survival. And so if I had a stage II or a resected stage 3, especially a RET fusion positive patient today, I would definitely talk to them about off-label use of a RET inhibitor if I could not find a trial. Now, I understand that there are going to be reimbursement issues and whatnot associated with that, but I think the extrapolation is worth discussing. Dr. Vamsi Velcheti: Yeah, I think it's really challenging because some of these fusions are so rare and it's hard to really do large adjuvant trials for some of these rarer subgroups. Nate, fascinating insights. Our listeners will find links to the abstracts we discussed today in the transcript of the episode. And Nate, I look forward to catching up with you at the Annual Meeting, and again after the meeting for our wrap up podcast to discuss the practice-changing lung cancer abstracts and highlights from the Plenary Session. Thank you so much for joining us and sharing your insights today. Dr. Nathan Pennell: Thanks for inviting me. Vamsi. I look forward to touching base after we get to see all the late-breaking abstracts. Like I said, this is, I think, a year for lung cancer with a lot of exciting data, and I know we'll have a lot to talk about. Dr. Vamsi Velcheti And thank you so much to all our listeners for your time. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate and review and subscribe wherever you get your podcast.   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. Vamsi Velcheti @VamsiVelcheti   Dr. Nathan Pennell @n8pennell   Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures: Dr. Vamsi Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   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 

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/SKH865. CME/MOC/AAPA/IPCE credit will be available until March 20, 2025.Making Precision Decisions in the Treatment of NSCLC With Common and Uncommon EGFR Mutations: How to Navigate the Expanding Options and Increasing Complexity In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerJoshua Sabari, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AstraZeneca; Genentech, Inc.; Gilead Sciences, Inc.; Janssen Pharmaceuticals, Inc.; Jazz Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; Navire; Pfizer; Regeneron Pharmaceuticals Inc.; Sanofi Genzyme; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; and Regeneron Pharmaceuticals Inc.Faculty/PlannerJyoti D. Patel, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AnHeart Therapeutics; AstraZeneca; Blueprint Medicines Corporation; Daiichi Sankyo, Inc.; Genentech, Inc.; Gilead Sciences, Inc.; Lilly; Sanofi; and Takeda Pharmaceutical Company Limited.Other Financial or Material Support for Travel from Daiichi Sankyo, Inc. and Tempus.Faculty/PlannerAlexander I. Spira, MD, PhD, FACP, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Amgen Inc.; Array BioPharma Inc.; AstraZeneca/ MedImmune; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bristol Myers Squibb; Daiichi Sankyo, Inc./AstraZeneca; Incyte; Gritstone bio, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Lily; Merck & Co., Inc.; Mersana Therapeutics; Mirati Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Grant/Research Support from ADC Therapeutics SA; AbbVie Inc.; Alkermes; Amgen Inc.; Arch Therapeutics, Inc.; ArriVent Biopharma; Astellas Pharma US, Inc.; Astex Pharmaceuticals; AstraZeneca; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bluprint Oncology; Boehringer Ingelheim International GmbH; Bristol Myers Squibb; CytomX Therapeutics, Inc.; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche Ltd; Gritstone bio, Inc.; Ignyta Inc; Incyte; Janssen Oncology; LAM Therapeutics, Inc.; Loxo Oncology; MacroGenics, Inc.; Medikine, Inc; MedImmune; Mersana Therapeutics; Mirati Therapeutics, Inc.; NALO Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Plexxikon; Regeneron Pharmaceuticals Inc.; Revolution Medicines, Inc.; Rubius Therapeutics; Scorpion Therapeutics; Synthekine; and Takeda Pharmaceutical Company Limited.Honoraria from Amgen Inc.; AstraZeneca/ MedImmune; Bayer; Bristol Myers Sqiubb; CytomX Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Takeda Pharmaceutical Company Limited.Stock Shareholder in Lilly.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/SKH865. CME/MOC/AAPA/IPCE credit will be available until March 20, 2025.Making Precision Decisions in the Treatment of NSCLC With Common and Uncommon EGFR Mutations: How to Navigate the Expanding Options and Increasing Complexity In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerJoshua Sabari, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AstraZeneca; Genentech, Inc.; Gilead Sciences, Inc.; Janssen Pharmaceuticals, Inc.; Jazz Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; Navire; Pfizer; Regeneron Pharmaceuticals Inc.; Sanofi Genzyme; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; and Regeneron Pharmaceuticals Inc.Faculty/PlannerJyoti D. Patel, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AnHeart Therapeutics; AstraZeneca; Blueprint Medicines Corporation; Daiichi Sankyo, Inc.; Genentech, Inc.; Gilead Sciences, Inc.; Lilly; Sanofi; and Takeda Pharmaceutical Company Limited.Other Financial or Material Support for Travel from Daiichi Sankyo, Inc. and Tempus.Faculty/PlannerAlexander I. Spira, MD, PhD, FACP, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Amgen Inc.; Array BioPharma Inc.; AstraZeneca/ MedImmune; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bristol Myers Squibb; Daiichi Sankyo, Inc./AstraZeneca; Incyte; Gritstone bio, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Lily; Merck & Co., Inc.; Mersana Therapeutics; Mirati Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Grant/Research Support from ADC Therapeutics SA; AbbVie Inc.; Alkermes; Amgen Inc.; Arch Therapeutics, Inc.; ArriVent Biopharma; Astellas Pharma US, Inc.; Astex Pharmaceuticals; AstraZeneca; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bluprint Oncology; Boehringer Ingelheim International GmbH; Bristol Myers Squibb; CytomX Therapeutics, Inc.; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche Ltd; Gritstone bio, Inc.; Ignyta Inc; Incyte; Janssen Oncology; LAM Therapeutics, Inc.; Loxo Oncology; MacroGenics, Inc.; Medikine, Inc; MedImmune; Mersana Therapeutics; Mirati Therapeutics, Inc.; NALO Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Plexxikon; Regeneron Pharmaceuticals Inc.; Revolution Medicines, Inc.; Rubius Therapeutics; Scorpion Therapeutics; Synthekine; and Takeda Pharmaceutical Company Limited.Honoraria from Amgen Inc.; AstraZeneca/ MedImmune; Bayer; Bristol Myers Sqiubb; CytomX Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Takeda Pharmaceutical Company Limited.Stock Shareholder in Lilly.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/SKH865. CME/MOC/AAPA/IPCE credit will be available until March 20, 2025.Making Precision Decisions in the Treatment of NSCLC With Common and Uncommon EGFR Mutations: How to Navigate the Expanding Options and Increasing Complexity In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerJoshua Sabari, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AstraZeneca; Genentech, Inc.; Gilead Sciences, Inc.; Janssen Pharmaceuticals, Inc.; Jazz Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; Navire; Pfizer; Regeneron Pharmaceuticals Inc.; Sanofi Genzyme; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; and Regeneron Pharmaceuticals Inc.Faculty/PlannerJyoti D. Patel, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AnHeart Therapeutics; AstraZeneca; Blueprint Medicines Corporation; Daiichi Sankyo, Inc.; Genentech, Inc.; Gilead Sciences, Inc.; Lilly; Sanofi; and Takeda Pharmaceutical Company Limited.Other Financial or Material Support for Travel from Daiichi Sankyo, Inc. and Tempus.Faculty/PlannerAlexander I. Spira, MD, PhD, FACP, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Amgen Inc.; Array BioPharma Inc.; AstraZeneca/ MedImmune; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bristol Myers Squibb; Daiichi Sankyo, Inc./AstraZeneca; Incyte; Gritstone bio, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Lily; Merck & Co., Inc.; Mersana Therapeutics; Mirati Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Grant/Research Support from ADC Therapeutics SA; AbbVie Inc.; Alkermes; Amgen Inc.; Arch Therapeutics, Inc.; ArriVent Biopharma; Astellas Pharma US, Inc.; Astex Pharmaceuticals; AstraZeneca; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bluprint Oncology; Boehringer Ingelheim International GmbH; Bristol Myers Squibb; CytomX Therapeutics, Inc.; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche Ltd; Gritstone bio, Inc.; Ignyta Inc; Incyte; Janssen Oncology; LAM Therapeutics, Inc.; Loxo Oncology; MacroGenics, Inc.; Medikine, Inc; MedImmune; Mersana Therapeutics; Mirati Therapeutics, Inc.; NALO Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Plexxikon; Regeneron Pharmaceuticals Inc.; Revolution Medicines, Inc.; Rubius Therapeutics; Scorpion Therapeutics; Synthekine; and Takeda Pharmaceutical Company Limited.Honoraria from Amgen Inc.; AstraZeneca/ MedImmune; Bayer; Bristol Myers Sqiubb; CytomX Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Takeda Pharmaceutical Company Limited.Stock Shareholder in Lilly.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/SKH865. CME/MOC/AAPA/IPCE credit will be available until March 20, 2025.Making Precision Decisions in the Treatment of NSCLC With Common and Uncommon EGFR Mutations: How to Navigate the Expanding Options and Increasing Complexity In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerJoshua Sabari, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AstraZeneca; Genentech, Inc.; Gilead Sciences, Inc.; Janssen Pharmaceuticals, Inc.; Jazz Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; Navire; Pfizer; Regeneron Pharmaceuticals Inc.; Sanofi Genzyme; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; and Regeneron Pharmaceuticals Inc.Faculty/PlannerJyoti D. Patel, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AnHeart Therapeutics; AstraZeneca; Blueprint Medicines Corporation; Daiichi Sankyo, Inc.; Genentech, Inc.; Gilead Sciences, Inc.; Lilly; Sanofi; and Takeda Pharmaceutical Company Limited.Other Financial or Material Support for Travel from Daiichi Sankyo, Inc. and Tempus.Faculty/PlannerAlexander I. Spira, MD, PhD, FACP, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Amgen Inc.; Array BioPharma Inc.; AstraZeneca/ MedImmune; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bristol Myers Squibb; Daiichi Sankyo, Inc./AstraZeneca; Incyte; Gritstone bio, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Lily; Merck & Co., Inc.; Mersana Therapeutics; Mirati Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Grant/Research Support from ADC Therapeutics SA; AbbVie Inc.; Alkermes; Amgen Inc.; Arch Therapeutics, Inc.; ArriVent Biopharma; Astellas Pharma US, Inc.; Astex Pharmaceuticals; AstraZeneca; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bluprint Oncology; Boehringer Ingelheim International GmbH; Bristol Myers Squibb; CytomX Therapeutics, Inc.; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche Ltd; Gritstone bio, Inc.; Ignyta Inc; Incyte; Janssen Oncology; LAM Therapeutics, Inc.; Loxo Oncology; MacroGenics, Inc.; Medikine, Inc; MedImmune; Mersana Therapeutics; Mirati Therapeutics, Inc.; NALO Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Plexxikon; Regeneron Pharmaceuticals Inc.; Revolution Medicines, Inc.; Rubius Therapeutics; Scorpion Therapeutics; Synthekine; and Takeda Pharmaceutical Company Limited.Honoraria from Amgen Inc.; AstraZeneca/ MedImmune; Bayer; Bristol Myers Sqiubb; CytomX Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Takeda Pharmaceutical Company Limited.Stock Shareholder in Lilly.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/SKH865. CME/MOC/AAPA/IPCE credit will be available until March 20, 2025.Making Precision Decisions in the Treatment of NSCLC With Common and Uncommon EGFR Mutations: How to Navigate the Expanding Options and Increasing Complexity In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerJoshua Sabari, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AstraZeneca; Genentech, Inc.; Gilead Sciences, Inc.; Janssen Pharmaceuticals, Inc.; Jazz Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; Navire; Pfizer; Regeneron Pharmaceuticals Inc.; Sanofi Genzyme; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; and Regeneron Pharmaceuticals Inc.Faculty/PlannerJyoti D. Patel, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AnHeart Therapeutics; AstraZeneca; Blueprint Medicines Corporation; Daiichi Sankyo, Inc.; Genentech, Inc.; Gilead Sciences, Inc.; Lilly; Sanofi; and Takeda Pharmaceutical Company Limited.Other Financial or Material Support for Travel from Daiichi Sankyo, Inc. and Tempus.Faculty/PlannerAlexander I. Spira, MD, PhD, FACP, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Amgen Inc.; Array BioPharma Inc.; AstraZeneca/ MedImmune; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bristol Myers Squibb; Daiichi Sankyo, Inc./AstraZeneca; Incyte; Gritstone bio, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Lily; Merck & Co., Inc.; Mersana Therapeutics; Mirati Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Grant/Research Support from ADC Therapeutics SA; AbbVie Inc.; Alkermes; Amgen Inc.; Arch Therapeutics, Inc.; ArriVent Biopharma; Astellas Pharma US, Inc.; Astex Pharmaceuticals; AstraZeneca; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bluprint Oncology; Boehringer Ingelheim International GmbH; Bristol Myers Squibb; CytomX Therapeutics, Inc.; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche Ltd; Gritstone bio, Inc.; Ignyta Inc; Incyte; Janssen Oncology; LAM Therapeutics, Inc.; Loxo Oncology; MacroGenics, Inc.; Medikine, Inc; MedImmune; Mersana Therapeutics; Mirati Therapeutics, Inc.; NALO Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Plexxikon; Regeneron Pharmaceuticals Inc.; Revolution Medicines, Inc.; Rubius Therapeutics; Scorpion Therapeutics; Synthekine; and Takeda Pharmaceutical Company Limited.Honoraria from Amgen Inc.; AstraZeneca/ MedImmune; Bayer; Bristol Myers Sqiubb; CytomX Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Takeda Pharmaceutical Company Limited.Stock Shareholder in Lilly.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/SKH865. CME/MOC/AAPA/IPCE credit will be available until March 20, 2025.Making Precision Decisions in the Treatment of NSCLC With Common and Uncommon EGFR Mutations: How to Navigate the Expanding Options and Increasing Complexity In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerJoshua Sabari, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AstraZeneca; Genentech, Inc.; Gilead Sciences, Inc.; Janssen Pharmaceuticals, Inc.; Jazz Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; Navire; Pfizer; Regeneron Pharmaceuticals Inc.; Sanofi Genzyme; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; and Regeneron Pharmaceuticals Inc.Faculty/PlannerJyoti D. Patel, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AnHeart Therapeutics; AstraZeneca; Blueprint Medicines Corporation; Daiichi Sankyo, Inc.; Genentech, Inc.; Gilead Sciences, Inc.; Lilly; Sanofi; and Takeda Pharmaceutical Company Limited.Other Financial or Material Support for Travel from Daiichi Sankyo, Inc. and Tempus.Faculty/PlannerAlexander I. Spira, MD, PhD, FACP, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Amgen Inc.; Array BioPharma Inc.; AstraZeneca/ MedImmune; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bristol Myers Squibb; Daiichi Sankyo, Inc./AstraZeneca; Incyte; Gritstone bio, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Lily; Merck & Co., Inc.; Mersana Therapeutics; Mirati Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Grant/Research Support from ADC Therapeutics SA; AbbVie Inc.; Alkermes; Amgen Inc.; Arch Therapeutics, Inc.; ArriVent Biopharma; Astellas Pharma US, Inc.; Astex Pharmaceuticals; AstraZeneca; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bluprint Oncology; Boehringer Ingelheim International GmbH; Bristol Myers Squibb; CytomX Therapeutics, Inc.; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche Ltd; Gritstone bio, Inc.; Ignyta Inc; Incyte; Janssen Oncology; LAM Therapeutics, Inc.; Loxo Oncology; MacroGenics, Inc.; Medikine, Inc; MedImmune; Mersana Therapeutics; Mirati Therapeutics, Inc.; NALO Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Plexxikon; Regeneron Pharmaceuticals Inc.; Revolution Medicines, Inc.; Rubius Therapeutics; Scorpion Therapeutics; Synthekine; and Takeda Pharmaceutical Company Limited.Honoraria from Amgen Inc.; AstraZeneca/ MedImmune; Bayer; Bristol Myers Sqiubb; CytomX Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Takeda Pharmaceutical Company Limited.Stock Shareholder in Lilly.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/SKH865. CME/MOC/AAPA/IPCE credit will be available until March 20, 2025.Making Precision Decisions in the Treatment of NSCLC With Common and Uncommon EGFR Mutations: How to Navigate the Expanding Options and Increasing Complexity In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerJoshua Sabari, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AstraZeneca; Genentech, Inc.; Gilead Sciences, Inc.; Janssen Pharmaceuticals, Inc.; Jazz Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; Navire; Pfizer; Regeneron Pharmaceuticals Inc.; Sanofi Genzyme; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; and Regeneron Pharmaceuticals Inc.Faculty/PlannerJyoti D. Patel, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AnHeart Therapeutics; AstraZeneca; Blueprint Medicines Corporation; Daiichi Sankyo, Inc.; Genentech, Inc.; Gilead Sciences, Inc.; Lilly; Sanofi; and Takeda Pharmaceutical Company Limited.Other Financial or Material Support for Travel from Daiichi Sankyo, Inc. and Tempus.Faculty/PlannerAlexander I. Spira, MD, PhD, FACP, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Amgen Inc.; Array BioPharma Inc.; AstraZeneca/ MedImmune; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bristol Myers Squibb; Daiichi Sankyo, Inc./AstraZeneca; Incyte; Gritstone bio, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Lily; Merck & Co., Inc.; Mersana Therapeutics; Mirati Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Grant/Research Support from ADC Therapeutics SA; AbbVie Inc.; Alkermes; Amgen Inc.; Arch Therapeutics, Inc.; ArriVent Biopharma; Astellas Pharma US, Inc.; Astex Pharmaceuticals; AstraZeneca; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bluprint Oncology; Boehringer Ingelheim International GmbH; Bristol Myers Squibb; CytomX Therapeutics, Inc.; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche Ltd; Gritstone bio, Inc.; Ignyta Inc; Incyte; Janssen Oncology; LAM Therapeutics, Inc.; Loxo Oncology; MacroGenics, Inc.; Medikine, Inc; MedImmune; Mersana Therapeutics; Mirati Therapeutics, Inc.; NALO Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Plexxikon; Regeneron Pharmaceuticals Inc.; Revolution Medicines, Inc.; Rubius Therapeutics; Scorpion Therapeutics; Synthekine; and Takeda Pharmaceutical Company Limited.Honoraria from Amgen Inc.; AstraZeneca/ MedImmune; Bayer; Bristol Myers Sqiubb; CytomX Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Takeda Pharmaceutical Company Limited.Stock Shareholder in Lilly.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/SKH865. CME/MOC/AAPA/IPCE credit will be available until March 20, 2025.Making Precision Decisions in the Treatment of NSCLC With Common and Uncommon EGFR Mutations: How to Navigate the Expanding Options and Increasing Complexity In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerJoshua Sabari, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AstraZeneca; Genentech, Inc.; Gilead Sciences, Inc.; Janssen Pharmaceuticals, Inc.; Jazz Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; Navire; Pfizer; Regeneron Pharmaceuticals Inc.; Sanofi Genzyme; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Boehringer Ingelheim Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Mirati Therapeutics, Inc.; and Regeneron Pharmaceuticals Inc.Faculty/PlannerJyoti D. Patel, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; AnHeart Therapeutics; AstraZeneca; Blueprint Medicines Corporation; Daiichi Sankyo, Inc.; Genentech, Inc.; Gilead Sciences, Inc.; Lilly; Sanofi; and Takeda Pharmaceutical Company Limited.Other Financial or Material Support for Travel from Daiichi Sankyo, Inc. and Tempus.Faculty/PlannerAlexander I. Spira, MD, PhD, FACP, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Amgen Inc.; Array BioPharma Inc.; AstraZeneca/ MedImmune; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bristol Myers Squibb; Daiichi Sankyo, Inc./AstraZeneca; Incyte; Gritstone bio, Inc.; Janssen Research & Development; Jazz Pharmaceuticals, Inc.; Lily; Merck & Co., Inc.; Mersana Therapeutics; Mirati Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Grant/Research Support from ADC Therapeutics SA; AbbVie Inc.; Alkermes; Amgen Inc.; Arch Therapeutics, Inc.; ArriVent Biopharma; Astellas Pharma US, Inc.; Astex Pharmaceuticals; AstraZeneca; Black Diamond Therapeutics; Blueprint Medicines Corporation; Bluprint Oncology; Boehringer Ingelheim International GmbH; Bristol Myers Squibb; CytomX Therapeutics, Inc.; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche Ltd; Gritstone bio, Inc.; Ignyta Inc; Incyte; Janssen Oncology; LAM Therapeutics, Inc.; Loxo Oncology; MacroGenics, Inc.; Medikine, Inc; MedImmune; Mersana Therapeutics; Mirati Therapeutics, Inc.; NALO Therapeutics, Inc.; Novartis Pharmaceuticals Corporation; Plexxikon; Regeneron Pharmaceuticals Inc.; Revolution Medicines, Inc.; Rubius Therapeutics; Scorpion Therapeutics; Synthekine; and Takeda Pharmaceutical Company Limited.Honoraria from Amgen Inc.; AstraZeneca/ MedImmune; Bayer; Bristol Myers Sqiubb; CytomX Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Takeda Pharmaceutical Company Limited.Stock Shareholder in Lilly.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

Drs. John Sweetenham and Shaji Kumar discuss the emergence of CAR T-cell therapy for multiple myeloma, its benefits and challenges for patients, and its potential role earlier in the treatment of disease. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast.  Multiple myeloma is the second most common hematologic malignancy, and the American Cancer Society estimates that there will be more than 35,000 new cases of the disease diagnosed in the United States this year. The emergence of several novel therapies over the last decade has transformed the therapeutic landscape for multiple myeloma, and chimeric antigen receptor – or CAR T-cell therapy – is one of the newest treatments for this disease, which has created a great deal of buzz.  Dr. Shaji Kumar is an internationally renowned investigator of novel therapeutics and next-generation treatment options for patients with multiple myeloma, and I'm delighted to welcome him to the podcast today to discuss innovations in CAR T-cell therapy in this space. Dr. Kumar is a professor of medicine and chair of the Myeloma Group, as well as chair of research in the Division of Hematology at the Mayo Clinic in Rochester, Minnesota. He is also the editor-in-chief of The Hematologist.  You'll find our full disclosures available in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod.  Shaji, it's great to have you on the podcast today. Dr. Shaji Kumar: Thanks, John. Dr. John Sweetenham: Shaji, to begin with, maybe we could ask you for an overview of where CAR T-cell therapy sits in multiple myeloma right now. We know that CAR T-cell therapy has improved the survival for some patients with myeloma in recent years. But of course, relapse still remains a problem. Can you tell us a little about the therapies that are currently approved for multiple myeloma in the CAR T-cell space, and what are the potential benefits and challenges of these products? Dr. Shaji Kumar: Absolutely. It has been a revolution, I think, in terms of therapies for multiple myeloma during the past decade. We have seen so many new treatments approved for myeloma, and consequently, the survival of patients with myeloma has significantly improved. Two decades ago, we used to tell patients a median survival of 3 years, and today we tell patients a median survival of 8 to 10 years, a number that is continuing to go up. And it is all because of the new treatments that have become available for patients, especially over the past decade, and CAR T-cell therapy has been a game changer.   Now, the main treatments that we were relying on for the past 2 decades have been the immunomodulatory drugs, the proteasome inhibitors, and more recently, the anti-CD38 monoclonal antibodies. Unfortunately, what we see in the clinic is that patients go through these therapies and various combinations of these agents, and often over the 6 to 10 years after the diagnosis, they often become refractory to these drugs. And then we are left with very few choices, if any, for controlling the disease. And that's where the CAR T cells have really made an impact.  Over the past several years, clinical trials have shown that CAR T-cell therapy is highly effective. In fact, when we look at the initial trials that have been done in this space, the majority of these CAR T cells have been targeted towards what we call BCMA, or a B-cell maturation antigen that is present on both normal and abnormal plasma cells. Now, the concept of CAR T cells has been around for a while, and we have already seen success in other hematological malignancies, but it has been a little late compared to the other diseases in terms of its arrival in the myeloma field. But over the past few years, we have seen some dramatic progress. We currently have two different CAR T cells that are approved and available in the clinic. We have idecabtagene vicleucel (ide-cel) and also ciltacabtagene which is also called cilta-cel. Both of these CAR T cells are targeted towards BCMA.   In the early trials conducted with both of these CAR T cells, we've seen patients who have become refractory to all the available therapies, and now upwards of 90% of these patients are responding to these CAR T cells. We are now seeing responses that we had typically not seen previously in any of the other therapies – not only the high response rates but also the depth of response. What we are seeing is a significant number of these patients – nearly half – of these patients can actually be minimal residual disease (MRD)-negative in the bone marrow after the CAR T-cell therapy. And this is clearly unprecedented in this myeloma space. Now, the approval for both these CAR T cells has been based on the experience in patients who have become refractory to the currently available therapies. And the ‘line in the sand' that the FDA has drawn for approval for these drugs has been at least 4 prior therapies. In those patients, when you look at the studies that have been done both for the ide-cel and the cilta-cel, it clearly demonstrates the advantages. And we can look at the data that's available in 3 groups. So we have the single-arm studies, the early phase I and phase 2 trials that have been done with both these CAR T cells. For ide-cel, we have the KarMMa trial, and for the cilta-cel, we have the CARTITUDE trials. In the initial studies, as I previously mentioned, we are seeing responses upwards of 90%, and we are seeing disease control that is lasting at least a year or more with these CAR T cells.   Now, of course, the question is, we do need randomized phase 3 trials to demonstrate that this is indeed true. Even before the phase 3 trials came along, there have been multiple case-control studies that have been done where the outcomes of patients getting these CAR T cells were compared to real-world controls or cohorts of patients who did not get these therapies. And these studies demonstrated that the outcomes of patients getting CAR T cells were significantly better than what has been shown in the real-world controlled population. And then finally, we have, of course, the phase 3 trials that have read out in patients with relapsed myeloma, in fact, in a group of patients in an earlier stage of the disease than who were studied in those single-arm studies. Now, based on the results from the single-arm studies, we got the approval from the FDA for the use of CAR T cells in this late stage of the disease. And with the phase 3 trials that have read out, both the KarMMa-3 trial and the CARTITUDE-4 trial again clearly demonstrate that these CAR T cells are much more effective than what we would have seen with the conventional therapies if those patients were assigned to those treatments. Now, clearly, it's not only a question of efficacy. We also know that they do come with some toxicities, and we have a good sense of the toxicities from those initial phase I and phase 2 trials. Now, as we have seen with the other diseases, the 2 major categories of toxicities that we see are the cytokine release syndrome and the neurological toxicity associated with CAR T-cell therapy.  In terms of the clinical features and the presentations, they are not different than what we have seen with the CAR T cells used in other hematological malignancies, but we do see different frequencies of these in the myeloma patient population. The cytokine release syndrome is something that is seen in a majority of the patients, at least in the lower grades. And over the time since we have been using CAR T-cell therapy, I think we have all become a lot more familiar with the management of the cytokine release syndrome, and we have very effective therapies to manage, and to some extent, maybe even prevent the onset of the cytokine release syndrome in patients undergoing CAR T-cell therapy.  The neurological toxicity is another toxicity that is unique to these immunological therapies, known as the ICANS, or the immune cell effector-associated neurological syndromes. And these, again, thankfully, are much less frequent than what we see with the cytokine release syndrome. But even with the ICANS and other neurological toxicities associated with CAR T-cell therapy, we have a better understanding of the biology behind it, and we also have better modalities to monitor the patients for these toxicities and intervene in an appropriate and timely manner to take care of them.  In addition to the ICANS and the cytokine release syndrome, we certainly do see other toxicities as well. We do see hematological toxicities, which are common for many of the treatments we use for hematological malignancies. Thankfully, these other toxicities can be easily managed. They often reverse themselves over time and haven't really posed any major hurdles in terms of the utilization of these modalities of therapy for patients with myeloma. Dr. John Sweetenham: Okay, that's great. Thank you very much, Shaji. I'll return to some of the potential late effects of CAR T-cell therapy in a moment. But before we get to that, as you know, in other hematologic malignancies, there has been a trend in recent years to moving CAR T-cell therapy further up the therapeutic algorithm, as it were. So there is consideration being given to using this as a first-line or second-line therapy. Do you think there is a potential role for CAR T cell earlier in the treatment of multiple myeloma? For example, could you see a time when it may be used as second-line treatment for this disease? Dr. Shaji Kumar: Absolutely. I think that's a very good point. And I think, just as with other cancers and as with myeloma, too, with many of the therapies we use for myeloma in the newly diagnosed setting or the time of first relapse, were all initially tested in these later relapses. We are following the same script even for the CAR T cells. In fact, the 2 phase 3 trials, the KarMMa-3 trial and the CARTITUDE-4 trial, enrolled patients in the earlier lines of therapy, either 1 prior line or 2 prior lines for these trials. And what we have seen with both phase 3 trials is that the outcomes, both the progression-free survival outcomes and the response rates, are significantly better compared to the standard-of-care therapies that these patients would have otherwise received.  Now, what is unclear at this point is, does every patient at the time of the first relapse need a CAR T-cell therapy, or can we be more selective in terms of deciding which particular subgroup of patients can benefit more from this CAR T-cell therapy in different lines or different relapses? The bottom line is, I think the data that we have right now clearly points towards the utility of CAR T-cell therapy at earlier lines of treatment. The question now is, which patients do we need to do at which stage? In fact, when you look at the newly diagnosed setting, there are ongoing clinical trials that are looking at replacing autologous stem cell transplant with CAR T-cell therapy. Those phase 3 trials are currently enrolling where patients are being randomized to either the autologous stem cell transplant, which is considered a standard of care for eligible patients, or giving them a CAR T-cell therapy. Similarly, even in transplant-ineligible patients, trials are exploring the possibility of using CAR T-cell therapy instead of giving patients a prolonged course of maintenance and consolidation.  One of the beauties with the CAR T-cell therapy right now is that it's a one-time treatment. You get the treatment and you do not get any additional therapies after that. It's a protocol that is being debated – whether we will need maintenance therapies after CAR T-cell therapy, but I think that is something that will have to be explored in the context of clinical trials. But certainly, I think over the next 5 years, we will see the CAR T-cell therapy moving to earlier and earlier lines of therapy. My guess is in 5 years, there will be a subset of patients where we would offer them CAR T-cell as part of the first-line therapy, some others, maybe based on disease and patient characteristics, we might use it at the time of first or second relapse.   Dr. John Sweetenham: Great, thank you. Just to return to toxicities and some of the potential late effects. As you know, last November, the FDA launched an investigation to determine whether CAR T-cell therapy can, in rare cases, cause secondary cancers. You may remember that this was in response to reports of T-cell malignancies in patients who had received various types of CAR T-cell immunotherapies. The FDA determined that the risk of T-cell malignancies is applicable to all of the currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T-cell immunotherapies. Could you care to comment on this whether you have seen any evidence of this in your own work, and whether the events and the FDA investigation have impacted your clinical research or your clinical practice in any way in terms of patient monitoring or maybe in terms of trial approval? Dr. Shaji Kumar: This has been an important observation. As with all new therapies, whenever the question of long-term toxicities is brought up, especially second malignancies, it is something that needs to be looked into very carefully, and I think the FDA is doing exactly that. There have been reports of second cancers, particularly T-cell cancers. In fact, there were some statements that came out recently from the FDA where they commented on the fact that they had seen 22 cases of T-cell cancers by the end of 2023. And, in fact, in 3 of those cases where genetic sequencing was performed, they did notice that the genetic material or the chimeric antigen receptor was inserted into these cancer cells as part of the process. So I think there is a lot more work that needs to be done in terms of understanding the mechanism and probably also understanding how prevalent these instances are.  But I think, based on what we know as of now, these cases form a very tiny fraction of the total number of CAR T-cell therapies that have been used in patients with lymphoma and myeloma. In our own day-to-day practice, this has not really affected how we view this therapy. It clearly has made a significant impact for patients with no other treatment options. So in our daily practice, we continue to use CAR T-cell therapy as we have done before these reports came out. But we do inform patients about the risk and what we know about the risk of these T-cell malignancies.   In addition to T-cell malignancies, there have also been reports of myelodysplastic syndromes in patients undergoing CAR T-cell therapy. Again, it is important to remember that, at least in the myeloma setting, many of these patients have had multiple lines of therapy, often with drugs that can cause second malignancies, particularly myelodysplastic syndrome. So I think a lot more work needs to be done in terms of understanding what is the direct impact of CAR T-cell therapy versus what was lurking underneath because of the treatments that these patients had previously received. So I think it is important for us to continue to be very diligent, as with any new therapies that we introduce for the treatment of our patients. But at the same time, understand that, in the context of the benefits that these therapies bring to our patients, especially when they have no other treatment options.  Dr. John Sweetenham: Absolutely. So, at least for now, and probably in the longer term, the benefits of the therapy certainly appear to outweigh the risks, although it is important not to underestimate or minimize those risks.   I wanted to change direction a little bit and talk a little bit in the final question about care disparities and CAR T cell. Of course, CAR T-cell therapy is typically offered at large cancer centers and is very expensive. This means that there are issues of access to treatment. In addition, the literature shows us that non-Hispanic Black individuals are twice as likely to develop multiple myeloma compared to their White counterparts. Furthermore, at least right now, Black patients are less likely to receive these novel CAR T-cell therapies and continue to be underrepresented in clinical trials. So, this is a big, complex question, but can you talk a little bit about how outcomes differ between racial and ethnic groups who actually receive CAR T-cell therapy for multiple myeloma? And could you address what you think are the most appropriate strategies for minimizing the disparities in access? Dr. Shaji Kumar: That's a very, very important question, particularly in the context of multiple myeloma, where African American individuals are at a higher risk of getting plasma cell malignancies. I think we need to think about this in the context of what we know about disparities even before the CAR T cell came along. There has been a good amount of literature that has looked at the outcomes based on the types of therapies that could be impacted by this. There have been studies that have looked at cooperative group trials, which often have a good representation of minorities and have shown that if patients have equal access to advanced therapies that we have, their outcomes are comparable or sometimes even better for African American patients compared to Caucasian patients. So I think it's very important that the treatment strategies that we develop are equally accessible to everyone.  In terms of CAR T-cell therapy or immunotherapies, I don't think we have any concrete evidence to suggest that there is any difference in outcomes. And I think it's reasonable to assume that if patients are exposed to similar therapies, they will have similar outcomes, even in the context of immunotherapies. But at the same time, I think we must continue to study this diligently, and the only way to do that is to ensure that clinical trials include patients reflective of society in general. This will allow us to understand if any differences exist. In addition, I think there is a serious risk that with these expensive therapies, this gap can only widen. And I think that is one reason that we must be proactive, particularly with therapies like CAR T-cell therapy, which not only are expensive but also require quite a bit of logistical support for patients to go to larger centers to get these therapies, stay around these larger centers for upwards of a couple of months, which means they are living outside of their usual societal structure, and ensure there is access to the resources that are needed to enable them to do that. So I think there is a lot that is still unknown, but I think we really need to be proactive in ensuring equal access to these therapies. Dr. John Sweetenham: Yes. Thanks for a very thoughtful response to that question, also for the work that you are obviously doing to help address this extremely important issue.  I'd like to thank you for sharing your insights with us today and for the extraordinary work that you're doing and your team are doing to advance care for patients with multiple myeloma. Dr. Shaji Kumar: Thank you, John. Dr. John Sweetenham: And thank you also to our listeners for joining us today. If you value the insights 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 inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. The guests on this podcast express their own opinions, experience, and conclusions. Guest statements do not necessarily reflect the opinions of ASCO. 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. Shaji Kumar @myelomaMD   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. Shaji Kumar: Consulting or Advisory Role: Takeda, Janssen Oncology, Genentech/Roche, Abbvie, Bristol-Myers Squibb/Celgene, Pfizer, Regeneron, Sanofi, K36 Research Funding (Inst.): Takeda, Abbvie, Novartis, Sanofi, Janssen Oncology, MedImmune, Roche/Genentech, Carsgen Therapeutics Ltd., Allogene Therapeutics, GlaxoSmithKline, Regeneron, Bristol-Myers Squibb/Celgene Travel, Accommodations, Expenses: Abbvie, Pfizer

Drs. Neeraj Agarwal and Todd Morgan discuss CONTACT-02, KEYNOTE-564, CheckMate-67T, and other notable studies featured at the 2024 ASCO Genitourinary Cancers Symposium, as well as additional key abstracts in prostate, kidney, and bladder cancers that will significantly influence clinical practice. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program and professor of medicine at the Huntsman Cancer Institute at the University of Utah, and editor-in-chief of ASCO Daily News. Today, we'll be discussing practice-changing abstracts and other key advances in GU oncology featured at the 2024 ASCO Genitourinary Cancers Symposium. Joining me for this discussion is Dr. Todd Morgan, the chair of this year's ASCO GU. Dr. Morgan is a urologic surgeon, chief of urologic oncology at Michigan Medicine, and a professor of urology at the University of Michigan. Our full disclosures are available in the transcript of this episode, and the disclosures of all guests on the podcast can be found at asco.org/DNpod. Todd, thank you for joining us today. Dr. Todd Morgan: Thanks so much, Neeraj. It's an honor to be here and I'm just thrilled to be able to do this with you. Dr. Neeraj Agarwal: Thank you. So, the GU meeting showcased significant advancements across the spectrum of GU malignancies. Can you tell us about the hot topics that captured the headlines this year? What did you find exciting this year at the ASCO GU Symposium? Dr. Todd Morgan: The theme of this year's meeting was "20 Years of Advancing Science and Transforming Patient Care," and this reflected ASCO GU's incredible milestone in GU cancer research over the last 2 decades. We were thrilled to welcome over 5,200 attendees from over 70 countries, and, believe it or not, there were more than 875 abstract submissions, compared to more than 300 in the meeting's first year. Most of the participants were present in person and that was fantastic. It enabled great networking opportunities and opportunities for experts, trainees, and mentees to exchange knowledge and ideas. Without a doubt, ASCO GU remains the annual meeting in our field, and it's amazing to hear the breadth and depth of the state-of-the-art science that's presented at this meeting, and so much of it impacts patient care the second that you return home. Additionally, the meeting's focus on diversity and interactivity, networking, multidisciplinary collaboration, and evidence-based care were absolutely phenomenal from my standpoint. We had a lunch session for women's networking that was a huge success—the first time we've done that. The keynote lecture by Dr. Cheryl Lee that talked about ensuring adequate representation in clinical trials was a huge hit, and we had tremendous positive feedback from that lecture. There were also multiple featured sessions on different diagnostic and therapeutic challenges in localized, recurrent, and advanced GU cancers. And, Neeraj, my personal favorite during the symposium is always the Trainee and Early-Career Networking Luncheon on the first day and then the additional networking luncheons on the 2 following days. I had great conversations with a ton of trainees and junior faculty, and I feel so fortunate for the opportunity to get to know the future superstars in our field. So I'd like to kick it back to you for a second because the first day started with a focus on prostate cancer and some of the key clinical trials. A great example is Abstract 17, which was the second oral presentation delivered, and really congratulations to you, Neeraj, on sharing the exciting data from the CONTACT-02 trial which we were eagerly awaiting. And I'd love to get your thoughts on the data that you presented. Could you tell us more about that trial? Dr. Neeraj Agarwal: Yes, Todd, I agree with you. It was such an exciting conference overall, and thank you for your leadership of this conference. So let's talk about the CONTACT-02 trial. It was a phase 3 randomized trial assessing the combination of cabozantinib and atezolizumab versus a second NHT in patients with metastatic castration-resistant prostate cancer after progression on one NHT. This patient population had to have extrapelvic soft tissue metastases, which could be liver metastases, lung metastases, or lymph nodal metastases, and about up to a quarter of patients had liver metastases. And overall, this was a high-risk patient population which was randomized to, as I said, cabozantinib plus atezolizumab versus a second line NHT. And these patients had received a prior NHT, mostly in the mCRPC setting.  The co- or dual primary endpoints were overall survival and progression-free survival (PFS). And a unique thing was that PFS was assessed only by RECIST 1.1 because, as per our discussions with regulatory authorities, the trial was focused on soft tissue metastases because of questions in the past that cabozantinib can affect bone lesions in an artifactual fashion, possibly concerns. That's why the PCWG 3 criteria were not used as the primary endpoint, but, of course, indeed used as another key endpoint, so we have information on both. Anyway, coming back to the endpoint 1:1 randomization. The randomization was stratified by presence or absence of liver metastases, prior docetaxel chemotherapy, and the setting in which NHT was given (mCSPC or CRPC). The PFS or primary endpoint was significantly improved with a 35% reduction in risk of progression or death with the cabozantinib-atezolizumab combination versus second NHT. And there was a trend for overall survival, with a hazard ratio of 0.79 favoring the cabozantinib-atezolizumab combination. Interestingly, all subgroups benefitted, regardless of age, region, site of metastases, but we decided to choose three clinical subgroups of interest such as patients with liver metastases, patients with prior docetaxel chemotherapy in the castration-sensitive setting, and bone metastases, and all these subgroups seemed to be benefitting with the strongest signal in the liver metastasis subgroup, with a 57% reduction in risk of progression or death, which I would argue we have never seen with any combination or any regimen in the metastatic prostate cancer setting yet, barring some targeted therapies in very selected patients. But overall, across the non-biomarker-selected patients, we have never seen this kind of signal. Toxicity — no discussion is complete without discussing toxicity, so I would like to highlight that. Safety signal — there were no new safety signals. The most common grade 3-4 adverse events were hypertension in 7%, anemia in 6%, which were similar in both arms, and, of course, diarrhea and fatigue in 4% each. And if we look at the secondary endpoints, such as time to chemotherapy and time to symptomatic skeletal events, they tended to favor the cabozantinib-atezolizumab. To sum it up, cabozantinib-atezolizumab showed a significant PFS benefit, with a 35% reduction in risk of progression or death, with a trend for overall survival in this patient population with an unmet need. So thank you so much, Todd, for allowing me to summarize the results of this trial. Dr. Todd Morgan: Yeah, wow. That's so impressive, and not surprising that you could so fluidly go right through all that data. Amazing. We heard some discussion of the NHT control arm in this trial. Could you discuss that for a bit? Because it obviously has implications on the similar control arm of other ongoing trials in this setting. Dr. Neeraj Agarwal: Absolutely. Pretty much all trials, every trial which has recently been reported or started in metastatic castrate-resistant prostate cancer have a similar second NHT arm. Whether there were multiple immunotherapy trials which we have just reported, or new trials which are starting or just started enrolling patients. And the reason for that is no randomized trial has ever shown superiority of docetaxel chemotherapy over a second NHT after failure of prior NHT in the mCRPC setting. That's number one. If you look at NHT as a control, it is accepted by health authorities globally with multiple recent trials which are just starting also having NHDR and it would not have been possible without the approval of global regulatory authorities across the world.  Then, if you look at the recently reported trial in the mCRPC setting with prior treatment with an NHT, there is an indication that chemotherapy may not be superior to NHT. For example, in the KEYNOTE-641 trial in patients with mCRPC with prior NHT, randomizing patients to enzalutamide plus pembrolizumab versus enzalutamide, the median PFS with enzalutamide was 9 months. This is very similar with docetaxel in patients randomized to docetaxel plus pembrolizumab versus docetaxel; the median PFS with docetaxel is 8 months or 8.3 months. And lastly, if you really want to have a comparison of chemotherapy with NHT which has been done after progression on NHT and docetaxel chemotherapy, so later line of mCRPC setting, that is the CARD trial, as you can imagine, cabazitaxel versus NHT, especially in patients with visceral metastasis, which was the point of discussion. For example, people may not feel comfortable randomizing patients to NHT compared to taxane. The hazard ratio for PFS supporting cabazitaxel was 0.79, so almost a 0.80 PFS hazard ratio, which we have never seen turning out to be a clinically significant benefit. So, if you combine all these data together, I think it was absolutely acceptable to us as investigators to have a second NHT as the control arm. And of course, when we are consenting the patient, we have to keep alternatives in mind, and we do talk about those alternatives with the patients. And if alternatives seem more applicable, we should not be talking to patients about those clinical trials or a given clinical trial in the clinic. I'm glad you brought this up, Todd, because this control NHT arm is not an issue with this trial, but all trials which should be presented in GU ASCO in the future meetings in the coming years. So, thank you. Dr. Todd Morgan: Yeah, thank you. It's such an important topic and controversy at some level, but it's a difficult problem to think about and obviously highly relevant to all the trials that we're looking at. Congrats again on that trial, that's tremendous. There was another important randomized phase 3 trial and it covers radiotherapy in patients with high-risk localized prostate cancer. Can you give us your insights on that one? Dr. Neeraj Agarwal: Yeah, Todd, I think you are referring to LBA259, titled "Long-term Results of Dose Escalation of Radiation Therapy from 70 Gy to 80 Gy Combined with Long-term Androgen Deprivation Therapy in High-risk Prostate Cancer: The GETUG-AFU 18 Randomized Trial." As you mentioned, in this randomized phase 3 trial, Dr. Christophe Hennequin and colleagues randomized patients with high-risk prostate cancer, which means they had to have either clinical stage T3 or T4 disease, or PSA ≥20 nanograms per milliliter, or a Gleason score between 8 and 10. These patients were randomized to receive ADT for 3 years combined with either dose-escalated intensity-modulated radiotherapy. So, I'd like to highlight, this was in the context of IMRT in the dose of 80 Gy or a conventional dose of 70 Gy. Now, you can argue that more people are using more than 70 Gy nowadays, but across the world, the conventional dose is still considered 70 Gy. So, 80 Gy versus 70 Gy were tested. Patients also had to have negative lymph node status on CT scans and MRI. The primary endpoint was biochemical progression-free survival or clinical progression-free survival at 5 years following the ASTRO Phoenix definition. Secondary endpoints – and these are quite important secondary endpoints – include overall survival, acute and late toxicity, and quality of life. The best part is that this trial met its primary endpoint with a 44% reduction in risk of biochemical or clinical progression or death in the dose-escalation radiotherapy arm compared with the conventional radiotherapy arm. Interestingly, a significant 52% improvement in prostate cancer-specific survival and a 39% improvement in overall survival was observed in the dose-escalated arm. So, 80 Gy continued to be superior to 70 Gy IMRT across the primary and secondary endpoints. Now, the best part is, regarding the toxicity profile, there was no significant difference between the 2 arms, with 78% of patients in the higher dose arm and 76% of patients in the conventional arm experiencing grade 2 or more toxicities. Dr. Todd Morgan: Great summary and really important, great news for our patients. Of course, it's a slightly different setting as it's high-risk localized prostate cancer. I checked in with our radiation oncologists at the University of Michigan after that [presentation] because I couldn't remember exactly where we are in terms of dose on these patients. And they were like, “Yeah, we've been doing 80 to 90 Gy for several years,” so it's great having this data to support that. And I think, as you said, the field at many centers has already moved that way. And again, the key takeaway from this abstract would be that IMRT, in combination with long-term androgen deprivation therapy, is effective and safe and increases not only the biochemical or clinical PFS rate, but also the cancer-specific survival and overall survival, again, in high-risk localized prostate cancer patients. And it does not appear to increase long-term toxicity. So really important. It'd be great to switch gears and discuss kidney cancer, if that's okay, and talk about some key abstracts in that field. What do you think? Dr. Neeraj Agarwal: There were so many exciting data in all cancers, which is amazing. So, Todd, could tell us about the LBA359, which I thought was one of the most impactful abstract presentations in the ASCO GU this year. It was titled, “Overall Survival Results from the Phase 3 KEYNOTE-564 Study of Adjuvant Pembrolizumab Versus Placebo for Treatment of Clear Cell Renal Cell Carcinoma (ccRCC)."   Dr. Todd Morgan: Yeah, this was a really big moment in our field, complete with a mid-presentation round of applause that was well deserved. And so this abstract was presented by Dr. Toni Choueiri from Dana-Farber Cancer Institute, and it included patients with clear cell renal cell carcinoma at intermediate high or high risk of recurrence, meaning that they had positive nodal disease or negative nodal disease with PT 2 and grade 4, or sarcomatoid features, or stage PT 3 or 4. These patients underwent nephrectomy with or without metastasectomy less than 12 weeks before randomization and had not received prior systemic therapy for clear cell RCC. Patients were randomized to receive either pembrolizumab 200 milligrams or placebo IV every three weeks for at least 17 cycles, or until disease recurrence, intolerable toxicity, or withdrawal of consent. Disease-free survival by investigator assessment was the primary endpoint, and overall survival was a key secondary endpoint. In this abstract, Dr. Choueiri and colleagues report results of the third prespecified interim analysis with a median follow-up of around 57 months in 496 patients receiving pembrolizumab and 498 patients receiving placebo. So, just as a reminder to the audience here, the first interim analysis reported at a median follow-up of 24 months and showed a significant reduction of 32% in the risk to recurrence or death in patients in the pembrolizumab arm. Then subsequently in November of 2021, the FDA approved pembrolizumab for the adjuvant treatment of patients with RCC who are at intermediate high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions. At that time, though, overall survival data were still immature. So, at the third prespecified interim analysis with a median follow-up of around 57 months, pembrolizumab showed, for the first time in an adjuvant RCC setting, improved overall survival with a 38% reduction in the risk of death. The estimated OS rate at 48 months was 91.2% with pembrolizumab and 86% with placebo. Furthermore, the OS benefit was observed across key subgroups, including patients with non-metastatic disease, patients with metastatic but no evidence of disease, patients with PDL-1 combined positive score less than or greater than or equal to one, and patients with presence or absence of sarcomatoid features. In each of these subgroups, the forest plot looks really impressive. And the DFS benefit was similar to previously reported interim analyses with a hazard ratio of 0.72. Also, no new safety signals with pembrolizumab were observed so just tremendous data. Dr. Neeraj Agarwal: Thank you, Todd, for such a great summary of these very important results. So the key message from this abstract, as you said, is that after a median follow-up of around 57 months, which is a long follow-up, adjuvant pembrolizumab demonstrates a statistically significant and clinically meaningful improvement in overall survival versus placebo in patients with RCC at high risk of disease recurrence after surgery. And this is, by the way, the first phase 3 study to show improved overall survival with any adjuvant therapy in RCC. Basically, this means we should continue to use adjuvant pembrolizumab or at least bring it up in our discussion with our patients who are in a similar situation with high-risk RCC after surgery. So this is great news overall. Todd, there was another kidney cancer abstract, LBA360, which compared, interestingly, subcutaneous nivolumab with intravenous nivolumab in patients with metastatic renal cell carcinoma. Could you please give us your insight about this abstract?   Dr. Todd Morgan: Sure. Really interesting study. Really interesting data that were presented. So as you mentioned, CheckMate 67T was a multicenter, randomized, open-label phase three study led by Dr. Saby George and colleagues that evaluated pharmacokinetics and objective response rate non-inferiority of subcutaneous nivolumab versus IV nivolumab in patients with locally advanced or metastatic clear cell RCC. So patients with measurable disease that progressed during or after 1 to 2 prior systemic regimens and who did not receive a prior immuno-oncology treatment were randomized 1-1 to receive either subcutaneous nivolumab 1200 milligrams every 4 weeks or IV nivolumab 3 milligrams per kilogram every two weeks until disease progression, unacceptable toxicity, withdrawal of consent, completion of two years of treatment, or death. The coprimary pharmacokinetics endpoints for non-inferiority testing were time-average serum concentration over the first 28 days and minimum serum concentration at steady state determined by a population pharmacokinetics analysis. A key secondary endpoint was objective response rate by independent review. So in 248 patients receiving subcutaneous nivolumab and 247 patients receiving IV nivolumab, non-inferiority for the coprimary pharmacokinetics and key-powered secondary objective response rate endpoints were met. The relative risk ratio for objective response rate was 1.33. The median PFS by independent review was 7.23 months in the subcutaneous group and 5.65 months in the IV group. Treatment-related serious adverse events occurred in 6.5% of patients in each group, and study drug toxicity led to 3 deaths in the subcutaneous group and 1 death in the IV group. These results could support using subcutaneous nivolumab as a new option to improve healthcare efficiency, especially since the average injection time with subcutaneous nivolumab was less than 5 minutes. I think we all know what issues are going on in infusion beds across the country, including, I'm sure, your center and mine. Dr. Neeraj Agarwal: Yes, absolutely. I think this is great news for our patients, Todd. Thank you. This shows that we are not only improving therapeutic options and diagnostic tools, but maybe we're also on the right track towards more practical administration routes, assisting in addressing the treatment burden and improving the efficiencies of healthcare systems. We love to have this option available for our patients, especially those who are pressed for time. So, Todd, would you like to move on to bladder cancer now?  Dr. Todd Morgan: Yeah, Neeraj, that'll be fantastic. I'm sure listeners would love to hear more about LBA530. Could you tell us more about this one, Neeraj? Dr. Neeraj Agarwal: Of course. I think this abstract is titled "Enfortumab Vedotin in Combination with Pembrolizumab Versus Chemotherapy in Previously Untreated, Locally Advanced or Metastatic Urothelial Carcinoma: Subgroup Analysis Results from EV-302," which was a global phase three study and was presented by Dr. Michiel Van Der Heijden. As our audience may recall, the EV-302 trial was presented at the ESMO 2023 meeting by Dr Tom Powles and the results were very exciting where, for the first time, a combination outperformed traditional gemcitabine-cisplatin chemotherapy. In this trial, patients with previously untreated with metastatic advanced urothelial carcinoma were randomized 1-1 to receive a 3-week cycle of a combination of enfortumab vedotin, which, as we know, is an antibody-drug conjugate targeting nectin-4 expressed on the cancer cells and pembrolizumab, which is a PD-1 inhibitor, versus gemcitabine and cisplatin or carboplatin, which were, until recently, the standard of care in this setting, and continue to be so in many countries in the world. The combination of enfortumab and pembrolizumab reduced the risk of progression or death by 55% and reduced the risk of death by 53% in the overall population. So consistent decrease in the hazard ratios for PFS and OS, and consistent improvement in overall survival and PFS in that previously reported presentation in the ESMO 2023. Now, based on these results, this combination was recently approved by the FDA in December 2023 for patients with advanced or metastatic urothelial carcinoma. So now the abstract, which was presented at the ASCO GU 2024 meeting, reported the results of a prespecified subgroup analysis. Select secondary endpoints included objective responses, duration of response, and safety. In 442 patients receiving the combination of enfortumab vedotin plus pembrolizumab, and a similar number of patients receiving chemotherapy both PFS and OS were higher for the combination of EV and pembro among prespecified subgroups such as race, platinum eligibility, PDL-1 expression, metastatic site, involvement of the liver or kidney function. Interestingly, the combination of EV and pembro reduced the risk of death by 53% in patients with visceral metastasis and 54% in patients with node-only metastasis. The improvement in PFS seems to be consistent regardless of the site of metastasis. In patients with moderate to severe renal function, the risk of death was reduced by 50% in patients receiving combination therapy. This is one of the best findings of these results because we always face challenges in treating patients with suboptimal kidney function and we cannot use cisplatin. Overall, EV plus pembro continues to show superior efficacy compared to platinum-based regimens across subgroups across the subgroups across the site of metastasis regardless of kidney function and so on. Dr. Todd Morgan: Yeah, just amazing data. I love hearing you spell it out like that. So, thank you again for the opportunity for me to sit here with you and listen to you talk about these data. It's impressive that we have been able to expand our therapeutic arsenal for urothelial carcinoma with an immune-targeting regimen that can spare our patients potential side effects of chemotherapy. What would your final takeaway on this abstract be? Dr. Neeraj Agarwal: I agree with you, Todd. I would add that the OS benefit was consistently observed across these select prespecified subgroups, including those historically associated with poor prognosis. The results of this new analysis support the finding of primary results, which indicate that EV plus pembro is a potentially new standard of care for patients with newly diagnosed, locally advanced, or metastatic urothelial carcinoma. Before we wrap up the bladder cancer session and the podcast, Todd, could you please give us insights about LBA531? Dr. Todd Morgan: Yeah, absolutely. I loved getting to hear this abstract presented. This one is titled “Ambassador,” known as the AMBASSADOR trial aligns A031501, a phase 3 randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma versus observation, that was presented by Dr. Andrea Apolo. It's an open-label, randomized, phase 3 trial that included patients with muscle-invasive urothelial carcinoma of the bladder, upper tract, or urethra. Eligible patients had pathologic tumor stage T2 or greater and/or positive pathologic nodal disease or positive margins at surgery following neoadjuvant chemotherapy, or patients with pathologic tumor stage T3 or greater and/or positive pathologic nodal disease or positive margins at surgery without prior neoadjuvant chemotherapy, and who were cisplatin ineligible or declined adjuvant cisplatin-based therapy. These patients were randomized one to one to either receive pembrolizumab 200 milligrams every 3 weeks for 1 year or observation. The dual primary endpoints were disease-free survival and overall survival. Secondary objectives included evaluation of DFS and OS in PDL-1 positive and negative patients and assessing safety. A total of 354 patients were enrolled to receive pembrolizumab and 348 to the observation arm, and 21% of the patients in the observation arm received a subsequent immune checkpoint inhibitor. At a median follow-up of 22.3 months for DFS, the median disease-free survival in the pembrolizumab arm was 29 months, while it was only 14 months in the observation arm with a hazard ratio of 0.69. At the interim analysis, OS data showed only a trend toward better outcomes in the pembrolizumab arm, which did not, however, reach statistical significance, with a median of 50.9 months in the pembrolizumab arm and 55.8 months in the observation arm with a hazard ratio of 0.98. These results could nevertheless have been impacted by the subsequent treatment of patients in the observation arm with an immune checkpoint inhibitor, especially after the FDA approval of nivolumab in 2021 for patients with muscle-invasive urothelial carcinoma, based on results of the CheckMate 274 trial. In terms of the safety profile, grade three or more adverse events occurred in 48.4% of patients in the pembrolizumab arm and 31.8% of patients in the observation arm. Dr. Neeraj Agarwal: That's great, Todd. This is such a great summary of this trial, and this is exciting news for our patients with muscle-invasive urothelial carcinoma. I'm hoping that pembrolizumab will be another option for our patients when we are discussing adjuvant immunotherapy in the clinic, moving forward very soon. With that, we have covered several abstracts addressing prostate, bladder, and kidney cancer, significantly influencing our medical practices, at least at the current moment or in the near future. Todd, thank you for sharing your insights today. These are undoubtedly exciting updates for all members of the GU oncology community, and we are grateful for your valuable contribution to the discussion. Many thanks. Dr. Todd Morgan: Thanks, for having me, Neeraj; this was really fun. I'm just really proud and excited to still be part of this field, to be part of the GU oncology field, and it continues to be exciting for all the folks who are coming up. Dr. Neeraj Agarwal: Indeed. 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. Thank you very much.   Disclaimer: The purpose of this podcast is to educate and 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. Neeraj Agarwal @neerajaiims   Dr. Todd Morgan @wandering_gu   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. Todd Morgan: Consulting or Advisory Role: Myriad Genetics, MDxHealth, TerumoBCT Research Funding (Institution): Prostate Cancer Foundation, National Institutes of Health, Department of Defence, GenomeDX Biosciences, Myriad Genetics, MDxHealth  

Drs. Neeraj Agarwal and Jeanny Aragon-Ching discuss several key abstracts to be presented at the 2024 ASCO GU Cancers Symposium, including sequencing versus upfront combination therapies for mCRPC in the BRCAAway study, updates on the CheckMate-9ER and CheckMate-214 trials in ccRCC, and a compelling real-world retrospective study in mUC of patients with FGFR2 and FGFR3 mutations. TRANSCRIPT Dr. Neeraj Agarwal: Hello, everyone, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah's Huntsman Cancer Institute, and editor-in-chief of ASCO Daily News. I am delighted to welcome Dr. Jeanny Aragon-Ching, a genitourinary oncologist and the clinical program director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing key posters and oral abstracts that will be featured at the 2024 ASCO Genitourinary Cancer Symposium, which is celebrating 20 years of evolution in GU oncology this year.  You will find our full disclosures in the transcript of this podcast, and disclosures of all guests on the podcast at asco.org/DNpod.  Jeanny, it's great to have you on the podcast today to highlight some key abstracts for our listeners ahead of the GU meeting. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. It's an honor to be here. Dr. Neeraj Agarwal: Jeanny, as you know, this year we are celebrating the 20th anniversary of the ASCO GU Cancers Symposium, and judging from this year's abstracts, it's clear that this meeting continues to play a major role in advancing GU cancer research. Dr. Jeanny Aragon-Ching: Indeed, Neeraj. This year's abstracts reflect the important strides we have made in GU cancers. So, let's start with the prostate cancer abstracts. What is your takeaway from Abstract 19 on BRCAAway, which will be presented by Dr. Maha Hussein, and of which you are a co-author? As our listeners know, several PARP inhibitor combinations with second-generation androgen receptor pathway inhibitors, or ARPIs, have recently been approved as first-line treatment for patients with metastatic castrate-resistant prostate cancer, or metastatic CRPC, and the question of sequencing PARP inhibitors and ARPIs instead of combining them has emerged. From that perspective, the results of the BRCAAway trial are very important. Can you tell us a little bit more about this abstract, Neeraj?  Dr. Neeraj Agarwal: I totally agree with you, Jeanny. The BRCAAway study attempts to answer the crucial questions regarding sequencing versus upfront combination of therapies in the mCRPC setting. It is a phase 2 trial of abiraterone versus olaparib versus abiraterone with olaparib in patients with mCRPC harboring homologous recombination repair mutations. Enrolled patients had mCRPC disease and no prior exposure to PARP inhibitors or ARPIs or chemotherapy in the mCRPC setting and had BRCA1 or BRCA2 or ATM mutations. As previously mentioned, these patients were randomized to 3 arms: abiraterone monotherapy at 1000 milligrams once daily, or olaparib monotherapy at 300 milligrams twice daily, or the combination of abiraterone and olaparib. The primary endpoint was progression-free survival per RECIST 1.1 or Prostate Cancer Working Group 3-based criteria or clinical assessment or death, so, whichever occurred first was deemed to be progression.   Secondary endpoints included measurable disease response rates, PSA response rate, and toxicity. This was a relatively small trial with 21 patients in the combination arm, 19 patients in the abiraterone monotherapy arm, and 21 patients in the olaparib monotherapy arm. It should be noted that 26% of patients had received docetaxel chemotherapy in the hormone-sensitive setting, and only 3% of patients had any prior exposure to an ARPI, and these were darolutamide or enzalutamide or in the non-metastatic CRPC setting.  The results are very interesting. The median progression-free survival was 39 months in the combination arm, while it was 8.4 months in the abiraterone arm and 14 months in the olaparib arm. An important finding that I would like to highlight is that crossover was also allowed in the monotherapy arms. Of the 19 patients receiving abiraterone, 8 crossed over to receive olaparib, and of the 21 patients receiving olaparib, 8 crossed over to the abiraterone arm. The median PFS from randomization was 16 months in both groups of patients who received abiraterone followed by olaparib or those who received olaparib followed by abiraterone. This is striking when compared to 39 months in patients who started therapy with the combination therapy of abiraterone with olaparib. Dr. Jeanny Aragon-Ching: Thank you so much for that wonderful summary, Neeraj. So the key message from this abstract is that combining olaparib and abiraterone upfront seems to be associated with improvement in PFS compared to just sequencing those agents. Dr. Neeraj Agarwal: Exactly, Jeanny. I would like to add that these results are even more important given that in real-world practice, only half of the patients with mCRPC receive a second-line treatment. Based on these results, upfront intensification with a combination of an ARPI plus a PARP inhibitor in the first-line mCRPC setting seems to have superior efficacy compared to sequencing of these agents. Dr. Jeanny Aragon-Ching: Thank you so much. Now, moving on to a different setting in prostate cancer, there were a couple of abstracts assessing transperineal biopsy compared to the conventional transrectal biopsy for the detection of prostate cancer. So let's start with Abstract 261. Neeraj, can you tell us a little bit more about this abstract? Dr. Neeraj Agarwal: Sure, Jeanny. So, in Abstract 261 titled "Randomized Trial of Transperineal versus Transrectal Prostate Biopsy to Prevent Infection Complications," Dr. Jim Hugh and colleagues led a multicenter randomized trial comparing these 2 approaches, so, transperineal biopsy without antibiotic prophylaxis with transrectal biopsy with targeted prophylaxis in patients with suspected prostate cancer. The primary outcome was post-biopsy infection. Among the 567 participants included in the intention-to-treat analysis, no infection was reported with the transperineal approach, while 4 were detected with the transrectal approach, with a p-value of 0.059. The rates of other complications, such as urinary retention and significant bleeding, were very low and similar in both groups. The investigators also found that detection of clinically significant cancer was similar between the 2 techniques and concluded that the transperineal approach is more likely to reduce the risk of infection without antibiotic prophylaxis. Dr. Jeanny Aragon-Ching: So the key takeaway from this abstract sounds like office-based transperineal biopsy is well-tolerated and does not compromise cancer detection, along with better antibiotic stewardship and health care cost benefits.  Moving on to Abstract 273, also comparing these two approaches, what would be your key takeaway message, Neeraj?  Dr. Neeraj Agarwal: In this Abstract 273, titled "Difference in High-Risk Prostate Cancer Detection between Transrectal and Transperineal Approaches," Dr. Semko and colleagues found that the transperineal biopsy based on MRI fusion techniques was also characterized by a higher possibility of detecting high-risk prostate cancer and other risk factors as well, such as perineural and lymphovascular invasion or the presence of cribriform pattern, compared to the conventional transrectal method. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So we can see that the transperineal approach is gaining more importance and could be associated with more benefits compared to the conventional methods.   Let's now switch gears to kidney cancer, Neeraj. Dr. Neeraj Agarwal: Sure, Jeanny. Let's start by highlighting Abstract 361, which discusses patient-reported outcomes of the LITESPARK-005 study. So what can you tell us about this abstract, Jeanny?  Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So as a reminder to our listeners, based on the LITESPARK-005 trial, it was a Phase 3 trial looking at belzutifan, which is an inhibitor of hypoxia inducible factor 2 alpha or I'll just call HIF-2 alpha for short, was very recently approved by the FDA as a second-line treatment option for patients with advanced or metastatic clear cell renal cell carcinoma after prior progression on immune checkpoint and antiangiogenic therapies. The title of Abstract 361 is "Belzutifan versus Everolimus in Patients with Previously Treated Advanced RCC: Patient-Reported Outcomes in the Phase 3 LITESPARK-005 Study," and this will be presented by Dr. Tom Pells at the meeting. At a median follow-up of 25.7 months, the median duration of treatment with belzutifan was 7.6 months, while it was only 3.9 months with everolimus. At the time of data cutoff date for the second interim analysis, 22.6% of patients remained on belzutifan while only 5% remained on everolimus. In the quality of life questionnaires, the time of deterioration to various quality of life scores, as assessed by standardized scales, was significantly longer in patients randomized to the belzutifan arm compared to those in the everolimus arm. Also, patients in the everolimus arm had worse physical functioning scores. Dr. Neeraj Agarwal: Yes, Jeanny. In addition to the improved outcomes associated with belzutifan, patient-reported outcomes indicate better disease-specific symptoms and better quality of life among patients treated with belzutifan compared to everolimus. This is great news for patients with advanced renal cell carcinoma.  Now, Jeanny, can you please tell us about the two abstracts that reported longer follow-up of CheckMate 9ER and CheckMate 214 trials in untreated patients with advanced or metastatic renal cell carcinoma? Dr. Jeanny Aragon-Ching: Yes, Neeraj. So you are referring to Abstracts 362 and 363. Let's start with Abstract 362. This abstract reports the results after a median follow-up of 55 months in the CheckMate 9ER trial, comparing the combination of nivolumab and cabozantinib to sunitinib in patients with advanced RCC without any prior treatment, so first-line therapy. The primary endpoint was PFS per RECIST 1.1 as assessed by an independent central review. So there were key secondary outcomes including overall survival (OS), objective response rates, and safety. Consistent with prior analysis at a median follow-up time of 18.1 and 44 months, the combination of nivolumab and cabozantinib at a median follow up of 55.6 months continues to show a significant reduction in the risk of progression or death by 42% and in the risk of death by 23% compared to sunitinib.  Dr. Neeraj Agarwal: And Jeanny, what can you tell us about the efficacy results of this combination by IMDC risk categories? Dr. Jeanny Aragon-Ching: Similar to prior results in patients with intermediate to poor risk IMDC risk category, the combination treatment maintained significant efficacy and reduced the risk of progression or death by 44% and the risk of death by 27%. To put it simply, the update now shows a 15-month improvement in overall survival with the cabozantinib-nivolumab combination compared to sunitinib, which is amazing. Also, in patients with favorable IMDC risk group, which represented truly a small number of patients in the trial, there was a strong trend for improvement of outcomes as well. I would like to point out that no new safety concerns were identified. Dr. Neeraj Agarwal: So, it looks like the key message from this abstract is that with longer follow-up, the combination of nivolumab and cabozantinib maintains a meaningful long-term efficacy benefit over sunitinib, supporting its use for newly diagnosed patients with advanced or metastatic renal cell carcinoma.   Let's move on to Abstract 363, which compares nivolumab with ipilimumab to sunitinib in first-line advanced renal cell carcinoma. What would you like to tell us about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Yes, Neeraj. The title of this abstract is "Nivolumab plus Ipilimumab versus Sunitinib for the First-Line Treatment of Advanced RCC: Long-Term Follow-Up Data from the Phase 3 CheckMate 214 Trial." In this abstract, Dr. Tannir and colleagues report outcomes with the longest median follow-up in first-line advanced RCC setting for any clinical trial. So the median follow-up now is about 18 months. The primary endpoints were OS, PFS, and objective response rates, as assessed by an independent review according to RECIST 1.1 criteria in the intermediate to poor risk IMDC risk group, which is the intent-to-treat (ITT) analysis, while secondary outcomes included the same outcomes in the ITT population of patients. Although the progression-free survival was similar in both arms, the combination of nivolumab-ipilimumab reduced the risk of death by 28% compared to sunitinib in the ITT population of patients. When stratifying the results by IMDC risk groups, the combination arm of nivolumab-ipilimumab showed significant improvement in the intermediate to poor risk group, but there was no difference in the favorable risk group. But in the study, no new safety signals were identified. Dr. Neeraj Agarwal: Thank you, Jeanny, for such a comprehensive description of the results of these two studies. I'd like to add that the median overall survival of patients with metastatic renal cell carcinoma in the ITT population in the CheckMate 214 trial has now reached 53 months, which would have been unimaginable just a decade ago. This is wonderful news for our patients. So the key takeaway from these two abstracts would be that immune checkpoint inhibitor-based combinations remain the backbone of first-line advanced renal cell carcinoma treatment.  Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. This is wonderful news for all of our patients, especially for those who are being treated for first-line therapy.  Now, let's move on to the bladder cancer abstracts. We have two exciting abstracts from the UNITE database. What are your insights on Abstract 537, titled "Outcomes in Patients with Advanced Urethral Carcinoma Treated with Enfortumab Vedotin After Switch-Maintenance of Avelumab in the UNITE Study"? Dr. Neeraj Agarwal: As our listeners know, enfortumab vedotin is an antibody-drug conjugate that binds to a protein called Nectin 4 expressed on bladder cancer cells. In this abstract, Dr. Amanda Nizam and colleagues describe outcomes in 49 patients receiving third-line enfortumab vedotin after prior progression on platinum-based therapy and maintenance avelumab. At a median follow-up of 8.5 months, the median progression-free survival was 7 months and the median overall survival was 13.3 months with enfortumab vedotin in this treatment-refractory setting, the objective response rates were 54%. The message of this study is that enfortumab vedotin is an effective salvage therapy regimen for those patients who have already progressed on earlier lines of therapies, including platinum-based and immunotherapy regimens. Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for that comprehensive review.  I want to focus on another patient population in the UNITE database, which is the use of fibroblast growth factor receptor (FGFR) alterations. Can you tell us more about the sequencing now of erdafitinib and enfortumab vedotin in these patients with metastatic urothelial cancer, as discussed in Abstract 616? Dr. Neeraj Agarwal: Sure, Jeanny. As a reminder, erdafitinib is a fibroblast growth factor receptor kinase inhibitor approved for patients with locally advanced or metastatic urothelial carcinoma harboring FGFR2 or FGFR3 alterations after progression on platinum-based chemotherapy. However, the optimal sequencing of therapies in these patients is unclear, especially with enfortumab vedotin being approved in the salvage therapy setting and now in the frontline therapy setting.  So in this retrospective study, all patients with metastatic urothelial carcinoma had FGFR2 or FGFR3 alterations. Dr. Cindy Jiang and colleagues report outcomes in 24 patients receiving enfortumab vedotin after erdafitinib, 15 patients receiving erdafitinib after enfortumab vedotin, and 55 patients receiving enfortumab vedotin only. This is a multicenter national study. Interestingly, patients receiving both agents had a longer overall survival in a multivariate analysis, regardless of the treatment sequencing, than patients receiving enfortumab vedotin alone or only with a hazard ratio of 0.52. The objective response rate of enfortumab vedotin in the enfortumab vedotin monotherapy arm was 49%. When these agents were sequenced, the objective response with enfortumab vedotin was 32% after erdafitinib and 67% when used before erdafitinib. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. I think these are important real-world data results, but I would like to point out that larger and prospective studies are still needed to confirm these findings, especially regarding the outcome of erdafitinib after enfortumab vedotin, particularly when the latter is used in the first-line setting. Dr. Neeraj Agarwal: I totally agree, Jeanny. Now, let's discuss some abstracts related to disparities in the management of patients with genitourinary cancers.  Dr. Jeanny Aragon-Ching: Sure, actually, I would like to discuss 2 abstracts related to disparities in patients with prostate cancer. So the first one, Abstract 265, titled "Patient-Provider Rurality and Outcomes in Older Men with Prostate Cancer." In this study, Dr. Stabellini, Dr. Guha and the team used a SEER Medicare-linked database that included more than 75,000 patients with prostate cancer. The primary outcome was all-cause mortality, with secondary outcomes included prostate cancer-specific mortality. The investigators showed that the all-cause mortality risk was 44% higher in patients with prostate cancer from rural areas who had a provider from a non-metropolitan area compared to those who were in a metropolitan area and had a provider also from a metropolitan area. Dr. Neeraj Agarwal: Those are very important data and highlight the healthcare disparities among the rural population with prostate cancer that still exist.  So what is your key takeaway from Abstract 267, titled "Rural-Urban Disparities in Prostate Cancer Survival," which is a population-based study? Dr. Jeanny Aragon-Ching: Of course. This abstract discusses, actually, a very similar issue regarding access to healthcare among rural versus urban patients. In this study, Dr. Hu and Hashibe and colleagues and team at the Huntsman Cancer Institute assessed all-cause death and prostate cancer-related death risk in a retrospective study in which patients with prostate cancer based on rural versus urban residencies looked at 18,000 patients diagnosed with prostate cancer between 2004 and 2017. 15% lived in rural counties. Similar to the prior abstract we talked about, patients living in rural areas had about a 19% higher risk of all-cause mortality and a 21% higher risk of prostate cancer-specific mortality in comparison to patients living in urban areas. Dr. Neeraj Agarwal: So Jeanny, we can say that both of these abstracts, led by different groups of investigators, highlight that patients with prostate cancer living in rural areas have inferior survival outcomes compared to those living in urban areas, and it is time to focus on the disparities experienced by the rural population with prostate cancer.  Dr. Jeanny Aragon-Ching: Yeah, absolutely Neeraj. I concur with your thoughts.  So, any final thoughts before we wrap up the podcast today? Dr. Neeraj Agarwal: Yes, before concluding, Jeanny, I want to express my gratitude for your participation and the valuable insights you have shared today. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today.   As we bring this podcast to a close, I would like to highlight the significant advances happening in the treatment of patients with genitourinary cancers during our upcoming 2024 ASCO GU meeting. Many studies featuring practice-impacting data will be presented by investigators from around the globe. I encourage our listeners to not only participate at this event to celebrate these achievements, but to also play a role in disseminating these cutting-edge findings to practitioners worldwide. By doing so, we can collectively maximize the benefit for patients around the world.  And thank you to our listeners for joining us today. You will find links to the abstracts 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. Thank you very much.  Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guest speakers express their own opinions, experience, and conclusions. Guest statements on the podcast do not necessarily reflect 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. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    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. Jeanny Aragon-Ching:    Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 

As geography and regional differences can play a major role in disparities in cancer care, learn how cancer programs can collaborate with local community outreach organizations to improve access to care and support underserved populations. In this episode, CANCER BUZZ speaks with Farrukh T. Awan, MD, MS, professor of Internal Medicine and director of Lymphoid Malignancies at the Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, about their approach to addressing regional barriers to improve care for patients with chronic lymphocytic leukemia. “Time to get to appointments, the driving distance, the traffic issues, the cost of travel, housing/lodging, food—I think those are some of the biggest challenges we see in our patients, especially in our part of the country, where distances are huge and traffic can be an issue in major cities…” – Farrukh Awan, MD, MS   Guest:  Farrukh T. Awan, MD, MS Professor of Internal Medicine Director of Lymphoid Malignancies Program Harold C. Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center Dallas, TX   This podcast was created in connection with the education program A Regional Approach to Advancing Care for Patients with Chronic Lymphocytic Leukemia. This episode was made possible with support by AstraZeneca, Janssen Oncology, and Pharmacyclics.   Additional Reading/Sources ·       Chronic Lymphocytic Leukemia (CLL) Resources ·       Multidisciplinary Chronic Lymphocytic Leukemia Care (accc-cancer.org) ·       Quality Improvement Case Studies ·       CLL: Models of Effective Care Delivery ·       Podcast EP 104: Addressing Regional Challenges to Equitable Care for Patients with CLL ·       Podcast EP 105: Best Practices in Caring for Patients with CLL in a Post-COVID Era ·       Podcast EP 57: COVID-19 Challenges: Managing Patients with CLL ·       Chronic Lymphocytic Leukemia (CLL) (cancer.org) ·       Addressing Racial Disparities in CLL Care - Patient Empowerment Network (powerfulpatients.org) ·       CLL Resources - CLL Society

In this latest episode of ASTCT Talks, Rahul Banerjee interviews Josh Epworth, a lead nurse practitioner in the plasma cell disorders clinic at the Fred Hutchinson Cancer Center. They delve into the topic of monitoring after CAR-T therapy for multiple myeloma. Mr. Epworth shares insights from his experience in the outpatient setting, discussing issues like hypogammaglobulinemia, immune cell functionality, and infections that may arise after CAR-T treatment. They also touch on monitoring for cytomegalovirus (CMV) and other respiratory viruses, as well as the importance of developing close relationships with local healthcare providers to ensure patients receive timely care. About Josh Epworth, MSN, ARNP Josh Epworth is a Nurse Practitioner at the Fred Hutchinson Cancer Center (FHCC) and is a Teaching Associate at the University of Washington School of Medicine. He is board-certified in Adult/Gerontology medicine and specializes in the treatment of multiple myeloma. As a staff member of FHCC's multiple myeloma team, Mr. Epworth is involved in disease treatment, symptom management, patient education and clinical trials. About Dr. Rahul Banerjee, MD, FACP Dr. Banerjee, MD, FACP, (@RahulBanerjeeMD) is an Assistant Professor in the Division of Medical Oncology at the University of Washington and at the Fred Hutchinson Cancer Center. Prior to moving to Seattle, he completed his hematology/oncology fellowship and advanced fellowship in BMT/CAR-T therapy at the University of California San Francisco. His clinical interests are in multiple myeloma, AL amyloidosis, and CAR-T therapy. His research interests are in toxicity management, digital health, and the patient experience. This episode was sponsored by Janssen Oncology and Legend Biotech.

Drs. Vamsi Velcheti, Taofeek Owonikoko, and Janakiraman Subramanian discuss their experiences navigating the cancer drug shortage in the United States, the impact on patients and clinical trial enrollment, lessons learned, and proactive strategies to mitigate future crises. TRANSCRIPT  Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic oncology at the Perlmutter Cancer Center at NYU Langone. On today's episode, we'll be discussing the impact of the shortage of cancer chemotherapy drugs across the United States. This has been affecting several thousands of patients with adult and pediatric cancers and hampering enrollment in clinical trials. Among the shortages are very commonly used drugs like cisplatin, carboplatin, methotrexate, and fludarabine. Some of these shortages have persisted since the time of the pandemic in 2020.   So today, to discuss this really troubling scenario, I have two outstanding colleagues, Dr. Janakiraman Subramanian, the director of thoracic oncology at Inova Schar Cancer Institute in Virginia, and Dr. Taofeek Owonikoko, a professor of medicine and the chief of the Division of Hematology and Oncology at the University of Pittsburgh Hillman Cancer Center in Pittsburgh.   Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available at asco.org/DNpod.  So, a recent survey by the NCCN found that 90% of the nation's largest cancer centers have experienced a shortage in carboplatin, and 70% of the centers have reported a shortage in cisplatin. These are platinum-based chemotherapies we use frequently in patients with cancer, and these are often curative intent treatments for several cancers, and these are used in several tumor types, both solid tumors and hematologic malignancies. So, the scale of the problem is immense.   Dr. Owonikoko, I'd like to hear your take on this situation and how are you dealing with this at the UPMC Cancer Center.  Dr. Taofeek Owonikoko: Yeah, thank you, Dr. Velcheti, and happy to be part of this panel. As you rightly surmised, the chemotherapy drug shortage is what we've all experienced across the length and breadth of the United States. Our cancer center here in Pittsburgh is not an exception. We've had to be proactive as well as think outside the box to be able to manage the challenge. Just like every other cancer center across the country, maybe to varying degrees, we've had to look at patients in need of chemotherapy with these standard-of-care agents such as cisplatin or carboplatin, and to some degree docetaxel, during this past episode of drug shortage that we all went through. And while we did not have to, fortunately, cancel any patient treatment, we all went through it with bated breath; not sure of where the next batch of chemotherapy drugs will come through, but I would say in the past couple of weeks, we've actually seen some improvement in drug availability.   But before then, we've had to have contingency plans where, on a weekly basis, we review our patient list and the drug regimens that they're going to need, and must make sure that we have enough drug on hand for those patients. And in situations where we thought we might not have enough drug; we also had a plan to use alternative regimens. We were proactive in having guiding principles that are consistent with ASCO's recommendations in terms of quality care delivery for cancer patients. So, I'm sure that this is more or less the same approach adopted by other leading cancer centers across the country.   Dr. Vamsi Velcheti: Thank you, Dr. Owonikoko. And Dr. Subramanian, you're in a community setting, a large cancer center that serves a lot of patients in the state of Virginia. So, what is the scale of the problem at your institution and how are you handling it?   Dr. Janakiraman Subramanian: First of all, Dr. Velcheti, thanks for having me here on this panel. And as you rightly said, this is a significant problem, and it is across the country like Dr. Owonikoko said. And as medical oncologists, we are not always thinking of drug shortages. Our focus is on taking care of our patients. So, this is one more issue that we need to keep in mind now as we manage our patients with cancer. When this shortage started, the biggest problem, as you know, was when we became aware of this was primarily in cisplatin and we had some of our patients who were getting curative treatment and we had to make a decision - can they get cisplatin or can they get carboplatin. And one of the things we did was to have an ethics committee that will review each patient that is being planned to receive cisplatin-based chemotherapy and come to a decision on how best we can support them.   The template for some of this was based upon some of the triage mechanisms we used during COVID, as well as the ASCO guideline document for managing this chemotherapy shortage, which was one of the blueprints we used. And they have reviewed all cases, all patients that are being planned for cisplatin or carboplatin for that matter, and we come to a decision based on that. And we also have another committee that constantly monitors drug availability on a weekly basis and tries to forecast where the next problem would be as we take care of our patients.   And particularly as a lung cancer doctor, we've had situations where we had to use carboplatin instead of cisplatin and even we also have carboplatin shortage. And so, the committee usually approves two cycles at a time, but thankfully so far we have not had a situation where we could not offer our patients the chemotherapy treatment. But we are very carefully monitoring the situation, hoping that this will improve.   The other aspect of the shortage has been in 5FU. A lot of our GI colleagues; I treat esophageal cancer patients as well, where we've had to forego the bolus 5FU and have a 10% reduction on all 5FU infusions. And we've been using some of that dose reduction to ensure that we can have 5FU available for all our patients. And that's how we've been trying to manage this shortage situation here at Inova Schar.   Dr. Vamsi Velcheti: Dr. Subramanian and Dr. Owonikoko, we are oncologists, we are treating patients, and the toughest part really is telling a patient that we don't have access to certain drugs and we have to switch treatments to perhaps another treatment regimen that may be suboptimal. And it's always a very anxiety-provoking discussion, and especially for patients with metastatic cancer, they're already under a lot of stress and it's a really difficult conversation. How do you handle that, Dr. Owonikoko?  Dr. Taofeek Owonikoko: That's a conversation we all hope we don't have to have. And fortunately, with this current crisis, I've actually not had such misfortune of having to inform a patient that we don't have drugs to treat them or that we have to switch to something inferior. But conceptually, it's possible that could have happened and that would have been very difficult. But the one thing that we did, though, as part of our mitigation strategy was actually to inform the patient ahead of time because the way we handled this was to look at our inventory on a week-by-week basis. And if there are patients where we felt maybe they will be coming in towards the end of the week and we may not have enough drugs for them, to let them know the possibility exists that we might have to switch them to something different. While we did not have to do that for any patient, yes, there are patients that we had to give that heads up to, to say, “We're having this shortage. We're doing everything we can to make sure it's available. But just in case it's not available…” I think what is most important for most patients is to be aware of that decision ahead of time, to be able to process it, and to be transparent.   The other challenge that we face was, if you have to choose between patients, what should be your guiding principles as to who gets the drug and who doesn't get it? I think it's very easy for all of us to say, “Oh, if it's curative intent, we do it. If it's not curative intent, we don't do it.” It's a little more complicated than that because if we put the equity hat on, curative intent doesn't actually mean that that life is more valuable than somebody who cannot be cured. And this is where really, I think having people with expertise in ethics of care delivery and disaster management will be very important for us to proactively anticipate that, should this become a recurrent problem in the future that we actually have a well-vetted approach, just like we did during COVID where you have to ration resources that we have those people with expertise to help us as oncologists because not all of us, at least personally I can speak for myself, that is not my area of expertise and comfort.  Dr. Vamsi Velcheti: Excellent points. Dr. Subramanian, anything to add?  Dr. Janakiraman Subramanian: Oh, absolutely. I echo what Dr. Owonikoko said. These are conversations that we would like to hopefully never have with our patients. But this is a crisis that we are facing now. And personally, I can tell you two situations where we ran into this problem. But overall, though, we never had to stop a treatment or cancel a treatment for our patient. In the first situation, we had a young man with a rare germ cell tumor in the hospital for whom cisplatin was key. He was already in the ICU and sometimes the treatment start dates are not perfect, unlike what we do in the outpatient setting, depending on how well he's doing or the treatment start dates might move by a day or so. So we basically had to hold a certain dose of cisplatin for him.   This brings the next question, which is how do we decide who gets cisplatin versus who can go for an alternative option? And I think Dr. Owonikoko made a great point where, just because it is a curative disease does not mean their life is more valuable. This is where I think trying to make that decision at an individual level, as an individual treating physician can be extremely hard. And that's why at our institution we have this ethics committee where we have oncologists, pharmacists, and ethicists that review these chemotherapy orders, particularly for cisplatin, and try to use some guiding principles that we learned from COVID as well as ASCO's guidance to decide how we assign our resources. That's one option, one way we have done it.    And then in another situation that was faced by one of my GI oncology colleagues was a patient that was originally planned to go on a clinical trial where the chemotherapy backbone was FOLFOX and because we had the 5FU shortage, we could not offer that patient clinical trial enrollment. And that was a tough conversation where they had to tell them that they could not go on a clinical trial that they were looking forward to. And this then brings the next question, which is by foregoing the bolus 5FU and by the 10% reduction in the infusional 5FU, are we providing them inferior treatment? And it's a conversation that's had at a very individual level. I don't envy my colleague who had to have that conversation. It's a challenge and we try to do our best to communicate to our patients that we are trying to provide care without trying to compromise the effectiveness of treatment for them.  Dr. Vamsi Velcheti: Thank you so much both of you. And we had the same issues here at NYU in New York City as well. It appears, you know, the degree of shortage and the drugs that are in shortage has been somewhat different at different locations across the United States. But the theme has been that we are having to ration treatments for our patients. And of course, there are some tumor types where there's really no adequate substitution, for example, GU cancers. I mean, you can't really not give them cisplatin. A lot of these are situations which have curative intent and young patients. So, it's really troubling.   And I think one of the things that really came out of this is there's been a lot of push from professional societies that actually ASCO has been spearheading and some intense discussions with CMS and legislators to kind of provide more long-term fix for these things. And I think all of us have to be more engaged in those discussions with our professional societies like ASCO to kind of help promote awareness. So if you kind of think about it, these drugs are not that expensive. These are generic drugs that we've all been using for such a long time. And the fact that we can't provide these drugs for various reasons is kind of really concerning. We spend so much money on research and more expensive drugs and not being able to manufacture these drugs within the country and kind of having to rely on complex supply chains is troubling, and I hope the situation improves very soon.    So, I know both of you are at large cancer centers that enroll patients on clinical trials. Of course, these drugs, especially carboplatin, for lung cancer, especially, are like core treatments that are used in managing cancer patients with lung cancer. So how is this affecting your clinical trial accrual? Are you prioritizing patients on clinical trials for these drugs? Have you had to make any decisions to hold clinical trial accrual for certain trials? Kind of curious to hear.  Dr. Taofeek Owonikoko: Yeah, so I can maybe weigh in a little bit on that in terms of what we've had to do for patients receiving treatment as standard of care versus those going on clinical trials. As we all recognize that when a patient goes on a clinical trial, even if they are going to receive a standard-of-care regimen as part of that trial, it still has to be administered in line with the protocol. So, during the extreme period of shortage anxiety, we actually had consideration for perhaps not putting patients on trial if we're not sure that they will be able to continue to receive the protocol-mandated treatment, whether it's a control intervention or the experimental intervention.   The good thing to come out of this is at least here at UPMC, we actually did not have any instance where we had to deny a patient clinical trial participation. But there were anxious periods when we already had patients enrolled and they were scheduled to receive a platinum-containing regimen and we were not sure whether or not we were going to have adequate supply of the drug for them while on trial. I think this really raises an important consideration going forward as we come out of this current shortage. I don't by any stretch of the imagination assume that this is going to be the last one we experience, but I think the lessons learned here, we have to also carry that forward both in the design of the trial as well as in the regulatory environment surrounding clinical trial conduct, to say, should another incidence of drug shortage are to happen, how do we actually operationalize that with respect to patients on trial, whether starting or already on trial?   I think it's much more challenging when the patient is already on the trial, they've already started. It's less challenging if you just have to make a decision about somebody starting newly on the trial. But equally important is that by not allowing new patients to go on trial is denying something that potentially could be of benefit to them, albeit it is still a trial, it's not an established treatment option yet.  Dr. Janakiraman Subramanian : I completely agree with Dr. Owonikoko. Those were very key points and issues that we face as well. In terms of my patients with lung cancer, we haven't had a problem in getting them on clinical trials. Even though we have had carboplatin shortage patients who are already on treatment, they were able to get the carboplatin. For new patients, we were still able to provide them carboplatin as well. The biggest problem for clinical trials has been primarily with my GI colleagues who have to use 5FU. And there, as I said before, we are unable to give bolus 5FU and there is a 10% reduction of the infusional 5FU. So, we can't have any of these patients go on clinical trials.    And as a result, anything that has to do with 5FU has come to a screeching halt in terms of clinical trials for our patients. And I think I echo the point of Dr. Owonikoko that by no means this is the last drug shortage we're going to be dealing with and we are here today discussing this, also because this shortage has not ended. It's been ongoing. It's one of the longest drug shortages in my memory as a medical oncologist, and that's concerning. We still see that there is some improvement, but we haven't gotten past it yet.     And therefore, as we develop clinical trials and we need to have methods to address drug shortages and how we manage patient enrollment as well as how do we manage existing patients who are already on a clinical trial and, if possible, what might be their options in that situation. We may not have all the answers, but it is definitely an issue that we need to think about in the future as we develop and implement newer clinical trials for our patients.  Dr. Vamsi Velcheti: I completely agree and great points, both of you. And we've had the same issues with clinical trials at NYU Langone as well due to the shortage. It's been a challenge, and I think this is a problem that's so complex because of supply chain issues and the way the drugs are priced and incentives for manufacturing these drugs in the United States are not lucrative enough to actually onshore a lot of the production of these drugs.   I think at the end of the day, I think we have to come up with some creative, innovative, reimbursement structures for these generic chemotherapy drugs. I think this would require a very complex economic solution that perhaps ASCO and other organizations should kind of really foster an environment of innovation to kind of help facilitate onshoring some of the manufacturing of these key drugs within the United States. I think ASCO is already trying to do that, trying to collaborate with all the stakeholders to kind of address this problem is very critical, and I think all of us have to be engaged in some of the advocacy efforts that are ongoing to kind of address these drug shortages. And this is not a short-term problem.  So, Dr. Owonikoko and Dr. Subramanian, any final thoughts before we wrap up the podcast today?  Dr. Janakiraman Subramanian: So, Vamsi, you mentioned the whole complex supply chain and the fact that we rely primarily on overseas manufacturers to get these drugs that are off-patent but still a key backbone of our cancer treatment. I think those are all key issues that policymakers and leaders in the field have to keep in mind. As an institution at Inova, one of the key mechanisms that have helped us to sort of stay ahead of the shortage was to have this inventory management team that monitors the inventory out there. And in fact, the inventory management team does have access to what the inventory is in some of their main suppliers in terms of the drugs. And they also have an idea of how many patients are going through treatment, what is the weekly usage of a specific drug like carboplatin. And they try to forecast what is coming down the road and try to prepare for it.   And as we try to look for solutions, maybe a forecasting mechanism in a larger scale like either spearheaded by ASCO or by policymakers level that can, for the overall country, try to see where some of the inventory is for some of these critical drugs and try to prepare for it ahead of time, rather than wait till we hit the shortage and then try to find alternative suppliers to get the drug, which obviously doesn't happen quick enough. It takes months or even longer to catch up and get the inventory back to the level where we can comfortably take care of our patients.  I think that is something we should be advocating for that as well as the professional societies should take a handle on that and see if they can support something like that as well as letting the institutions know ahead of time what's coming might be very helpful.  Dr. Vamsi Velcheti: Yeah, very good point, Janakiraman, and I think that's a key takeaway here. I think we have to learn from other industries and try to– I mean this is not unique to healthcare by any means. I mean these chronic shortages due to supply chain issues, inventory management, there might be some learnings from other industries here that we probably should also focus on inventory management and improve supply chain logistics.   Dr. Owonikoko, any closing thoughts?   Dr. Taofeek Owonikoko: Yeah, I agree as well with all the points made by Dr. Subramanian and yourself. This is a chronic problem that requires a long-term strategy. I think it's both an economic problem as well as a regulatory problem. As we all know, part of the reason why we went through this current crisis is the regulatory decision by the FDA regarding safety of one of the manufacturers. So being proactive in terms of how these audits are conducted and giving people lead time I think will help avoid similar situations in the future.    It's an economic problem. There's a reason why a lot of the big pharma companies are not producing these drugs. And if the cost of production is such that the amount of money you get paid is enough to cover your price, I think there is an economic issue there to be addressed. That is unfortunately not within the scope of what any one of us can do individually, but as advocates in terms of the structure of incentivizing new drug versus old drug, some of these newer drugs are quite expensive, but oftentimes they are used along with standard drugs that are not as expensive. So, where do we strike that balance where we do not stifle innovation but at the same time, we don't create a perverse incentive system where everybody just wants to come up with the newest, most expensive drug and nobody is interested in really producing the backbone chemotherapy and other agents that will make those new drugs work well.   So, I think we have to pay attention. We have to advocate for our patients through our different institutions and organizations, and I hope that society as a whole that we've learned a lot of lessons from this crisis and that will help us craft some long-term strategies.   Dr. Vamsi Velcheti: Thank you both Dr. Owonikoko and Dr. Subramanian for your time today to speak with me and our listeners and for sharing your insights with us on the ASCO Daily News podcast.   Dr. Taofeek Owonikoko: Thank you.   Dr. Janakiraman Subramanian: Thank you.  Dr. Vamsi Velcheti: And thank you to our listeners for your time today. If you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much.  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.  ASCO Resources Related to Drug Shortages are available here.     Follow today's speakers:    Dr. Vamsidhar Velcheti    @VamsiVelcheti    Dr. Janakiraman Subramanian  @RamSubraMD  Dr. Taofeek Owonikoko  @teekayowo    Follow ASCO on social media:     @ASCO on X (formerly Twitter)    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Vamsidhar Velcheti:     Honoraria: ITeos Therapeutics    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus    Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline      Dr. Janakiraman Subramanian:  Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Daichi, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology, Lilly, Blueprint Medicines, Axcess, BeiGene, Cardinal Health, Takeda, OncoCyte  Speakers' Bureau: AstraZeneca, Boehringer Ingelheim, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology  Research Funding (Inst.): G1 Therapeutics, Tesaro/GSK, Novartis, Genentech, Novocure, Merck   Dr. Taofeek Owonikoko:  Stocks and Other Ownership Interests: Cambium Oncology, GenCart, Coherus Biosciences  Consulting or Advisory Role: Novartis, Celgene, Abbvie, Eisai, GI Therapeutics, Takeda, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Merck, Jazz Pharmaceuticals, Zentalis, Wells Fargo, Ipsen, Roche/Genentech, Janssen, Exelixis, BeiGene, Triptych Health Partners, Daichi, Coherus Biosciences  Speakers Bureau: Abbvie  Research Funding (Inst.): Novartis, Astellas Pharma, Bayer, Regeneron, AstraZenece/MedImmune, Abbvie, G1Therapeutics, Bristol-Myers Squibb, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Oncorus, Ispen, GlaxoSmithKline, Calithera Biosciences, Eisai, WindMIL, Turning Point Therapeutics, Roche/Genentech, Mersana, Meryx, Boehringer Ingelheim  Patents, Royalties, Other Intellectual Property (Inst.):   Overcoming Acquired Resistance to Chemotherapy Treatments Through Suppression of STAT3  Selective Chemotherapy Treatments and Diagnostic Methods Related Thereto  DR4 Modulation and Its Implications in EGFR-Target Cancer Therapy Ref: 18089 PROV (CSP) United States Patent Application No. 62/670,210 June 26, 2018 (Co-Inventor)  Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor)  Other Relationship: Roche/Genentech, EMD Serono, Novartis  Uncompensated Relationships: Reflexion Medical           

In this episode of ASCO Educational podcasts, we'll explore how we interpret and integrate recently reported clinical research into practice. Part One involved a 72-year old man with high-risk, localized prostate cancer progressing to hormone-sensitive metastatic disease. Today's scenario focuses on de novo metastatic prostate cancer. Our guests are Dr. Kriti Mittal (UMass Chan Medical School) and Dr. Jorge Garcia (Case Western Reserve University School of Medicine). Together they present the patient scenario (1:13), going beyond the one-size-fits-all approach (4:54), and thinking about the patient as a whole (13:39). Speaker Disclosures Dr. Kriti Mittal:  Honoraria – IntrinsiQ; Targeted Oncology; Medpage; Aptitude Health; Cardinal Health  Consulting or Advisory Role – Bayer; Aveo; Dendreon; Myovant; Fletcher; Curio Science; AVEO; Janssen; Dedham Group  Research Funding - Pfizer Dr. Jorge Garcia:  Honoraria - MJH Associates: Aptitude Health; Janssen Consulting or Advisor – Eisai; Targeted Oncology Research Funding – Merck; Pfizer; Orion Pharma GmbH; Janssen Oncology;  Genentech/Roche; Lilly  Other Relationship - FDA Resources  ASCO Article: Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019 ASCO Course: How Do I Integrate Metastasis-directed Therapy in Patients with Oligometastatic Prostate Cancer? (Free to Full and Allied ASCO Members) If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT Disclosures for this podcast are listed on the podcast page.  Dr. Kriti Mittal: Hello and welcome to this episode of the ASCO Education Podcast. Today, we'll explore how we interpret and integrate recently reported clinical research into practice. In a previous episode, we explored the clinical scenario of localized prostate cancer progressing to metastatic hormone-sensitive disease. Today, our focus will be on de novo metastatic prostate cancer. My name is Kriti Mittal and I am the Medical Director of GU Oncology at the University of Massachusetts. I am delighted to co-host today's discussion with my colleague, Dr. Jorge Garcia.  Dr. Garcia is a Professor of Medicine and Urology at Case Western Reserve University School of Medicine. He is also the George and Edith Richmond Distinguished Scientist Chair and the current Chair of the Solid Tumor Oncology Division at University Hospitals Seidman Cancer Center.  Here are the details of the patient case we will be exploring: The patient also notes intermittent difficulty in emptying his bladder with poor stream for the last six months. A CT scan of the abdomen and pelvis demonstrates enlarged prostate gland with bladder distension, pathologically enlarged internal and external iliac lymph nodes, and multiple osteolytic lesions in the lumbar sacral, spine, and pelvic bones. A CT chest also reveals supraclavicular lymphadenopathy and sclerotic foci in three ribs. So this patient meets the criteria for high-volume disease and also has axial and appendicular lesions.  The patient was admitted for further evaluation. A bone scan confirmed uptake in multiple areas identified on the CT, and a PSA was found to be greater than 1500. Biopsy of a pelvic lymph node confirmed the diagnosis of prostate cancer. This patient is somewhat different from the first case we presented in terms of timing of presentation; this patient presents with de novo metastatic high-volume disease, in contrast to the first patient who then became metastatic after undergoing treatment for high-risk localized disease.  Would you consider these two cases different for the purposes of dosing docetaxel therapy when you offer upfront triplet therapy combinations?  Dr. Jorge Garcia: That's a great question. I actually do not. The natural history of someone with localized disease receiving local definitive therapy progressing over time is different than someone walking in with de novo metastatic disease. But now, with the challenges that we have seen with prostate cancer screening, maybe even COVID, to be honest with you, in North America, with the late care and access to testing, we do see quite a bit of patients actually walking in the office with de novo metastatic disease. So, to me, what defines the need for this patient to get chemotherapy is the volume of his disease, the symptoms of his disease – to be honest with you – and the fact that, number one, he is clinically impaired. He has symptomatic disease, and he does have a fair amount of disease, even though he may not have visceral metastasis. Then his diseases give him significant pain.  Oral agents are very good for pain control. I'm not disputing the fact that that is something that actually these agents can do. But I also believe I'm senior enough and old enough to remember that chemotherapy, when it works, can actually really alleviate pain quite drastically. So for me, I think that the way that I would probably counsel this patient is to say, "Listen, we can give you ADT plus an oral agent, but I really believe your symptomatic progression really talks about the importance of rapid control of your disease.” And based upon the charted data from the United States, and equally important, PEACE-1, which is the French version of ADT, followed by abiraterone, if you will, and certainly ARASENS is the standard of care for me for a patient like this will be triple therapy with ADT and docetaxel.  What I think is important for us to remember is that, in ARASENS, it was triple therapy together. I am worried sometimes about the fatigue that patients can have during the first six cycles of docetaxel. So oftentimes, I tell them if they're super fit, I may just do triple therapy up front, but if they I think they're going to struggle, what I tell them is, "Hey, we're going to put you on ADT chemotherapy. Right after you're about to complete chemo, we'll actually add on the darolutamide." So I do it in a sequence, and I think that's part of the data; we just still don't know if it should be given three at front or ADT chemo, followed by immediately, followed by an ARI. So I love to hear if that's how you practice or you perhaps have a different thought process. Dr. Kriti Mittal: So I usually start the process of prior authorization for darolutamide the day I meet them for the first time. I think getting access to giving docetaxel at the infusion center is usually much faster than the few weeks it takes for the prior authorization team to get copay assistance for darolutamide. So, in general, most of my patients start that darolutamide either with cycle two or, depending on their frailty, I do tend to start a few cycles in like you suggested. I've had a few patients that I've used the layered-in approach, completing six cycles of chemotherapy first and then layering in with darolutamide.  I think conceptually the role of intensifying treatment with an androgen receptor inhibitor is not just to get a response. We know ADT will get us a PSA response. I think the role of an androgen receptor inhibitor is to prevent the development of resistance. So, delaying the development of resistance will be pertinent to whether we started with cycle one, cycle six, or after. So, we really have to make decisions looking at the patient in front of us, looking at their ECOG performance status, their comorbidities, and frailty, and we cannot use a one-size-fits-all approach.  Dr. Jorge Garcia: Yeah, I like that and I concur with that. Thank you for that discussion. I think that you may recall some of our discussions in different venues. When I counsel patients, I tell the patients that really the goal of their care is on the concept of the three Ps, P as in Peter. The first P is we want to prolong your life. That's the hallmark of this regimen, the hallmark of the data that we have. That's the goal, the primary goal of these three indications is survival improvement. So we want to prolong your life so you don't die anytime soon from prostate cancer.  The second P, as in Peter, is to prevent, and the question is preventing what? We want to prevent your cancer from growing, from growing clinically, from growing radiographically, and from growing serologically, which is PSA and blood work. Now, you and I know and the audience probably realize that the natural history of prostate cancer is such that traditionally your PSA will rise first. There is a lead time bias between the rise and the scan changes and another gap in time between scans and symptoms. So it's often not the case when we see symptomatic disease preceding scans or PSAs, but sometimes in this case, it's at the same time. So that is the number one. And as you indicated, it's prevention of resistance as well, which obviously we can delay rPFS, which is a composite endpoint of radiographic progression, symptomatic progression, and death of any cause.  But the third P is I called it the P and M, which is protecting and maintaining, and that is we want to protect your quality of life while we treat you. And we want to maintain your quality of life while we treat you. So to me, it's critically important that in addition of aiming for an efficacy endpoint, we don't lose sight of the importance of quality of life and the protection of that patient in front of us. Because, undoubtedly, where you get chemo or where you get an oral agent, anything that we offer our patients has the potential of causing harm. And I think it is a balance between that benefit and side effect profile that is so critically important for us to elucidate and review with the patient.  And as you know, with the charted data, Dr. Alicia Morgans now at Dana-Farber, published a very elegant paper in JCO looking at the impact of docetaxel-based chemotherapy as part of the charted data in the North American trial and into quality of life. And we clearly define that your quality of life may go down a bit in the first few months of therapy, predictably because you're getting chemotherapy. But at the end of the six months, nine months, and certainly at the end of a year mark, the quality of life data for those who receive ADT and chemotherapy was far better than those who actually got ADT alone.  Now, if you look at the quality of data for RSNs, a similar pattern will appear that although chemotherapy is tied to misconceptions of significant toxicity, in our hands, in good hands, and I think our community of oncology in North America are pretty familiar with the side effects and how to manage and minimize side effects on chemotherapy, I think it still requires a balance and a thoughtful discussion to make sure that we're not moving forward chasing a PSA reduction at the expense of the quality of life of the patient. So I think orchestrating that together with the patient as a team is critically important as well.  Dr. Kriti Mittal: Thank you, Dr. Garcia. Moving on to the next concept we'd like to discuss in today's podcast the role of PARP inhibitors. Case Two was treated with androgen deprivation docetaxel and darolutamide. Consistent with current guidelines, the patient was also referred to germline testing and was found to be BRCA 2-positive. The patient's disease remained stable for 24 months, at which time he demonstrated disease progression, radiographically and clinically, and his disease was termed castration-resistant. There has been a lot published in the last few years regarding the role of PARP inhibitors in metastatic castration-resistant prostate cancer, or mCRPC.  The PROfound trial led to the approval of olaparib in patients with deleterious mutations in HRR genes for those who had been treated previously with AR-directed therapy. The TRITON2 trial led to the approval of rucaparib in the same month for mCRPC patients with BRCA mutation for those patients who had previously been treated with AR inhibitors and taxine-based chemotherapy. More recently, we saw data from the TRITON3 trial exploring the role of rucaparib versus physicians' choice of docetaxel versus AR-inhibitor therapy in the mCRPC space for patients harboring BRCA 1, BRCA 2, or ATM mutation. Based on these data, it would be very tempting to offer a PARP inhibitor to the patient in case two. While regulatory authorities are still reviewing those data for approval, how would you consider treating this newly castrate-resistant patient in the frontline setting? Would you consider a PARP inhibitor in the frontline treatment of mCRPC in this patient with a BRCA 2 mutation? Dr. Jorge Garcia: So that's a loaded question, to be honest with you. We have compelling data, but controversial data, as you know as well. So I think that since we have a genomic profile on this patient and we know he had high volume disease, then the first thought to me is not a genetic or a genomic question or a sequence. It's actually a clinical question, to be honest with you. And that is: How are you progressing? Because I think that if you're progressing serologically, you and I may think of that patient differently. If you're progressing radiographically with alone plus minus PSA production but no symptoms, you may also tilt your scale into this life-prolonging agents in a different way. Whereas if you have true symptomatic disease, knowing what you know, prior therapy, CrPC with a BRCA 2 alteration, then you may actually go for something different.   So if it's a rising PSA, if it is radiographic, but the patient is stable clinically, is not basically compromised by symptomatic disease, I do feel that a PARP inhibitor as a single agent would be a very reasonable choice. In this case, you can use, obviously, rucaparib. You can use olaparib. I don't have a vested interest in either/or. I think either/or is fine. The subtleties and side effects, as you know, the olaparib data was probably the data that you and I probably are more accustomed to, used to the most just by virtue of how the agents got registered in the United States. But either/or, I think a PARP inhibitor would be a reasonable approach.   I think the question perhaps, and I pitch that back to you, is what are you looking for with a PARP inhibitor? Because, as you know, all DNA repair deficiencies are not biologically the same. They do not respond the same way to PARP inhibitors. And even BRCA 2, where we think it's monoallelic or biallelic, may have subtleties in how those patients respond to PARP therapy. But the answer is yes, obviously, you have a biomarker, the patient has it, you can use it. I think the question is, how are you going to follow the patient? And what is going to be the endpoint that you're going to pay attention to in this case to find that the patient has a benefit or not granted, that could be PSA driven, but I think that perhaps I'm pushing you to think beyond PSA.  Dr. Kriti Mittal: I agree, Dr. Garcia. I think we need to think about the patient as a whole. PSA-based changes in treatment are not generally part of our practice. I think evaluating the patient for symptoms and also thinking about the sites of progression, sites of disease they've had in the past, preventing development of cord compression, because some of these patients progress very rapidly and present with cord compression at the time of progression. Those are the things we are trying to predict and prevent. I think in a patient with BRCA 2 mutation, in this situation, I would feel compelled to offer rucaparib, given that even in the intention-to-treat analysis, the hazard ratio was 0.6 in terms of median progression-free survival. I think what was quite impressive was the subset analysis comparing rucaparib versus docetaxel. And that was something surprising. And I think we'll have to wait for long-term outcomes. But certainly, for a BRACA 2-mutated patient, this could be a reasonable consideration provided the drug is available and approved.  Dr. Jorge Garcia: As you know, the three most common DNA repair deficiencies that we see are BRCA1, BRCA2, and ATM. BRCA2 is probably the one that we see the most. But we also recognize that with the limited data we have for ATMs, that patients with an ATM abnormality do not tend to benefit the most. And then yet we have also another series of DNA repair deficiencies, deficiencies, PALB2, CHEK2, CDK12 and so forth. And yet we have some exquisite responses to some of those patients.   So I can tell you that I have a patient of mine who had an ATM mutation, a germline ATM mutation, and I predicted that initially that the likelihood of benefit to a PARP inhibitor would be low. He was placed on a PARP inhibitor and surprise, surprise, he was on a PARP inhibitor for almost a couple of years. What I want to convey to the audience is that if you have the appropriate biomarker, you certainly should consider a PARP inhibitor in this scenario.   I think the bigger question is also understanding that not every DNA repair would benefit the same way. So being very thoughtful and very structured as to how you're going to manage the patient, it cannot be PSA only, the patient has to be followed radiographically and clinically because I would argue that if this patient had just a serologic progression, I would put the patient on a PARP inhibitor and the PSA kinetics change north, but slowly, what is the urgency of you switching the patient to something else?   And also the misconception that if you look at PROfound, that olaparib for that matter has to always be given after docetaxel. That's not the case. The makeup of PROfound is different than this patient, obviously, because this patient got triple therapy upfront, whereas most patients on the PROfound were CRPC who receive chemotherapy in the CRPC space. But yet undoubtedly, I think that your case illustrates the importance of next-generation sequencing and the importance of understanding the access to two oral PARP inhibitors that are super solid.  I think that perhaps the bigger question is going to be should you do a PARP inhibitor alone or should we use a combination of a PARP inhibitor plus an oral agent, such as in this case, maybe abiraterone acetate plus olaparib. Or maybe even thinking of TALAPRO, maybe enza plus a PARP inhibitor. So I don't know where you sit on those thoughts, Doctor-. Dr. Kriti Mittal: I change toxicity considerations, temper my enthusiasm for offering PARP inhibitors in combination with AR inhibitors or abiraterone at this time. I think I would certainly consider monotherapy with rucaparib for a patient in this situation. I am not entirely convinced that putting a patient through dual treatment in the mCRPC setting in the frontline, I don't think we are there yet. Dr. Jorge Garcia: There are two very important trials that are looking at the combination of an adrenal biosynthesis inhibitor plus olaparib in this context, and one is PROpel and the other one is MAGNITUDE. And both trials have very different results in many ways because they look at patients with a biomarker, meaning DNA repair, and patients without the biomarker. And I think the bigger question is, should this patient who was an abiraterone– Let's say this patient hypothetically was on a PEACE-1-like style. So the patient got ADT or triple therapy but was an abiraterone or an adrenal biosynthesis inhibitor instead of chemotherapy. And the patient was progressing slowly on abiraterone, you knew that the patient had a DNA repair deficiency. How comfortable with the PROpel and MAGNITUDE data would you and I feel to add on or layer, if you allow me to express it like that, a PARP inhibitor into this regime? Dr. Kriti Mittal: My personal interpretation of the currently available data is that at this point, combination therapy is not something I would use in my clinical practice. I think there are two camps in the GU oncology community of how people interpret the PROpel, MAGNITUDE, TRITON, and TALAPRO data in full. I think each of these trials had very different patient populations. I think in a biomarker unselected population, I would certainly not advocate for combination therapy. But even in the biomarker-selected population, I think how the biomarkers were tested and how the populations were defined may not always match what we are doing in clinical practice. And so I would, at this time, advocate for monotherapy over combination therapy. Dr. Jorge Garcia: I'm sure the audience will have probably read or heard about PROpel and MAGNITUDE and the data in patients without a biomarker positivity disease. So I'd love to hear your thoughts as to if you had no biomarker. By that I mean if you had a patient with CRPC, with metastatic CRPC without a DNA repair deficiency, would you consider using an adrenal biosynthesis inhibitor and a PARP inhibitor together based upon the potential synergistic of additive benefits and some of the data to suggest that you can delay rPFS when you combine therapy, but in the absence of biomarker positivity. Dr. Kriti Mittal: In the absence of biomarker positivity, I think the preclinical data are stronger than the clinical results we are seeing in trials. So while I think we should continue researching further into this because there certainly is preclinical rationale, looking at the clinical outcomes from these several trials, I would not offer PARP inhibitor to an unselected patient. Dr. Jorge Garcia: Great. Dr. Kriti Mittal: Moving on to second-line treatment for castration-resistant prostate cancer. I think talking of access issues and talking about the current treatment paradigms in the United States, there is still not widespread availability of lutetium. The listeners would love to hear your thoughts, Dr. Garcia, on practical management tips, safety issues, and the multidisciplinary nature of the management of lutetium therapy.  Dr. Kriti Mittal: So I think the challenges with lutetium are multiple. Number one is the correct identification of the patient, the ideal patient for lutetium. Secondly is who manages the patient and as you indicated, the importance of a team approach in that. Thirdly is how do we follow that patient during therapy? So it's beyond the technical aspects of who infuses the patient. Fourthly is what are the true goals of lutetium for that patient population and the side effects that those patients may embark on that some people may not be fully aware of and creates complexity. And lastly, perhaps, is how the movement, how we develop lutetium in CRPC and how we're going to move lutetium or have started to move lutetium and alike, meaning radiopharmaceuticals, radioligand-based therapies outside lutetium opinion and others as you know, earlier into the natural history of prostate cancer, maybe even in the locally advanced disease in combination with radiation or for patients with N1 positive disease. So it's a lot of movement in that space. I think that this is just the beginning of radiopharmaceutical entering diagnostics. But let me just address this succinctly, if I may. Number one, you do need a PET PSMA in order for you to select the patient because we're talking about a potential biomarker. But this is what I call an imaging biomarker. If you see it, you treat it.  So the standard of care right now for lutetium is very simple: you need to have men with metastatic castration-resistant prostate cancer. Two, you need to have failed a prior oral agent, in this case, a novel hormonal agent, independent of which agent you have seen, independent of the timing when you have seen an oral agent at the front, the middle, the end. And lastly, you have to have progress through chemotherapy. Yet again, it depends on when you see chemo.  So if you have someone who has high volume metastatic disease from the beginning, de novo disease, and you got ADT, daro, and docetaxel, and the patient progresses, that patient can go on. If that patient has a positive PSMA PET, that patient can go on to get lutetium. Similarly, if you have someone who got ADT alone in the adjuvant space for radiation therapy, progress, got an oral agent, progress, got a PARP or not, or got docetaxel, that patient could also be a candidate for lutetium. It's dependent on how you run the patient through therapy.  Secondly is who gives lutetium? So I do believe, and I may be biased, I certainly believe in the importance of a team approach with radiation oncology and nuclear medicine. But the reality of it is, I believe these patients are so advanced in their stage of their disease, then the idea of quarterback, in my personal opinion, resides in medical oncology. And I think the bigger question is going to be if nuclear medicine at your given institution is going to be delivering lutetium, or is it going to be radiation oncology? And I think, as you know, in places in America, it's RadOnC, in other places is NucMed, in our institution right now it is NucMed. Having said that, I do predict that for those places where nuclear medicine is heavily involved in delivering lutetium or partnering with MedOnc to deliver lutetium, radiation oncology in the future will have a bigger role as well because we are moving lutetium earlier in settings where radiation oncology is commonly used, such as high-risk prostate cancer patients, or even in the salvage setting, or even in patients with metastatic disease, where we want to combine radiation and lutetium, which are part of clinical trials as we think through for the future. But either/or, I think the quarterback should be really MedOnc in this case.  Thirdly is how do we do it? So clearly, at least in my practice, and I think it's probably standard across the United States, MedOnc will see the patient, determine viability and feasibility of therapy, determine who's the ideal candidate, discusses the pros and the cons, and then works along with RadOnc or NucMed to start the process. As you know, it is once every six weeks. So here in my practice, we will see the patient every time before treatment. Sometimes we see them the day off, sometimes we see them a few days before. Patients will get blood work. Specifically, we're interested in seeing everything CMPs, but certainly blood counts, red cell counts, platelets, and white cell counts, just to make sure that patients do not start with impaired bone marrow that can increase the risk for myelosuppression and therefore significant challenges with side effects, hematologic side effects, specifically. And we do that.   Sometimes we see them, sometimes our nurse practitioners would do so. And then the patient will basically follow through and complete up to six cycles of treatments. Six times six, that's actually 36 weeks or so. That's a long time on therapy for those who can get six cycles. I think the question becomes how do you follow those patients? And if we pay attention to the VISION data, as you know, those patients were actually followed serially quite closely on trial every eight weeks for the first 24 weeks, and then they stretch the scans out. But the scans that we're using in the trial are conventional imaging.  And I think the bigger question that you and I will have is if we get a PET PSMA to use to make that decision to get on lutetium PSMA, should I go back and use a CT or so to stage the patient? I think we're moving more toward PET follow-up, but we also don't know fully the impact of lutetium PSMA on PSMA metabolically during treatment. I think that we all recognize anecdotally and at least with some of the emerging data and we have the SUV may change, that PSA reductions also appear to be important as to define who is likely to benefit or not. But those are questions that remain to be seen, to be honest with you. We follow the patients serologically, clinically, and radiographically. And at least in my group, we tend to do PSMA PETs in between therapy to ascertain the impact of therapy in radiographic and also metabolic changes. And lastly is how we manage side effects. So I think that I'm pretty OCD about these patients because I have seen in my practice patients having outstanding responses to therapy but unfortunately become transfusion dependent, either transiently or permanently, just by virtue of side effects. And I think the importance of understanding the most common side effects of lutetium, in this case fatigue, myelosuppression, xerostomia, are really, really important. And that is the importance of having a multi-team effort approach so everybody is fully aware of the baseline characteristics of that patient or how the patient is enduring therapy and how the therapy is impacting the quality of life and impacting bone marrow production for those patients.  I think I remind the audience that the vast majority of our patients do have bone metastases. In fact, in the VISION trial it was around what, over 85, 90% of patients are so with bone metastases. So their marrow has already been impacted not only by disease but equally importantly by the prior chemotherapy that they may have seen. And some of the patients that we have in the first bubble effect is they have seen probably docetaxel, some may even have seen dual therapy with cabazitaxel as a second-line chemotherapy. So I think the understanding as to how you manage the side effects is critically important for our patients as well.  Dr. Kriti Mittal: Those are very relevant, practical life issues. Thank you Dr. Garcia for a terrific discussion on the application of recent advances in prostate cancer to clinical practice. [28:54] The ASCO Education podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncologists' well-being and professional development. If you have an idea for a topic or a guest you'd like to see on the ASCO Education Podcast, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, please visit education.asco.org. Dr. Jorge Garcia: Thank you, Kriti. It's great to see you and thanks again to ASCO for the amazing opportunity to be here with you guys today. I hope the audience can see the benefit of understanding how the many changes we have seen have impacted our patients in a positive way. So thank you again for the opportunity. Dr. Kriti Mittal: Thank you, Dr. Garcia, and thank you so much to the ASCO team for inviting me. This was a great experience.  Thank you Dr. Garcia for sharing your perspective on incorporating recent research advances into the management of patients with de novo metastatic prostate cancer. The ASCO Education Podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncologists' well-being and professional development. If you have an idea for a topic or a guest you'd like to see on the ASCO Education Podcast, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, please visit education.asco.org. 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, experiences, 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.    

Drs. Rana McKay and Jonathan Rosenberg highlight key advances in genitourinary cancers featured at the 2023 ASCO Annual Meeting, including the THOR study in mUCC, VESPER in muscle-invasive bladder cancer, CONTACT-03 in mRCC, and TALAPRO-2 in mCRPC. TRANSCRIPT  Dr. Rana McKay: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Rana McKay, your guest host for the podcast today. I'm a GU medical oncologist at the Morris Cancer Center at the University of California in San Diego and an associate professor at the University of California in San Diego School of Medicine. Joining me today is Dr. Jonathan Rosenberg, the chief of the Genitourinary Oncology Service at the Memorial Sloan Kettering Cancer Center in New York. We'll be discussing practice-changing studies and other key advances in genitourinary cancers that were featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests featured on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.  Jonathan, it's great to have you with us today. How are you?  Dr. Jonathan Rosenberg: I'm doing very well. Thanks so much for hosting today.  Dr. Rana McKay: Oh, of course. It's always fun to step back from ASCO and reflect on all the practice-changing and practice-informing studies that were presented.  Dr. Jonathan Rosenberg: Absolutely.  Dr. Rana McKay: Maybe we can dive right in with LBA4619. This is the much-talked-about THOR study of erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer with select FGFR alterations. What are your key takeaways from this study?  Dr. Jonathan Rosenberg: It is indeed a study we've been waiting for, for quite some time, to see the results in the confirmatory study after the accelerated approval of erdafitinib. This is half of the THOR trial. There were 2 cohorts of patients. One cohort were patients who previously received a checkpoint inhibitor randomized to chemotherapy or erdafitinib, and those data were reported at ASCO this year. The other cohort was randomized against a checkpoint inhibitor in patients who have not received a checkpoint inhibitor, and we'll see those data in a future meeting.   The bottom line for the THOR study is that FGFR3 inhibition improved overall survival compared with chemotherapy, and the chemotherapy in this study was a taxane. The overall survival was 12.1 months for erdafitinib compared to 7.8 months for chemotherapy with a hazard ratio of 0.64. This led to the DMC to stop the study and blind the data and cross people over. There was also a PFS advantage. There really weren't a lot of new toxicity signals seen; the usual suspects in terms of mucositis, hyperphosphatemia, diarrhea, dry mouth, and onycholysis.  And so, what it tells us ultimately is that in a patient who's progressed on a checkpoint inhibitor, we can feel comfortable about using erdafitinib knowing it provides a survival advantage in patients who've been previously treated for advanced urothelial cancer and have an FGFR alteration, either an FGFR2 or 3. And hopefully, we'll see more data in the future from the study, maybe not too long in the future from the other part of the study, comparing it to checkpoint inhibition.   Dr. Rana McKay: That's really exciting. I think it's exciting to see the data about the positivity of erdafitinib versus chemotherapy in this context. Looking at the phase 3 data is going to be really important. Looking at the data in the IO naive context is going to be really important. I feel like this sort of reaffirms what we've been doing in clinical practice. But how do you feel that the study is practice-changing?   Dr. Jonathan Rosenberg: I think it gives us reassurance that for these patients, erdafitinib is an appropriate option. There's no randomized data between erdafitinib and other choices, such as sacituzumab, which is also based on an accelerated approval, or enfortumab, which is based on randomized phase 3 trial. But it gives us level-1 evidence. I do wonder whether the comparison against the checkpoint inhibitor may turn out differently, but we'll see. Those data aren't in evidence. And I do think it was interesting that the majority of patients who were enrolled on the trial were PDL-1 low. We'll see what the comparison to a checkpoint inhibitor is like and whether those patients have similar characteristics.  Dr. Rana McKay: Yeah, you're almost kind of selecting for people that were not primed to respond.   Dr. Jonathan Rosenberg: Exactly.   Dr. Rana McKay: Well, that's really exciting, I think. Moving on to localized bladder cancer, Dr. Pfister presented the results of the VESPER trial. That's LBA4507. I think this study was really important. This was a trial that explored dose-dense MVAC with methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine-cisplatin as a perioperative chemotherapy for muscle-invasive bladder cancer. I think there's always been some discussion around these regimens and how they pair up against one another. Can you tell us about these data?   Dr. Jonathan Rosenberg: It's a very interesting study. It was designed back when it was felt that we could not give patients neoadjuvant therapy. And it was designed as either a neoadjuvant or adjuvant approach. Although, in reality, almost everybody who was enrolled in the study got neoadjuvant chemotherapy, which I think speaks to the shift in practice over the last 10 to 15 years towards neoadjuvant rather than adjuvant therapy. It's an interesting trial in that it used a duration of chemotherapy for the MVAC regimen, the dose-dense MVAC regimen that we don't usually use, which is 6 cycles. And functionally, about 40% of patients couldn't make it to 6 cycles and had to stop sooner, versus 4 cycles of q3-week gemcitabine and cisplatin.   And what the data show is that the progression-free survival for the entire intent-to-treat population didn't reach significance. But if you looked at the neoadjuvant population only, there was an improvement in progression-free survival as well as overall survival. So, it's sort of a negative positive trial. Negative for the primary endpoint, but positive for key secondary endpoints. They did a very interesting analysis looking at the number of cycles that patients received regardless of arm, but looking at it by arm. And it's clear from that analysis that the more chemotherapy they got, the better they did.   Although, the flaw in that analysis is that the healthier patients are, the more chemotherapy they're able to tolerate, and therefore that may translate to an improved overall survival irrespective of the amount of chemotherapy. And this was not necessarily a pre-specified analysis. I think some of the statisticians were clutching their chests during the report of this trial, having talked to several afterward. On the other hand, it does say to me that for a fit, younger patient, it is important to consider dose-dense MVAC instead of gemcitabine and cisplatin.   I'll also note, reading the publication from the first part of the trial, that it appears that nobody over 70 was enrolled from everything I could tell. And so, I question the validity of the tolerability of the results for the average 75-year-old that I see in my practice. Although age is not a bright line cut-off for anybody in terms of cancer treatment. But my own experience has been that dose-dense MVAC has been harder to tolerate for a lot of patients in their 70s, whereas I think we should feel quite comfortable giving it to patients in their sixties. And if you ask me how many cycles I would give, I probably wouldn't say 6, for dose-dense MVAC, I would probably say 4.   Dr. Rana McKay: Was there a predilection that there was a more aggressive disease like nodal disease or other things to prompt the 6 versus 4?  Dr. Jonathan Rosenberg: I think that they stopped primarily for toxicity reasons, but it wasn't clear to me that it was a disease-based issue. And for the neoadjuvant therapy, everyone was supposed to be clinically node-negative on entry, so that probably wouldn't have explained it.  Dr. Rana McKay: Very exciting. I know that the data were quite provocative, but I think it's always difficult to interpret these sorts of subgroup of subgroup analyses, and there's a lot of bias in why people may get more versus less. And I think trying to reduce these data to clinical practice is going to be really important, as you've stated.  Dr. Jonathan Rosenberg: Rana, I'd also like to talk about some key advances in renal cell carcinoma that were reported at ASCO. Dr. Choueiri presented data on LBA4500, the CONTACT-03 study, which really was the first study of its kind in solid tumors because it addressed a major question in the kidney cancer field and in other fields: Is there a role for immunotherapy rechallenge after progression on immunotherapy? Specifically, the study looked at the efficacy and safety of atezolizumab plus cabozantinib versus cabozantinib alone after progression with prior immune checkpoint inhibitor therapy in metastatic RCC. I'd like you to tell me what you think of this study and the results and how they may affect our practice.   Dr. Rana McKay: Absolutely. This was a critically important study looking at the role of IO post-progression on IO. It was a large phase 3 trial that enrolled patients with clear cell and non-clear cell patients. It actually allowed patients with papillary RCC, unclassified RCC, to enroll in the study, whereas most of these studies are excluding patients with non-clear cell disease. Patients had to have progressed on an immune checkpoint inhibitor given either as adjuvant first line or second line, given either as a single agent or in combination with one of the other combos, whether a VEGF or IO. And patients were randomized one-to-one to receive the combination of atezolizumab plus cabozantinib versus cabozantinib alone. And the dosing of the cabozantinib here is at 60 milligrams in the combination, which is the standard dosing of cabozantinib monotherapy. And the primary endpoints for the trial included PFS and OS.   And in essence, this trial was a completely negative study. The primary endpoint, which was centrally reviewed, rPFS, was negative. The hazard ratio there was 1.03. Overall survival was also negative with a hazard ratio of 0.94. And when you look at the subgroup analyses, there really wasn't any specific subgroup that seemed to derive any benefit, potentially those that had a prior response to an immune checkpoint inhibitor, but in essence, a negative study.   And I think these data are really informative because the discussion at ASCO was conducted by Dr. David Braun, and he actually had conducted a very highly scientific Twitter poll to help guide how to interpret the data and what people do. And from that, about 30% of individuals that completed the poll were actually layering on IO therapy, and continuing IO therapy after somebody progressed on therapy layering in a TKI while keeping the IO backbone going.   And I think what this study proves is that we really don't have any really robust data to guide doing that at the present time. And what we may end up doing is compromising the efficacy of the oral TKI or dose-compromising the oral TKI to try to maintain an ineffective IO. And so, I think at the present time these data, while negative, were truly practice-informing. There are other studies that are looking at this strategy as well. I think one of the criticisms here is that atezolizumab really has not had a great track record in renal cell carcinoma in every single context where it was tested, either alone or in combination. It has not met its primary endpoint and it's not utilized as a treatment in RCC. So, there's some discussion that could this be the fact that this is a PDL-1 inhibitor and that it's atezolizumab. And additionally, I think the thing to point out for is that in the modern era if we look at the cabozantinib control arm, cabozantinib in the refractory setting had a PFS of 10.8 months, which is pretty impressive for a later line PFS, if you will. So, there is another study currently ongoing called the TiNivo-2 study that's looking at tivozanib plus nivolumab versus tivozanib alone in a similar patient population. That trial is enrolling only clear cell patients that had progressed on prior IO. So, I think we'll have additional data, but very, I think, informative. I think this question comes up in a lot in other tumor sites as well because of the broad use of checkpoint inhibitors across hematologic and solid tumor malignancies.   Dr. Jonathan Rosenberg: I think this was the most informative negative study and the most negative trial I've seen in a while as well. But it did highlight the importance of asking these questions where people assume they know the answer already, and in fact, we often don't, and our assumptions are wrong. So, I thought that was fascinating and very well described.    Staying in the kidneys arena. I'd like to talk to you also about the phase 2 KEYNOTE-B61, that's Abstract 4518. It looked at first-line lenvatinib and pembrolizumab across non-clear cell carcinomas. Tell me what you thought of the trial and what your takeaways were.   Dr. Rana McKay: This is an important study. I think the treatment of non-clear cell RCC has lagged. I guess the advances have lagged behind clear cell RCC, and really robust phase 3 randomized studies in people with non-clear cell histologies are very limited. This was a single-arm phase 2, so I think we need to kind of take that for what it's worth, that enrolled patients who had non-clear cell RCC per investigator that had received no prior systemic therapy. So, this was a frontline study, and patients received pembrolizumab plus lenvatinib until disease progression or toxicity.   The study enrolled a very robust 158 patients, which is pretty impressive for a modern-day non-clear cell cohort. We've seen data from nivo-cabo that had gotten presented previously by Dr. Lee. That study was a single institution, about 40 patients or so if you will. The primary endpoint of this study was objective response rate, and the bulk of the patients that were enrolled were papillary RCC. As you would imagine, around 60% of patients were papillary. It did include around 18% with chromophobe RCC. And when we break things down by IMDC risk category, about 44% of patients were favorable-risk disease. I think the percentage of patients who were favorable is higher than if we were to take an all-comer metastatic RCC patient population.   But the objective response rate was pretty impressive at 49% with this combination. The CR rate was right around 5.7%. So, I think certainly a pretty solid signal of efficacy. But again, this is a single-arm phase 2 study. I think what's also really interesting, and I think we have to take subset analyses with a grain of salt if you will, but there were responses that were seen across all histologies. And the prior nivo-cabo study that I had shared with you had previously done a futility analysis for patients with chromophobe RCC, and that cohort actually closed down. And in this study, the response rate for the chromophobe patients, though it wasn't a lot of patients, 29 patients with chromophobia RCC, was around 27.6%, so I think these data are certainly informative. If you look at the waterfall plot, there were some deep responses that were certainly observed, and the bulk of patients had some degree of tumor shrinkage with very little patients that had primary PD.   Dr. Jonathan Rosenberg: It's really provocative. So, are we getting to a point where we might start thinking about randomized trials in the non-clear cell population to try to establish the best standard of care?  Dr. Rana McKay: Well, I think PAPMET2 is currently enrolling patients. That study is looking at the combination of cabozantinib with atezolizumab versus cabozantinib alone for frontline papillary. PAPMET1, which was led by Dr. Pal, I mean, these studies are really magnanimous because it takes all hands on deck to get these patients enrolled because they're few and far between. So, I definitely think we need to be moving in that direction. And I think we need to be moving away from lumping all non-clear cells into one bucket because I think what we're seeing is that, one, the biology of these tumors is very distinct and unique, and they don't all behave the same to any one given therapy. So, we really need to move away from just lumping all non-clear cells into one bucket and try to actually conduct studies for each specific subtype.    Dr. Jonathan Rosenberg: Understood and agree. Let's switch gears for a second and talk about prostate cancer. Can you talk about the data from Abstract 5004, the TALAPRO-2 study of talazoparib and enzalutamide compared to placebo and enzalutamide as a first-line treatment with metastatic CRPC that have HR homologous recombination repair gene alterations?    Dr. Rana McKay: Absolutely. So the TALAPRO-2 study is one of three studies that have looked at the combination of PARP inhibitors with an ARSI in the frontline mCRPC setting. And this trial randomized patients to talazoparib and enzalutamide versus placebo enzalutamide. And again, this was first-line mCRPC. Patients were allowed to have received prior docetaxel or prior abiraterone in the castration-sensitive setting, and the primary endpoint was overall survival.  At GU ASCO this year, we saw the top-line data from TALAPRO-2 first get presented. And what was actually presented at this meeting was the subset of patients that were HRR-mutated only. They had two cohorts: an all-comer cohort that was previously presented, and then now they're presenting the subset of the patients that were HRR-mutated. And I think what we've seen across the board is that the efficacy of PARP inhibitors kind of differs by underlying HRR mutations.     When we look at the entire population of HRR-deficient patients, the study was positive, talazoparib plus enzalutamide resulted in an improvement in rPFS compared to enzalutamide placebo. The hazard ratio there was 0.45. And then when we break things down by selected gene groups, they did this subset analysis in patients with only BRCA1, only BRCA2, only PALB2, only CDK12, ATM CHEK2 if you will. The data are most robust for those patients with a BRCA1/2 alteration with hazard ratios of 0.17, 0.19. Again, this is for rPFS.     But then, when we look at some of these other mutations, like ATM CHEK2, hazard ratios are higher, 0.76, 0.90. So, the effect size really kind of drops off for those non-BRCA1/2 altered HRR genes. But if we look across the different subgroup analyses, the interim OS data for the HR deficient, the time to PSA, time to cytotoxic chemo, all of that favored the combination versus placebo enzalutamide for patients that were HR deficient if we just lumped everybody all together.  Dr. Jonathan Rosenberg: How does this fit into the general landscape around this question with selection versus not selecting for HRR alterations?  Dr. Rana McKay: The data that were presented were for the selected patients, and I think that that's not where the controversy is. I think that the selected patients are the ones that seem to derive the most benefit. It's interesting because in looking at the data from PROpel and the final FDA label based off of the PROpel data, the label is only for BRCA1 and 2 patients and not for all comer HRR. It's even a more restricted label than olaporib monotherapy. So, I think it's going to be interesting. I don't know what the right answer is. I think it's going to be interesting to see how this is going to unfold for TALAPRO-2 and even for MAGNITUDE, if you will, like, how select is the selected population going to be. But at the present time, I think the label is what it is for olaparib plus abiraterone in those BRCA1/2 frontline. My hope is that this population is shrinking because everybody should be getting escalated in the metastatic hormone-sensitive setting, and we shouldn't be having people who are naive to an ARSI in frontline mCRPC.  Dr. Jonathan Rosenberg: Understood and agreed.   Dr. Rana Mckay: Well, thank you so much, Jonathan, for joining me today. It's really been a pleasure kind of going through all of the compelling advances in GU cancers from ASCO. I think it was a really exciting meeting, and thanks for your time. Dr. Jonathan Rosenberg: My pleasure. It's been great to talk to you today.     Dr. Rana Mckay: And thank you to our listeners for your time today. You will find links to the abstracts 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 podcast.    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. Guests' 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. Rana McKay  @DrRanaMcKay  Jonathan Rosenberg  @DrRosenbergMSK    Follow ASCO on social media:     @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:    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   Dr. Jonathan Rosenberg:   Honoraria: UpToDate, Medscape, Peerview, Research To Practice, Clinical Care Options, Physician Education Resource, MJH Life Sciences, EMD Serono, Pfizer  Consulting or Advisory Role: Lilly, Merck, Roche/Genentech, AstraZeneca/MedImmune, Bristol-Myers Squibb, Bayer, BioClin Therapeutics, QED Therapeutics, Pharmacyclics, GlaxoSmithKline, Janssen Oncology, Astellas Pharma, Boehringer Ingelheim, Pfizer/EMD Serono, Merck Therapeutics, Immunomedics, Tyra Biosciences, Infinity Pharmaceuticals, Gilead Sciences, Hengrui Pharmamedical, Alligator BioScience, Imvax  Research Funding (Institution): Genentech/Roche, Seattle Genetics, Bayer, AstraZeneca, QED Therapeutics, Astellas Pharma  Patents, Royalties, Other Intellectual Property (Institution): Predictor of platinum sensitivity      

Drs. John Sweetenham and Marc Braunstein discuss advances in hematologic malignancies featured at the 2023 ASCO Annual Meeting, including the potentially practice-changing SWOG-S1826 study in Hodgkin lymphoma, the promise of bispecific antibodies in B-cell malignancies, and a novel approach to deliver vital anti-myeloma medications that could improve patient quality of life and alleviate barriers to care. TRANSCRIPT   Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and the host of the ASCO Daily News Podcast.    The 2023 ASCO Annual Meeting featured some exciting new data on hematologic malignancies. I'm delighted to have Dr. Marc Braunstein return to the podcast to discuss some of these potentially practice-changing studies and new approaches in the heme space. Dr. Braunstein is a hematologist and oncologist at the NYU Perlmutter Cancer Center.    You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.   Marc, it's great to have you back on the podcast, and thanks for being here again.   Dr. Marc Braunstein: Thank you, John. It's great to be back.   Dr. John Sweetenham: Marc, we already mentioned that there are some potentially practice-changing studies that were reported at ASCO this year. And among those, LBA4, which was presented in the Plenary Session, was a study which explored the treatment of advanced Hodgkin lymphoma. This was the Southwest Oncology Group study S1826. Could you give us your insights on this?    Dr. Marc Braunstein: Sure, happy to discuss S1826. So as background, you know, the ECHELON-1 study, which was published in the New England Journal of Medicine in 2022 showed a 40% decrease in the risk of death at six years follow-up by adding brentuximab to AVD compared to bleomycin AVD. And that was in high risk or advanced-stage patients and that led to adoption of brentuximab for upfront use in patients with classical Hodgkin lymphoma in advanced stage.    Also of note, immune checkpoint inhibitors such as pembrolizumab or nivolumab do have activity in the relapse setting. The SWOG S1826 study was a randomized control study looking at the use of the PD-1 inhibitor nivolumab plus AVD versus brentuximab AVD in patients with advanced stage classical Hodgkin lymphoma who are at least twelve years of age. And the primary endpoint in the study was progression-free survival.     It was a large study which enrolled 976 patients and randomized them one to one to either nivo AVD or brentuximab AVD. The median age in the study was 27 and the median follow-up was 12 months. And what the study found, which could be practice-changing, was that the primary endpoint of progression-free survival was superior in the nivolumab arm with a hazard ratio of 0.8 and a one-year PFS of 94% versus 86%, favoring the nivolumab arm. And while there were side effects associated with the class of medications, for example, hypo or hyperthyroidism was more frequent in the nivolumab group, whereas peripheral neuropathy was higher in the brentuximab group, I think that these results are particularly encouraging for how we can continue to improve outcomes for patients with advanced-stage classical Hodgkin lymphoma. And this may be practice-changing in terms of whether we use upfront immune checkpoint inhibitors in combination with our standard chemotherapy backbone.    Dr. John Sweetenham: Yeah, absolutely. There are a couple of things that occur to me. One in particular which is unique about this study, and the fact that it was for patients who are 12 years and older in many respects represents a first because I can't think of another large, randomized study of this type which has attempted to align pediatric and adult care of patients with Hodgkin lymphoma. So, I think it's something of a landmark in that regard. I don't know if you'd agree with that.    Dr. Marc Braunstein: I agree, especially with the range of ages from 12 to 83. It's a pretty broad population by age, but I agree it does kind of reconcile those two groups in a disease that has a bimodal presentation and clearly shows that immune checkpoint inhibitors are both potent and well tolerated in different age groups.    Dr. John Sweetenham: The other question that I have about this study is we haven't seen so far in this study an overall survival benefit to the nivo arm, which is maybe not surprising, but in terms of the practice-changing potential of this study, do you think that will matter?   Dr. Marc Braunstein:  I think that's an excellent question, John. Initially, the ECHELON-1 study only showed progression-free survival, and then the update did show overall survival. And so if we take the lead from that study, we expect to see an overall survival benefit in the SWOG study as well with nivolumab, but it remains to be seen. But I think that the data presented thus far at the Plenary Session is compelling enough to consider using nivolumab upfront.   Dr. John Sweetenham: Yeah, I absolutely agree. And then I guess the other question that we're going to have to wait probably several years to know is what happens in terms of relapse? So, for the minority of these patients who do relapse, how salvageable, if that's the right word, are they going to be with a second- or third-line regimen? But I think that's clearly something for the future, and it's a very interesting, exciting outcome from this study.   Dr. Marc Braunstein: Absolutely.    Dr. John Sweetenham: Let's move on. Marc, again, we're still in the lymphoma world here, but looking at high-risk follicular lymphoma. And this was Abstract 7506, looking at epcoritamab plus the R2 regimen in patients with follicular lymphoma. Could you walk us through this one?    Dr. Marc Braunstein: Yeah, absolutely. Bispecific T-cell engaging antibodies are showing impressive efficacy in relapsed and refractory non-Hodgkin lymphoma. Epcoritamab is a bispecific antibody that binds to CD3 on T-cells and CD20 B-cells. And this antibody is currently approved for diffuse large B-cell lymphoma patients after two or more prior lines of treatment.    In this study presented by Merryman and colleagues, they explored the addition of epcoritamab to standard lenalidomide-rituximab. In 109 patients with relapsed or refractory follicular lymphoma who had at least one prior therapy, and, of note, the study was enriched for high-risk patients for progression, including those who had progression of disease within 24 months of their initial treatment and those patients who had been refractory to prior anti-CD20 treatment. This study enrolled 109 patients with relapsed refractory follicular lymphoma. The median age was 65 and 56% of patients had FLIPI scores on the higher end of the spectrum from three to five, and 61% had stage 4 disease. Also of note, 38% of patients had progression of disease within 24 months of their prior treatment. So at a median follow-up of 8.8 months, the overall response rate was impressive at 97%, and 82% of patients were still on treatment at that time.     Now, of course, with this mechanism of action of bispecific antibodies, there is a risk of both cytokine release syndrome and immune-related neurotoxicity. The rates of CRS were primarily low grade, there were only 2% grade 3, and of note, most occurred after the first dose. And in terms of ICANS or neurological toxicity, there were no grade 3 adverse events, and those occurred in only two patients. Finally, the estimated six months progression-free survival was 93%. So, if we cross-compare these results historically to the R-squared regimen, which was published to be about 80%, just cross comparing, so it's not exactly the same study, this clearly shows high activity on par or better with R-squared alone. Although this study was not a randomized study, I think the addition of epcoritamab certainly shows high overall response rates and we'll need randomized data to confirm the efficacy, but it's definitely encouraging in high-risk follicular lymphoma patients.   Dr. John Sweetenham: Thanks, Marc. I agree. I think these data are really enticing, in as much as the response rates are so high, but of course, it is follicular lymphoma, so we'll have to wait a while. But the thing that it does make me reflect on is that bispecific antibodies really are turning out to be remarkably effective in a range of B cell malignancies, so, it's very interesting to continue to watch this space.    I'm going to change gears now and talk about something completely different for a moment. And this was Abstract 1536. I think that many of us are in a position where we're now looking at how we deliver our clinical services, and particularly inpatient services, to patients with hematologic malignancy. And this study addressed that very specifically. Can I have your thoughts on that?   Dr. Marc Braunstein: Sure. In the context of how our therapies are improving, our approaches to how we manage patients clinically is changing too, in many ways for the better. So, various models exist for, you know, which practitioners manage oncology patients who happen to be admitted to the hospital. This abstract, which was performed by authors at a large medical center in New York, describes the use of a dedicated hematologic malignancy hospitalist for managing medicine-related issues. And the authors did comparisons of that service to a service primarily managed by oncologists. The authors compared things such as length of stay, whether the patients were discharged by noon, which is a hospital metric that's used for facilitating turnover of patients and space availability, as well as 30-day readmission rates among patients cared for by an oncology attending versus this heme malignancy hospitalist between July of 2021 and July 2022.    The outcomes showed that admissions to the heme malignancy hospitalists were, although less because that service was primarily for patients who required medicine-related issues as opposed to primarily oncologic issues, there were 95 admissions to that service versus 669 to the oncology service. There was a significantly shorter length of stay on the heme malignancies hospitalist service by about 2 to 5 days compared to the oncology hospitalist service. The rates of patients who were discharged by noon or the length of stay were similar between the two groups.    So, while this study is confounded by differences in acuity of disease between the services, using a dedicated heme malignancy hospitalist has many benefits, not just to offload the oncology-managed service, which may have a higher level of acuity, but also allow for a deviation of care for medicine-specific issues, to a hospitalist that's specifically trained in managing patients with hematologic malignancies and then dedicating the oncology specialty service to those who need acute oncologic care, such as those with leukemia or other high acuity diseases.    Dr. John Sweetenham: Thanks, Marc. I think it is really interesting to see some outcome data for this model of care. A number of centers I know are looking at an APP-led inpatient service for these types of patients, too, so it's going to be very interesting to see how further studies of these kinds of approaches continue to develop.    And on a related theme of changes in patterns of care, Abstract TPS1609 looked at home infusion and of course, this is something that really started to attract a lot more attention during the COVID-19 pandemic. But I wonder if you could walk us through some of the details of this poster.    Dr. Marc Braunstein: This study was presented as a poster proposing a prospective study looking at home infusion of the anti-CD38 monoclonal antibody daratumumab, which has a vital role in managing patients with newly diagnosed or relapsed multiple myeloma. And monoclonal antibodies have really revolutionized the care of patients with multiple myeloma, but often their infusion schedule is weekly or biweekly, and it does require relatively frequent visits to an infusion center.    So, this single-arm, open-label study is going to examine whether we can provide home administration of subcutaneous daratumumab and assess whether it improves quality of life and assess its safety. So, in this study, a visiting nurse will come and deliver the medication after patients take their pre-medications at home prior to the arrival of the infusion nurse. And then the investigators will provide quality of life questionnaires prior to and after the infusions and at the end of the study, and they'll be looking at any barriers to adherence, any barriers to the logistics of this home infusion arrangement.    And I think that this has a lot of potential not just to improve quality of life, but also to facilitate care to patients who may be frail, who may not have good caregiver support, who may have barriers in traveling to an infusion center or perhaps in places that are more resource-deprived and don't have local infusion centers. This could be a potential approach to delivering vital anti-myeloma medications at home, and I'm looking forward to seeing the results.    Dr. John Sweetenham: Yeah, I agree. I think a lot of us still have anxieties about the safety of this approach, but I think there are increasing data to suggest that home infusion is not only safe but also, as you mentioned, is a big enhancer of the quality of life of these patients. And so, very interesting to see how this plays out in prospective studies.    So, to close out, I wonder if you could walk us through Abstract 7072, a poster looking at the issue of clonal hematopoiesis.    Dr. Marc Braunstein: Clonal hematopoiesis, which is a phenomenon in which the blood cells acquire somatic mutation, is associated with both cardiovascular disease adverse outcomes as well as hematologic malignancy. It's been shown to be a precursor for diseases such as leukemia. So, this relatively small study from MD Anderson Cancer Center examined clonal hematopoiesis in 78 patients with malignancies, 70% of which had a history of cancer, and the authors described outcomes associated with clonal hematopoiesis.    So, again, 78 patients were examined, and 76% of them had a history of malignancy, and 73% had other comorbidities. And the authors demonstrated clonal hematopoiesis by the finding of specific mutations in the blood associated with clonal hematopoiesis. The authors essentially looked at outcomes such as mortality. They noted that only 20% of the patients developed a myeloid neoplasm, and that's relevant because, again, clonal hematopoiesis is a precursor for myeloid neoplasms. They also noted that most patients had died from a primary malignancy rather than a myeloid neoplasm, which is not too surprising considering that most patients with clonal hematopoiesis will not develop a hematologic malignancy, but it is a marker for the potential transformation.    And so, I think the authors conclude that clonal hematopoiesis is important for monitoring patients who are at risk for potential myeloid transformation and hematologic malignancy, but it's not necessarily the case that patients who have a background of malignancy will often develop a myeloid malignancy. I think there are many implications of clonal hematopoiesis for cancer in general in terms of the risk of secondary malignancies in those treated with adjuvant chemotherapy, in terms of how we monitor patients who actually more and more are going to have this detected as we use more next-generation sequencing and liquid biopsies.     So, I look forward to future studies that are exploring how to actually prospectively assess clonal hematopoiesis and use it for clinical stratification for things like adjuvant chemotherapy or monitoring for risks of hematologic malignancy.    Dr. John Sweetenham: Thanks, Marc. I agree. Very important for the future, especially as we gain more and more sequencing data.    So, Marc, in conclusion, I want to thank you very much for sharing your insights with us today on the ASCO Daily News Podcast. It's been great to talk with you again.    Dr. Marc Braunstein: My pleasure. Happy to be back, and I look forward to a future podcast session.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in the transcripts of this episode. Finally, if you value the insights that you hear on 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. John Sweetenham   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. Nathan Pennell and Nancy Lin discuss emerging data on the growing problem of prior authorization and insurance denials in cancer care, their potentially harmful impact on patient outcomes, and what can be done to fix the problem. TRANSCRIPT Dr. Nathan Pennell: Hello, I'm Dr. Nathan Pennell, your guest host for the ASCO Daily News Podcast today. I'm the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research for the Taussig Cancer Institute. More importantly, today, for this podcast, I'm also the editor-in-chief for the ASCO Educational Book. On today's episode, we'll be discussing the growing problem of prior authorization and insurance denials, and how that impacts both providers and patients in their ability to access cancer care.  Joining me is Dr. Nancy Lin, a breast cancer medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School. She's addressed this problem in a recently published article in the 2023 ASCO Educational Book, and she's joining me today to highlight some emerging data on the possible harms from prior authorization and insurance denials, and what we can do to fix this problem.  Nancy, thanks so much for coming on the podcast today. Dr. Nancy Lin: Thank you for inviting me. Dr. Nathan Pennell: Some of our listeners may have noticed that we also did a podcast a number of years ago on a similar topic when we were with the Journal of Oncology Practice, and I was kind of hoping that prior authorizations would not be as big a problem, now, probably 8 or 9 years later, and unfortunately, it seems like it has gotten even worse.  Before we begin, I should mention that our disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.orgDNpod. So prior authorizations were, of course, originally intended as a cost control on the overuse of expensive medical care. However, in recent years, it seems like prior authorization has been extended to, more or less, all medical care, including supportive care medications and essential cancer care interventions that we need to use in almost every patient. We're also hearing more and more reports on patients who are denied coverage, and I think the doctors can sympathize with this, with their increasing peer-to-peer requests. And this is leading to patients being forced to wait to receive second-best options, impacting their out-of-pocket costs. And potentially, we all fear this is impacting patient outcomes, although we really would like to learn more about how this is really impacting their care. So, Nancy, can you talk to us a little bit about how prior auth is impacting patient access to cancer care today? Dr. Nancy Lin: Of course, we all have to acknowledge that part of the impetus for prior authorization is just the increasing cost of cancer care. There are some recent statistics that the U.S. spends over $200 billion annually on cancer care and that oncology drugs are a huge part of the overall drug cost in the nation and a large part of the oncology drug budget. So, I think we can't deny that the increasing costs of cancer care are in part driving this drive for more prior authorization. But this has costs, and there are costs in terms of direct patient costs as far as their quality of care, and also costs in terms of the health care providers and health care system.   And so we, as part of our article, actually solicited patients to provide their stories. And in fact, in our article, we have selected, with their permission, 3 patients who share their experiences. And these are experiences that, as a practicing oncologist, you'll be very familiar with. A patient wrote that she had been on capecitabine for a year, her disease is responding, and all of a sudden, on a Friday late in the day, she's told, “No, you need a prior authorization now, and you can't get your drug refilled.” And that led obviously to stress and delay and whatnot. And then another example is of a patient whose oncologist requested what sounds like next-generation sequencing, some sort of tumor panel and was denied. And the peer-to-peer here had apparently indicated that they are not aware of the data for the use of genomic testing and cancer treatment, which clearly there is a role for the use of genomic testing in cancer treatment. And in fact, we now have many articles that show that there's unequal access and, if we look at underrepresented minorities or other marginalized groups, that there is a dramatic difference in the utilization of advanced molecular testing. And then just the overall experience on patients and their families feeling like, at a time when they're sick, need to take charge of all of this paperwork and back and forth with insurers that is very stressful.   And then, from a provider or health care system standpoint, many, many hours are expended on prior authorizations for things like very new drug approvals that are maybe not on a pathway yet, or very commonly, simple things like a CAT scan for restaging of somebody who has advanced breast cancer where every scan requires prior authorization or antiemetics, or somebody receiving highly immunogenic chemotherapy and these kinds of death by a thousand cuts I think is how people in the health care experience the aspect of prior authorization.  Dr. Nathan Pennell: It's one of these things where we used to get a peer-to-peer for say, atypical reason for a PET scan, which made perfect sense, and you'd have to talk to an experienced expert to explain what you were doing and try to get a good rationale for that. And now, it's come to the point where a routine 2-month, 3-month CT scan is getting denied and having to be talking to someone who's not as experienced in this. Again, it feels still like a collection of anecdotes though in many ways. Is there any sort of published data on denials of care and prior auths and how this is impacting approvals and patient access? Dr. Nancy Lin: There are survey data, which one has to admit is not necessarily gold-standard data, but there are data from the American Medical Association, as well as a 2022 ASCO member survey. And in that ASCO member survey, over 90% of oncologists reported that they had personally experienced, in their patients, a delay in treatment related to prior authorization. Over 90% had issues getting needed diagnostic evaluations. Over 90% reported that they were, "forced to go to a second choice of therapy." And about a third of oncologists reported that they believed that the prior authorization, either delays or denial of care, led to changes or worsening of patient survival, which I think is the most concerning statistic of all.  Now, I think that one can argue that these are essentially physician self-report and what's the gold standard as far as whether there has been an impact? But I think that the fact that these reports are so prevalent means that, even if the reality is half of what has been reported, it's still a lot. And I think that  the power of these kinds of surveys is just enormous, that a high prevalence of the problems have been reported, I think, points to something even if we don't have gold standard quote data now.  Within our institution, Dana-Farber, we have done an analysis of oral medication prescribing. So, we do have gold standard and very granular data on patients that we've seen. And we've seen denials and requirements of prior authorization not only for expensive cancer medications and growth factors but also for even medicines like generic tamoxifen, which, honestly, how does that need prior authorization in this day and age? Medications like supportive care, antiemetics, and really things that ultimately, we were able to get approved 97% of the time, but [prior authorization now] introduces a delay and introduces stress. And although one may not be able to measure a so-called negative outcome from a patient recurrence standpoint, I think that there are other kinds of negative outcomes that are important, including just the experience of a cancer patient undergoing treatment, the stress of all of the denial letters and the delays that can occur as a result. Dr. Nathan Pennell: And it's not just patients. Obviously, we want to be patient-centered in our care and focus on how this impacts them. But this is also significantly impacting practitioners and cancer centers and physicians and the administrative burden of having to do the prior authorizations, which of course are not standardized in any way and vary from payer to payer and geographic area to geographic area. Is there data on how the changes in prior auth have impacted practices and physicians? Dr. Nancy Lin: Yes. In fact, there have been several surveys as well as in the practice types of studies trying to understand the staffing that is required to manage the prior authorization requests. And some of the estimates are an additional 40 hours per week per oncologist, that's a full-time position. Some of these tasks can be carried out by non-oncology-trained providers but many of them do require either the oncologist or a nurse practitioner equivalent to be on the phone for the peer-to-peer or a full-time clinical provider and you are given a 4-hour window to do a peer-to-peer in the middle of clinic, that's very disruptive. And I think that that's fine if it's every now and then for drugs that we all agree are perhaps outside of their usual indication. But if this is every CAT scan and every brain MRI and every time we prescribe an oral drug, it really does affect both clinic workflow, and just the psychology; I think it really contributes to burnout.  There was a very interesting survey actually of oncology trainees who, not even to the point where one is an attending physician, but at the trainee level indicating that this was something that was causing them a lot of distress, and in some cases, questioning the whole idea of going into medicine. And then when you think with the attrition that we're seeing in the health care workforce, we do really have to be careful about these burnout issues because we really can't afford to lose a lot of oncology staffing as the patient population ages and we're seeing higher prevalence of cancer. I think it's imperative that we take care of our oncology workforce. And I think this survey was very interesting because it went beyond the attending physician to other levels of oncology care, all of which are affected.  And there have been, as you know, many growing or nascent attempts at various residency programs to think about unionizing and what are the kinds of concerns or complaints that trainees bring up. And one of [the complaints] that  comes up a lot is, “We have to do these prior authorizations and there's all this administrative paperwork that doesn't require an entry-level person.” I'm not saying that they should or shouldn't do it - I'm not going to take a position on that - but the fact is that somebody has to do it in the current system, and whoever does it, it causes burnout. And I think that that is important. And the other piece of it has to do with equity and access to care because we're coming from academic institutions. We have a staff of people who help with prior authorization. That's not true in every practice in the United States. And I really worry about not so much denial of care but even a step beyond that, which is if you are in an under-resourced office and it's too hard to get certain things done, you don't do them because you just don't have the ability or you don't have the staffing to be able to find insurance. And I think that is very concerning to me in terms of access to care, access to some of our immune-targeted therapies, and access to the optimal support of care medications. We come from very well-resourced places as far as the administrative staff, relatively speaking, and that's just not true everywhere.  Dr. Nathan Pennell: This whole idea kind of falls under the idea of creating friction in the system to try to slow things down. I've seen data suggesting that things like peer-to-peer requests for appeals actually lead to a majority of physicians not having time or taking the time to actually do that. And that may be sometimes because they know it's indefensible and don't want to go through the process. But probably a lot of the time it's just because they don't have time to do it in their busy day and those patients then don't get their care covered. So, it's really a problem.  Now, the other thing that is really remarkable to me is, this is 2023 and everything is so technologically advanced. You can make major financial transactions electronically on your phone in just a few seconds, really complicated things. And yet this kind of [prior authorization] process really is still often done over the phone and by fax and with 100 different systems that don't talk to one another. And at the same time, oncology is becoming more and more guideline-driven where what we do actually have is really good evidence behind it. And there are even published guidelines for almost every disease and line of care about everything that we do from scan intervals to what kinds of treatment and how often and what supportive care is necessary. So, this would seem like an optimal situation for a technology solution where we tie in guidelines to what should and shouldn't be covered. What's going on out there in terms of trying to fix this? Dr. Nancy Lin: Some important questions are: Who makes the guidelines? What are the regulations as far as which guidelines insurance might adopt - their own internal guidelines or NCCN or comparable organizations? And what do you do when somebody wants to deviate from the guideline or pathway? And then finally a practical question, which is you don't really want to have a different platform and a different guideline for every insurance plan for every patient. And I think that is a little bit of even if we move to a purely electronic system, that will still be a problem.  The state of Florida had done this pilot study that tried to use or incorporate the NCCN guidelines as part of their approval or review process for prior authorization requests and at least based on the report that's published, saved $15 million in costs. And we would hope if the care was more NCCN guideline-concordant, which has been shown to improve outcomes, that would have been done without a detriment to patient outcomes. I don't think we have enough granular information to be 100% sure of that, but I would assume that that's most likely the case. I do think that some amount of guideline use could be useful.   And one of the things that we proposed in our article was the idea that one could create a sort of gold card system such that if a provider or a practice, for example, adheres to certain pre-agreed-upon guidelines or pathways more than 80% of the time, which is sort of considered good adherence and taking into account patient preference and comorbidities and whatnot, that that practice or provider could be sort of gold carded, so to speak, and actually have many of the prior authorization requirements go away so long as that is adhered to. And so that's one idea.  One of the concepts that Dario Trapani, who was the first author of our paper, put forward is that you don't necessarily need every person to be compliant with every guideline. Generally, you need for there to be compliance and that there could be different categories of treatment so that supportive care medications, pain medications for cancer-related pain, could potentially be exempt from prior authorization requirements completely. And then at the same time for other kinds of prior authorization requests, it's not enough to just change a fax form to an electronic form. That's an improvement from having faxes going back and forth by paper, but really isn't a fundamental change in the prior authorization process or vision. And so, this idea of the pathways and then only when something is deviated in some sort of major way in various categories to be determined that sort of triggers a peer-to-peer review that would both hopefully serve the purpose of reducing overuse of unnecessary or non- indicated treatments and save money. But also, in a way, I think that is less burdensome to the health care system. And I fully acknowledge that I am not a policy expert, I mostly research metastatic breast cancer, but this issue really affects us all very personally every day.   Dr. Nathan Pennell: I know you just said you're not a policy expert, but can you talk to us a little bit about what Congress and ASCO are doing to help from a legislation standpoint or a regulatory standpoint to help make this a little bit less painful? Dr. Nancy Lin: Yeah. So ASCO has endorsed the so-called “Improving Seniors Timely Access to Care Act.” And for those out there listening, particularly patients, you might say, “Well, I'm not a senior.” But it's important because how Medicare deals with issues often is then adopted by private insurers. And so starting with “Improving Seniors Timely Access to Care Act,” the intent is that it will also affect people with cancer at all age groups. But some of the provisions or the proposals are to convert to an electronic prior authorization system, to put systems in place for timely and efficient communication between providers and insurers, to ensure a process for real-time decisions that have some timeframe or timeline or deadline associated with it, to facilitate guidelines and pathway-informed decisions, and to also, importantly, be fully transparent about approvals and denials, portions that are denied, these sorts of reasons for denials, to really have transparency in that process which at the moment does not really exist. I think these are all very, very important steps with the overarching goal to promote timely and appropriate access to medications, procedures, and evaluations for oncology patients. Dr. Nathan Pennell: I'm just curious, in your opinion, do you think that there is actual inertia to try to change some of these things from a policy perspective? It can be kind of frustrating sometimes. It seems like the insurance industry has really kind of taken command of this by implementing these and we see the problems and we talk about them. But from a regulatory standpoint, it really seems like things are kind of maybe being a little bit neglected. Dr. Nancy Lin: I think that this is really something where I do think there will be some movement; maybe it's that I'm an optimist and that's what you need to be to be an oncologist.  I think that a big part is going to be really a focus on the impact on patients because although we certainly feel the impact on ourselves as providers and our staff, I don't know that that in and of itself is going to be enough to move the needle, like doctors complaining that they are having to spend too much time on the phone. I think the real impact is really related to the impact on patients. And as I said, I think that the AMA survey and the ASCO survey, those are very important because they really put the focus on [assessing] the impact on patients living with cancer.  Again, the limitations of a survey-based study are profound. And I do think that the current [White House] administration is very, very engaged in improving care for people with cancer. And in fact, part of this revised Cancer Moonshot [initiative] is not only better science around cancer and better molecular understanding of cancer but at the end of the day, if we can't get the right treatment to the right patient, it doesn't really matter how good the science is. And part of getting the right treatment to the right patient is not just training, guidelines and education. Part of it is just the practical aspect of insurance coverage as one important aspect of that. And so, I do think that there will be some movement on this because I think that it's really gotten to a point where this is not just inconvenient for doctors. I don't think that that's enough to drive anything forward personally, but I think that when you start to see impact on patients, that is really a big deal.  I was struck that one of the studies that we had identified was a study looking at over 13,000 chemotherapy requests and understanding how many were denied and why they were denied. And basically, about 11% of the requests ultimately were denied after peer-to-peer and all sorts of other appeals. And this was essentially the gold standard, so to speak. In this study was the oncologist's opinion as assessed by the so-called board certified oncologist, which is what was described in the publication employed by the insurer. We have these competing narratives and that is ultimately the problem: We have the AMA and the ASCO surveys which are survey-based asking the oncologists, and we have these data which are based on the insurer essentially as the gold standard arbiter. So it's hard to reconcile those two pieces of information because they're not really coming from the same place. And then I think you could also argue that, think about 13,000 chemotherapy requests, that means that essentially 90% were fine.  When we looked at our pathways employed at Dana-Farber where we check to make sure that our physicians are adhering to the pathways, we basically want to aim at about 80% with the idea that some patients decline a standard regimen, and we go to something else. They don't want alopecia with the idea that some patients have comorbidities, that you don't want to micromanage how oncologists are managing their patients. And honestly, in most pathway programs, we consider 80% to be pretty good. In this study, 80% were approved. And you might argue, is it worth reviewing 13,000 requests to this level of scrutiny for 90% to be approved? And again, I think that that really raises this idea of like rather than just switching a fax system to an electronic system to really rethink where's the low-hanging fruit? Where would prior authorization really serve a positive purpose? I think there are places where it could serve a positive purpose and where is it just adding unnecessary friction. Dr. Nathan Pennell: Yeah, it's a complicated picture and there are valid arguments on both sides. One of the things that is very appealing to me about the proposed legislation is requiring the payers to actually report and disclose their levels of denials and prior authorizations and this allow us to maybe take it beyond the anecdotal evidence to actually being able to document what they're doing. Because once you shine a light on things, sometimes it becomes a little bit harder to abuse the system.  Dr. Nancy Lin: Yes, I agree.  Dr. Nathan Pennell: Well, Nancy, thanks so much for coming on the podcast today to discuss this challenging problem. I know we could have talked about this for an hour or more. We really appreciate your work to highlight the impact of this problem both on providers and on patients, as well as outlining some efforts to find solutions. Dr. Nancy Lin: Great, thank you for having me. Dr. Nathan Pennell: I also want to thank our listeners for joining us today. If you value the insights you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Have a great day. 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. Nancy Lin @nlinmd   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. Nancy Lin: Stock and Other Ownership Interests: Artera Inc. Consulting or Advisory Role: Seattle Genetics, Puma Biotechnology, Daichi Sankyo, Denali Therapeutics, AstraZeneca, Prelude Therapeutics, Pfizer, Olema Pharmaceuticals, Aleta Biotherapeutics, Artera, Johnson & Johnson/Janssen, Blueprint Medicines, Genentech, Pfizer, Seattle Genetics, Merck, Zion, Olema Pharmaceuticals        

“Just like with anything we do in oncology, a lot of education is required. Nurses and coordinators are critical to start the education and provide effective resources that are reinforced throughout the treatment,” ONS member Beth Faiman, PhD, MSN, APN-BC, AOCN®, BMTCN®, FAAN, FAPO, advanced practice provider at Cleveland Clinic in Ohio, told Lenise Taylor, MN, RN, AOCNS®, BMTCN®, oncology clinical specialist at ONS, during a conversation about how to address knowledge gaps and barriers to practice regarding patients who are preparing for or who have received CAR T-cell therapy for hematologic malignancies. Faiman was one of the content experts for two ONS focus groups on the topic in March 2023. This podcast episode is produced by ONS and supported by funding from Janssen Oncology and Legend Biotech. ONS is solely responsible for the criteria, objectives, content, quality, and scientific integrity of its programs and publications. Music Credit: “Fireflies and Stardust” by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0 Episode Notes NCPD contact hours are not available for this episode. Oncology Nursing Podcast episodes: Episode 1: Experiences With CAR T-Cell Therapy Episode 139: How CAR and Other T Cells Are Revolutionizing Cancer Treatment Episode 176: Oncologic Emergencies 101: Cytokine Release Syndrome ONS Voice articles: Studies Show Best Practices to Manage CAR T-Cell Therapies' irAEs and Improve Outcomes CAR T-Cell Therapy Programs: Essential Elements to Establish a Successful System A Body of Evidence Helps Nurses Manage CAR T-Cell Therapy Toxicities Clinical Journal of Oncology Nursing articles: CAR T-Cell Therapy: Updates in Nursing Management Building a Program: Implications for Infrastructure, Nursing Education, and Training for CAR T-Cell Therapy Management Across Settings: An Ambulatory and Community Perspective for Patients Undergoing CAR T-Cell Therapy in Multiple Care Settings ONS clinical practice resources: Chimeric Antigen Receptor T-Cell Therapy: A Timeline of Events and Adverse Events Cytokine Release Syndrome ONS course: Nursing Considerations for CAR T-Cell Therapy for Patients With Hematologic Malignancies: Patient Education and Symptom Management ONS videos: CAR T-Cell Therapy Cytokine Release Syndrome American Society for Transplantation and Cellular Therapy Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated With Immune Effector Cells International Myeloma Foundation Leukemia and Lymphoma Society Multiple Myeloma Research Foundation New England Journal of Medicine article: Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma Transplantation and Cellular Therapy article: Overcoming Barriers to Referral for Chimeric Antigen Receptor T Cell Therapy in Patients With Relapsed/Refractory Diffuse Large B Cell Lymphoma Learn more about CAR T-cell therapy and risk evaluation and mitigation strategies (REMS). To discuss the information in this episode with other oncology nurses, visit the ONS Communities. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org. Highlights From Today's Episode “Just like with anything we do in oncology, there is a lot of education that is required. The same navigators that take care of our patients through the transplant and cellular therapy process, we have similar cellular coordinators that were part of the focus group. These navigators were critical to start the education and provide effective resources that were reinforced throughout the treatment.” Timestamp (TS) 09:00 “The nurses and coordinators play a huge role during the transition of care. Not only do they help with coordinating appointments, but also the scheduling of tests and coordinating with the referring team. I heard a lot in the focus groups about the nurses communicating from inpatient to outpatient, and also coordinating from center to center.” TS 10:22 “Patients can get really nervous when they're feeling sick. I explain it to them like, “You know how you get a flu shot, and you might get a little reaction as we're training your immune system to provide immunity? Well, it's like that, but way worse.' So, you can get really sick feeling and achy from this, and so that psychosocial support is super important.” TS 18:16 “It takes a lot of burden on the patient, caregiver, and the nurse to really be astute to those symptoms and intervene. We do provide wallet cards to patients. We educate the emergency department staff. We also heard about the infection monitoring and caregiver support is absolutely critical. Fortunately, the symptom management has become quite standardized, which really affords the nurses more autonomy to intervene more efficiently.” TS 20:46 “The nurses found for education a teach-back tool to be quite useful. One of the nurses mentioned asking the patient questions such as, ‘What will you do when you have a fever? Tell me what you do,' and “What do you understand from what the doctor just told you?' And so that was just kind of a way that they could go back and forth with the educational process and really understand what the patients understood.” TS 25:46

Dr. John Sweetenham and Dr. Neeraj Agarwal discuss advances across the spectrum of malignancies, including key studies in precision oncology and disparities in cancer care in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, now the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. I'm delighted to welcome Dr. Neeraj Agarwal, director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, who is editor-in-chief of the ASCO Daily News.  Today we'll be discussing some key advances across the spectrum of malignancies, as well as novel approaches in precision medicine and cancer disparities that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.  Neeraj, it's great to have you back on the podcast today. Dr. Neeraj Agarwal: Thank you so much, John, for having me. Dr. John Sweetenham: Neeraj, let's begin by discussing some practice-changing phase 3 trials, starting with Abstract 5500, the KEYNOTE-826 study. This study reports the final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer, which will be presented by Dr. Bradley Monk.  Dr. Neeraj Agarwal: I'd be happy to. The initial analysis of the KEYNOTE-826 study revealed that first-line pembrolizumab plus chemotherapy provided significant improvements in the overall survival and progression-free survival compared to placebo plus chemotherapy in patients with metastatic, persistent, or recurrent cervical cancer who had not previously received systemic chemotherapy and were not candidates for curative treatments such as surgery or radiation. In this study, patients were randomly assigned in a 1:1 ratio to receive pembrolizumab or placebo at 200 milligrams every three weeks for up to 35 cycles, along with chemotherapy with paclitaxel, plus a platinum therapy with or without bevacizumab.   From November 2018 to January 2020, 617 patients were enrolled with 308 receiving pembrolizumab plus chemotherapy and 309 patients receiving placebo plus chemotherapy. At the data cutoff of October 3, 2022, the median follow-up was 39 months. At this protocol-specified final overall survival analysis, pembrolizumab plus chemotherapy treatment continues to show a significant improvement in overall survival and progression-free survival, regardless of whether patients receive bevacizumab or not. The incidence of grade 3 or more adverse events was higher in the pembrolizumab plus chemotherapy arm than the placebo plus chemotherapy arm, with the most common adverse event being anemia, neutropenia, and hypertension. Dr. John Sweetenham: These are exciting data, Neeraj. So the main message from this trial is that pembrolizumab plus chemotherapy, with or without bevacizumab, can now be considered as standard of care for first-line treatment of persistent, recurrent, or metastatic cervical cancer. Dr. Neeraj Agarwal: Yes, I agree, John. Now, moving on to a different common type of cancer, let's discuss Abstract 1001, titled “Second-Line Endocrine Therapy with or without Palbociclib Maintenance in Patients with Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer: Results from the PALMIRA Trial,” which will be discussed by Dr. Antonio Llombart-Cussac. So, John, based on this abstract, can you please tell us about the role of palbociclib after prior progression on this drug? Dr. John Sweetenham: Yes. In this study, the authors aimed to determine if palbociclib maintenance with an alternative endocrine therapy improves the anti-tumor activity of second-line treatment in patients with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer who had disease progression to first-line treatment with palbociclib in combination with endocrine therapy. After including 198 patients in the trial with a 2:1 randomization, 136 patients received palbociclib with endocrine therapy and 62 patients received endocrine therapy alone. And at a median follow-up of 8.7 months, the primary endpoint of progression-free survival was not met with a median progression-free survival of 4.2 months in the palbociclib-containing combination versus 3.6 months in the control arm. Also, higher grade 3 to 4 adverse events were reported in patients treated in the palbociclib arm. Dr. Neeraj Agarwal: Thanks, John. So you are saying that continuing the CDK4/6 inhibitor palbociclib after prior disease progression on palbociclib, even when the primary endocrine therapy has been changed, doesn't seem to be beneficial, therefore, this practice may be discouraged in the clinical setting? Dr. John Sweetenham: Yes, that's correct. Neeraj, I think that's the conclusion from this study. Dr. Neeraj Agarwal: So, John, now let's switch gears and highlight some precision oncology studies.  Dr. John Sweetenham: Well, Abstract 3602, titled “Real World Rates of FDA-Approved Targeted Therapy and Immunotherapy Prescriptions for Metastatic Colorectal Cancer Patients in the VA's National Precision Oncology Program” will be presented by Dr. Alice Nono Djosta. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Well, comprehensive genomic profiling has the potential to guide the administration of FDA-approved biomarker-directed therapies and improve outcomes among patients with metastatic colorectal cancer. So, in this study, Abstract 3602, investigators sought to determine the rates of actionable biomarkers and prescription of associated FDA-approved therapies among veterans in the National Precision Oncology Program. Patients with metastatic colorectal cancer who had undergone comprehensive genomic profiling via tissue or liquid biopsy were included between 2019 and 2022 and had 1 of the following 5 actionable biomarker profiles including: NRAS, KRAS, BRAF wild-type, BRAF V600E mutation, MSI-high, TMB-high, NTRK fusion or rearrangements.  Prescription data for seven FDA-approved biomarker-directed therapies were extracted and rates of comprehensive genomic profiling (CGP)-directed therapy prescriptions were assessed by the investigators. A total of 908 patients with metastatic colorectal cancer underwent comprehensive genomic profiling, with 80% patients having colon adenocarcinoma and 20% with rectal adenocarcinoma. The combined rates of any actionable variants were 47% in patients with colon adenocarcinoma and 45% in patients with rectal adenocarcinoma. After including 424 eligible patients for FDA-approved biomarker therapy, only 70% patients with MSI-high, 48% patients with TMB-high, 38% patients with NRAS, KRAS, and BRAF wild-type, and only 17% of patients with BRAF V600E mutation received FDA-approved CGP-directed therapies.  Dr. John Sweetenham: Very important data, Neeraj. What's the main conclusion of this study? Dr. Neeraj Agarwal: So, in conclusion, this study found that almost 30% of patients with MSI-high metastatic colorectal cancer did not receive effective immune checkpoint inhibitors. And overall, a significant number of eligible patients did not receive FDA-approved biomarker-directed therapies. So, it is crucial that we evaluate the barriers to prescribing comprehensive genomic profiling-directed therapies in our patients with metastatic colorectal cancers.  So, John, let's move on to lung cancer, where the use of single-gene testing is still common in the community practice. Can you please tell us about Abstract 6506, titled “The Impact of Single-Gene Testing on Subsequent Comprehensive Genomic Profiling Success in Community Oncology Practice for Advanced Non–small Cell Lung Cancer”? These are results from a prospective observational reference laboratory testing program and these results will be presented by Dr. Mary Nesline. Dr. John Sweetenham: Yes, definitely. In this study, researchers aim to investigate the impact of prior single-gene testing on comprehensive genomic profiling success and therapeutic opportunities for patients with non–small cell lung cancer in community settings. They included patients who underwent at least 1 single gene testing for guideline recommending genomic variants in non–small cell lung cancer such as BRAF, EGFR, KRAS, MET exon 14 skipping mutations, ALK, RET, and ROS1 rearrangements as well as PD-L1 immunohistochemistry.  And they offered comprehensive genomic profiling either before or after receipt of a negative single gene test. Of 580 patients with non–small cell lung cancer with the comprehensive genomic profiling ordered between 2021 and 2022, around 30% of the patients had at least 1 single-gene testing ordered prior to the comprehensive testing, with a median of 5 prior single-gene tests. Compared to CGP-only cases. CGP per cases with prior negative single gene testing was canceled twice as often at tissue review, had a higher DNA extraction failure, and a lower DNA sequencing success. CGP also identified guideline-recommended variants in genes with no single-gene testing offered during the study period, such as ERBB2 mutations, or NTRK2/3 fusions, as well as variants targeted in ongoing clinical trials in 28% of patients. Dr. Neeraj Agarwal: Very interesting. So John, what is your key takeaway message from this? Dr. John Sweetenham: The main message is that in a community oncology setting, the practice of ordering single gene testing prior to comprehensive genomic profiling for patients with non–small cell lung cancer is common. Prior negative single-gene testing led to a higher rate of CGP test cancellation due to tissue insufficiency and increased CGP DNA extraction failures. The practice of single-gene testing does not align with practice guideline recommendations and may negatively impact the potential benefits of CGP testing for patients with non–small cell lung cancer.  Now, let's move on to another important abstract that our fellow clinicians should hear about. This is Abstract 1534 titled “Real-World Experience of an In-House Dihydropyrimidine Dehydrogenase Genotype Test to Guide Fluoropyrimidine Dosing at a Multi-Site Cancer Hospital” that will be presented by Dr. Jai Patel. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. Fluoropyrimidines, such as 5-fluorouracil and capecitabine, are commonly used to treat solid tumor cancers such as gastrointestinal and breast cancers. We know that severe toxicity occurs in one-third of patients, which delays the timely completion of treatments and result in prolonged hospitalization of these patients. These toxicities may be due in part to genetic variation in the DPYD gene. Five variants are known to have moderate to strong evidence according to the Clinical Pharmacogenetics Implementation Consortium. So, in this observational study, the authors describe the implementation of an in-house DPYD test and its impact on the dosing of these fluoropyrimidines, which include capecitabine and 5-fluorouracil.  From March 2020 to December 2022, 491 patients received DPYD genotyping testing, and 90% of them had gastrointestinal cancers. The median lab turnaround time was only 3 days. Pre-treatment testing was ordered in 80% of patients, and 93% of patients had results before starting cycle 1. Overall, 6% of patients were heterozygous carriers. Fluoropyrimidine dose was reduced, avoided, or discontinued in 90% of these patients. Moreover, in pre-treatment carriers, 90% of patients received an upfront dose reduction, avoidance, or they even declined chemotherapy. Dr. John Sweetenham: Thanks, Neeraj. So what do you think is the key takeaway message here? Dr. Neeraj Agarwal: So, DPYD genotype-guided dosing of fluoropyrimidine, including 5-fluorouracil and capecitabine, is logistically feasible with a rapid turnaround time and can result in treatment dose modifications for most carriers, potentially avoiding or mitigating severe toxicities, especially in those patients who received pre-treatment testing. Dr. John Sweetenham: Thanks again. Now let's transition to studies that focus on disparities in cancer care. Dr. Neeraj Agarwal: Definitely. Let's discuss Abstract 6530, titled “Impact of Free Hospital-Provided Rideshare Service on Radiation Therapy Completion Rates: A Matched Cohort Analysis.” In this study, Dr. Eric Chen and colleagues assess the potential of rideshare services in facilitating timely radiation therapy for patients facing barriers, such as limited transportation, financial constraints, and lack of adequate social support. So the authors analyzed data from about 2,900 patients who underwent radiation therapy and found that 58 of them utilized a free hospital-provided rideshare service.  These free hospital-provided rideshare service utilizers had a lower median age and were more likely to identify as Black or African American compared to those who did not utilize these services. They also had higher socioeconomic disadvantages and traveled shorter distances for treatment. Interestingly, more rideshare utilizers underwent radiation therapy with curative intent, had longer treatment course duration, and a higher number of fractions prescribed. In the matched-cohort analysis, the study found that radiation therapy completion rates were significantly higher for rideshare utilizers compared to non-rideshare utilizers, especially for patients who were undergoing radiation therapy with curative intent.  Dr. John Sweetenham: So what's the key take-home message from this abstract? Dr. Neeraj Agarwal: This study highlights the potential benefit of utilizing hospital-provided free ride-share services, particularly for patients facing barriers to timely treatment. So, using these services were associated with higher radiation therapy completion rates, especially in the curative setting.  So, John, there is another study, Abstract 1606, titled “Trends and Disparities in Oncology Telehealth after the Initial Pandemic Era” that will be presented by Dr. Michael Lee and colleagues. They evaluated whether telehealth utilization continued after the pandemic and if demographic differences in its users persist. So John, please tell us more about this abstract. Dr. John Sweetenham: Yes, the authors conducted a retrospective cohort study in 22 Kaiser Permanente Northern California hematology and oncology clinics between October 1, 2020, and June 1, 2022. The study investigated the use of office, video, and telephone visits, analyzing more than 340,000 hematology oncology visits with MD or DO providers. Of these visits, 25% were in-office, 37% were video visits, and 39% were telephone visits. Monthly telehealth visits peaked in January 2021, representing around 86% of total visits, and decreased to 69% of the total visits by June 2022. Video visits were more common for new appointments, whereas telephone visits were more common for return appointments. Moving to the post-pandemic period, telehealth visits remained popular, with video visits being the most commonly utilized. However, telehealth use varied among demographic populations. Video visits were a significantly higher proportion of all visits among individuals less than 45 years old, primary English speakers, patients with commercial insurance, non-Hispanic Whites and Asians, compared with Hispanic, Whites, and Blacks, and patients living in the deprived neighborhoods. Dr. Neeraj Agarwal: Interesting data, John. So what is the key takeaway message from this abstract? Dr. John Sweetenham: Well, overall, it's encouraging to see that even after the pandemic, telehealth continued to be widely used. However, the concerning issue is that telehealth is less utilized in patients who may need it most. The next step, in my view, will be to work on barriers to access telehealth by underprivileged populations.   And that brings our discussion to a close today. Before we wrap up the podcast, Neeraj, do you have any final thoughts to share? Dr. Neeraj Agarwal: Yes, thanks, John. I would urge our listeners to come and join us at the ASCO Annual Meeting, not only to celebrate these successes but also to help disseminate these cutting-edge data to practitioners and patients across the world. Dr. John Sweetenham: Absolutely. I'd like to thank our listeners for joining us today, and thank you, Neeraj, for sharing your insights with us as well.  You will find links to the abstracts discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on 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. John Sweetenham Dr. Neeraj Agarwal @neerajaiims 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. 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. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss the CLEAR study in renal cell carcinoma, a new exploratory analysis combining the TheraP and VISION trials in metastatic urothelial cancer, and compelling advances in prostate cancer and across GU oncology in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host for the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical director of the Genitourinary Cancers Program at the Inova Schar Cancer Institute in Virginia.   Today, we'll be discussing some key abstracts in GU oncology that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcript at asco.orgDNpod.   Jeanny, it's great to have you on the podcast today. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal, for having me. Dr. Neeraj Agarwal: Jeanny, let's begin with Abstract 4502 regarding long-term updated results on the CLEAR study. The abstract reports the final, prespecified overall survival analysis of the CLEAR trial, a four-year follow-up of lenvatinib plus pembrolizumab versus sunitinib in patients with advanced renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yes, I would be happy to. So, just as a reminder, the combination of lenvatinib and pembrolizumab was initially approved by the FDA in August 2021 for first-line treatment of adult patients with advanced renal cell carcinoma. So, this was based on significant benefits that were seen in progression-free survival, which was a primary endpoint, but also showed improvement in the overall response rates compared with sunitinib in first-line advanced renal cell carcinoma.   So this abstract reports on longer-term follow-up now at a median of 49.8 months, and PFS favored the combination lenvatinib and pembrolizumab compared to sunitinib across all MSKCC risk groups, and PFS benefit versus lenvatinib and pembro compared to sunitinib was maintained with a hazard ratio of 0.47. And even overall survival was also maintained with the combination with a hazard ratio of 0.79, and the overall survival favored the combination across all risk groups. If we look at the CR rate, it was 18.3% for the combination compared to 4.8% with sunitinib, unless patients in the combination arm received subsequent anticancer therapies, and that's intuitive. And the PFS2 was also longer with the combination at 43 months compared to 26 months. Now, it is important to note that grade III or more treatment-related adverse events did occur in about 74% of the patients in the combination of lenvatinib and pembro, compared to 60.3% in patients with sunitinib. Dr. Neeraj Agarwal: Jeanny, this is good news. So the main message from the abstract is that sustained results from this combination of lenvatinib plus pembrolizumab are being seen even after a longer follow-up of more than four years.  Dr. Jeanny Aragon-Ching: Yes, I agree. So now, moving on, Neeraj, to a different setting in the RCC space, let's look at Abstract 4519, which is titled “Efficacy of First-line Immunotherapy-based Regimens in Patients with Sarcomatoid and/or Rhabdoid Metastatic Non-Clear Cell RCC: Results from the IMDC,” which will be discussed by Dr. Chris Labaki. So, Neeraj, based on this abstract, can you tell us a little bit more about the impact of these adverse pathologic risk features in non-clear cell RCC?  Dr. Neeraj Agarwal: Of course. So, using real-world patient data, the IMDC investigators compared the outcomes of patients with metastatic non-clear cell RCC who were treated with immunotherapy-based combination regimens versus those who were treated with VEGF-TKIs alone. They also assessed the impact of sarcomatoid and rhabdoid features on response to IO-based combinations versus VEGF-TKIs. Of 103 patients with metastatic non-clear cell RCC who had rhabdoid or sarcomatoid features, 32% of patients were treated with immunotherapy-based combinations.   After adjusting for confounding factors, the authors show that those treated with a combination of two immune checkpoint inhibitors or an immune checkpoint inhibitor with a VEGF-TKI combination had significantly improved overall survival, which was not reached in the immunotherapy combination group versus seven months within the VEGF-TKI group. Time to treatment failure and objective responses were also prolonged, significantly higher, and better in the immunotherapy groups compared with patients who were treated with VEGF-TKIs alone. Interestingly, if you look at those 430 patients with metastatic non-clear cell RCC who did not have sarcomatoid or rhabdoid features, they didn't seem to benefit with immunotherapy-based combinations.  Dr. Jeanny Aragon-Ching: This is an exciting update, Neeraj. What are the key takeaways from this abstract? Dr. Neeraj Agarwal: So the main takeaway is if you see a patient with advanced non-clear cell RCC who has sarcomatoid and rhabdoid features, there appears to be a rather substantial and selective benefit with IO-based combinations. And in this context, I would like to highlight the ongoing SWOG 2200 trial also known as PAPMET2 trial, which is comparing the combination of cabozantinib plus atezolizumab. So immuno-therapy-based combinations versus cabozantinib alone in advanced papillary renal cell carcinoma setting. So this trial is being led by Dr. Benjamin Maughan and Dr. Monty Pal. And I like to encourage our listeners to consider referring their patients for involvement in this federally funded trial so that we can validate the data from this retrospective study in a prospective way. So, Jeanny, let's now move on to another important disease type which is urothelial carcinoma. There is a very recent accelerated FDA approval of the drug combination of enfortumab vedotin and pembrolizumab for cisplatin-ineligible metastatic urothelial carcinoma patients. This is Abstract 4505, which is being presented by Dr. Shilpa Gupta and colleagues. Can you please tell us more about this update? Dr. Jeanny Aragon-Ching: Yeah, absolutely. So, as you mentioned, Neeraj, the FDA just granted accelerated approval in April 2023 for this combination of enfortumab vedotin or EV, which is and ADC, antibody drug conjugate against nectin-4 and the PD-1 inhibitor pembroluzimab. So it's a combination for patients with locally advanced or metastatic urothelial carcinoma who are considered cisplatin ineligible. So this is nearly a four-year follow-up.   So as a reminder, this was a phase 1b/2 trial that included 45 patients and it had a primary endpoint of safety and tolerability although the key secondary endpoints included confirmed overall responses, duration of response, progression-free survival, and the resist criteria was investigated via investigator and BICRs which is in a blinded independent central review. Even overall survival was a key secondary endpoint.  So, the bottom line was the confirmed overall response by BICR was 73.3%, the disease control rate was about 84%, and the CR rate was 15.6% with a PFS of close to 13 months, and a 12-month overall survival rate of 83%. However, it is important to cite that there were treatment-related adverse events including skin reactions in 66%, neuropathy occurred in 62%, and ocular disorders in 40%. And there was a little bit of pneumonitis in close to 9%, colitis, and hypothyroidism, so there are side effects to watch out for.  Dr. Neeraj Agarwal: So, Jeanny this is great. What is the key takeaway from this trial?  Dr. Jeanny Aragon-Ching: So I think the most important thing is we now have a new combination of EV and pembro which shows very promising responses and survival in part which led to the FDA accelerated approval in the cisplatin-ineligible population of patients. However, we must note that the phase 3 trial of EV302 will ultimately establish which approach is really beneficial for all of our cisplatin-ineligible patients, either a carboplatin-based chemotherapy regimen or a non-platinum-based regimen such as EV and pembro. Dr. Neeraj Agarwal: Thanks Jeanny, would you like to discuss any other study in the bladder cancer space? Dr. Jeanny Aragon-Ching: Absolutely. I think Abstract 4508 from Dr. Seth Lerner and colleagues will be very relevant to our colleagues. This abstract is SWOG S1011, which is a phase 3 surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at the time of radical cystectomy for muscle-invasive bladder cancer.  Dr. Neeraj Agarwal: Yes. So this trial, as you said, is an important trial which randomized in a one-on-one fashion 618 patients with muscle-invasive bladder cancer undergoing radical cystectomy, and these patients were randomized to either standard lymph node dissection or an extended lymph node dissection. And standard lymph node dissection included, as we know, external and internal iliac and operative lymph node. The extended lymph node dissection included lymph nodes up to aortic bifurcation which included common iliac, presciatic, and presacral lymph nodes. At a median follow-up of approximately 6 years, there was no disease-free survival or overall survival benefit in patients undergoing an extended lymph node dissection compared to standard lymph node dissection. And extended lymph node dissection was also associated with greater morbidity and preoperative mortality. Dr. Jeanny Aragon-Ching: Very interesting data, Neeraj. So these results, I think, will be very useful for a lot of our surgical colleagues in both academia and the community who may still be inclined to perform extended lymphadenectomy during cystectomy. This study shows that it's actually not necessary. Dr. Neeraj Agarwal: Absolutely. So now let's move on to another disease type, which is very important - prostate cancer. There are several practice-informing abstracts that are worthwhile discussing. The first of these involves Abstract 5002, which looks at the impact of the PSA nadir as a prognostic factor after radiation therapy for localized prostate cancer, which will be presented by Dr. Praful Ravi and  colleagues. Jeannie, can you please tell us more about this abstract? Dr. Jeanny Aragon-Ching: Yeah, definitely. So this abstract, as you mentioned, Neeraj, is a prognostic impact of PSA nadir of more than or equal to 0.1 nanogram per ml within six months after completion of radiotherapy for localized prostate cancer - an individual patient data analysis of randomized trials from the ICECaP Collaborative. Basically, it refers to an attempt to evaluate early surrogate measures to predict for long term outcomes such as prostate cancer-specific survival, metastases-free survival, and overall survival. So they looked at a big registry from the ICECaP collaboration that included 10,415 patients across 16 randomized controlled trials. And those men underwent treatment for intermediate risk and high risk prostate cancer treated with either radiation therapy alone in about a quarter of patients, or they got RT with short-term ADT in about 58% of patients, and 17% of them got RT with long-term ADT.  So, after a median follow-up of ten years, what they found was, if you had a PSA nadir that is over or equal to 0.1 nanogram per ml within six months after completion of radiation therapy, it was associated with worse prostate cancer-specific survival, metastases-free survival, and overall survival. For instance, the five-year metastases-free survival for those who achieved a PSA nadir of less than 0.1 was 91% compared to those who did not, which was 79%. Therefore, they concluded that if you achieve a bad PSA of 0.1 or above within six months after you completed radiation, you had worse outcomes.  Dr. Neeraj Agarwal: Jeanny, what is the key takeaway message from this study? Dr. Jeanny Aragon-Ching: The key takeaway from this ICECaP analysis is that this information would be very important to augment a signal-seeking endpoint, especially for clinical trial development, so that we can develop further strategies to de-escalate for those who don't need systemic intensification or therapy intensification versus escalation for those who really do. Dr. Neeraj Agarwal: So, my radiation oncology colleagues need to watch out for those patients who do not achieve a PSA of less than 0.1 nanogram per ml within the first six months of finishing radiation therapy. Very interesting data.  Dr. Jeanny Aragon-Ching: Yes, absolutely. So. Neeraj another important abstract for our fellow clinicians, switching gears a little bit now, is Abstract 5011, which is titled “Do Bone Scans Overstage Disease Compared to PSMA PET?” This was an international, multicenter retrospective study with blinded, independent readers. Can you tell us more about this abstract? Dr. Neeraj Agarwal: Yes, a relatively small retrospective study, but still pertinent to our practice. So I'll summarize it. This study by Dr. Wolfgang Fendler and colleagues evaluated the ability of bone scans to detect osseous metastasis using PSMA PET scan as a reference standard. So in this multicenter retrospective study, 167 patients were included, of which 77 patients were at the initial staging of prostate cancer, 60 had biochemical recurrence after definitive therapy, and 30 patients had CRPC or castor-resistant disease.  These patients had been imaged with a bone scan and a PSMA PET scan within 100 days. And in all patients, the positive predictive value, negative predictive value and specificity for bone scan were evaluated at different time points. They had bone scan and PSMA PET scan and both were compared. And what they found was interesting. All these three values - positive predictive value, negative predictive value, and specificity for bone scan were 0.73, 0.82 and 0.82 in all patients, and in initial staging, it was even lower at 0.43 and 0.94 and 0.80.  So, without getting into too much detail regarding these numbers, I want to highlight the most important part of the study, that at the initial staging, 57% patients who had a positive bone scan had false positive bone scans. The interreader agreement for bone disease was actually moderate for bone scans and quite substantial for the PSMA PET scan.  Dr. Jeanny Aragon-Ching: So, Neeraj, what do you think is the key takeaway message here for our audience?   Dr. Neeraj Agarwal: The key takeaway message is that positive predictive value of bone scan was low in prostate cancer patients at initial staging, with the majority of positive bone scans being false positive. This suggests that a large proportion of patients which we consider to have low-volume metastatic disease by bone scan actually have localized disease. So in the newly diagnosed patients with prostate cancer, patients should ideally have a PSMA PET scan to rule out metastatic disease.   So, let's move on to another abstract I would like to discuss, which has important implications in treatment, especially now that lutetium 177 is approved, but frankly not available widely. Dr. Jeanny Aragon-Ching: Yeah, that's actually very timely. So the abstract you're referring to is 5045, which is being presented by Dr. Yu Yang Sun and colleagues entitled “Effects of Lutetium PSMA 617 on Overall Survival in TheraP Versus VISION Randomized Trials: An Exploratory Analysis.” So, Neeraj, can you tell us more about the relevance of this exploratory analysis? Dr. Neeraj Agarwal: Definitely. In this abstract, Dr. Yang Sun and colleagues assess the effect of lutetium PSMA on overall survival in two different trials, TheraP and VISION trials. So, just for our listeners' recollection, the phase 2 TheraP trial compared lutetium PSMA and cabazitaxel in patients with mCRPC who had progression on docetaxel and had significant PSMA avidity on gallium PSMA pet scan, which was defined as a minimum uptake of SUV max of 20 at least one site of disease and SUV max of more than 10 at all sites of measurable disease.  In this trial, 20 of 101 patients in the cabazitaxel arm crossed over to lutetium PSMA, and 32 of 99 patients in the lutetium PSMA arm crossed over to cabazitaxel. In the VISION trial, patients with mCRPC who previously progressed on at least one ARPI and one taxane-based therapy and had a positive gallium PSMA scan, and here, positivity was not stringently pre-specified as it was done in the context of TheraP trial. So, positive gallium pet scans were randomly assigned in two to one fashion to receive either lutetium PSMA plus best supportive care or standard of care versus standard of care.  And I'd like to highlight that the standard of care comprised ARPIs and bone protecting agents and these patients were not allowed to have cytotoxic chemotherapy such as cabazitaxel in the standard of care arm. Now, overall survival was similar in the lutetium PSMA group regardless of whether they got lutetium PSMA in the VISION trial or TheraP trial. There was no difference in overall survival with lutetium in the lutetium arms of VISION and TheraP trial with a hazard ratio of 0.92. And there was no difference in the overall survival between the lutetium PSMA and the cabazitaxel group in the TheraP trial if you use counterfactual analysis, assuming crossover had not occurred. So, quite interesting in my view. Dr. Jeanny Aragon-Ching: Yeah, thanks Neeraj for that wonderful synopsis and discussion. So, what is the key take home message then? Dr. Neeraj Agarwal: The main message in this new exploratory analysis, which combined both the TheraP and VISION trials, is that lutetium PSMA and cabazitaxel seem to be associated with similar overall survival benefit in these highly selected patients with PSMA positivity. Additionally, the difference in the observed effect of lutetium PSMA and overall survival in the TheraP and VISION trials may be actually better explained by the use of different treatments in the respective control arms of these trials. And these results, in my view, are quite pertinent for those patients and providers who do not have access to lutetium-177 therapy.  Let's go to another abstract that is currently relevant to our practice, given many patients with advanced prostate cancer who have concurrent diabetes; I'm talking about Abstract 5066. Jeanny, can you please tell us more about this abstract?  Dr. Jeanny Aragon-Ching: Certainly, Neeraj. So this abstract will be presented by Dr. Amy Shaver and colleagues. So it's also very relevant, since many men who are diagnosed with prostate cancer frequently also have a concomitant diagnosis of type 2 diabetes mellitus. So, this was a SEER-Medicare population database analysis that looked at men who were treated with either abiraterone or enzalutamide and also had concomitant diagnosis of type 2 diabetes mellitus (DM). And they were identified using ICD-9 and ICD-10 codes and they were all tied in to acute care utilization. So they looked at CMS research data codes and ER hospitalization visits six months after treatment initiation was recorded. So all in all, they took a sample of 11,163 men, of whom close to 62% were treated with abiraterone and about 38% were treated with enzalutamide.  So, of these, about 27% of them had type 2 DM, of whom 59% received abiraterone and about 41% had enzalutamide. So, the bottom line is, compared to those without diabetes mellitus, those who had type 2 diabetes had worse acute care utilization, which was 43% higher than those who got abiraterone compared to enzalutamide, and also had higher overall mortality. Therefore, the bottom line is, having type 2 diabetes mellitus, unfortunately, portends worse outcomes in men with prostate cancer, so careful attention needs to be paid to those who are starting out already with such comorbidities. So Neeraj, any final thoughts you have regarding this abstract and overall before we wrap up on the podcast today?  Dr. Neeraj Agarwal: Absolutely. So it looks like, based on this very important pertinent Abstract 5066, which talks about the impact of diabetes on our patients, I think we need to be very watchful regarding the impact of diabetes on our patients who are being treated with abiraterone or enzalutamide, especially drugs which are known to make the metabolic syndrome and diabetes worse. I think close monitoring and close attention to control of diabetes is very important. So with that, I would urge the listeners to come and join us at the Annual Meeting, not only to celebrate these successes but also to help disseminate this cutting-edge data to practitioners and maximize the benefit to our patients across the globe.   And thank you to our listeners for joining us today. You will find links to the abstracts we discussed today on the transcript of this episode. Finally, if you value the insights that you hear on our ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast.  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. Neeraj Agarwal @neerajaiims Dr. Jeanny Aragon-Ching 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. Jeanny Aragon-Ching: Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant,  Exelixis, Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics.

Dr. John Sweetenham and Dr. Marc Braunstein discuss the role of maintenance therapy in high-risk multiple myeloma, advances in myelodysplastic syndromes in the COMMANDS study, the promise of bispecific antibodies in the pivotal EPCORE NHL-1 in relapsed/refractory large B-cell lymphoma, and improving outcomes for patients with chronic lymphocytic leukemia in the CAPTIVATE trial.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. My guest today is Dr. Marc Braunstein, a hematologist and oncologist at the NYU Perlmutter Cancer Center. Today, we'll be discussing key posters and oral abstracts highlighting advances in hematologic malignancies that will be featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.  Dr. John Sweetenham: So, Marc, thanks for returning to us and coming to join us on the podcast today. Dr. Marc Braunstein: Thanks for inviting me back. Dr. John Sweetenham: I'd like to start out with Abstract 8001. This is a study which is addressing the role of maintenance therapy in patients with high-risk multiple myeloma. Could you take us through this study and the key take-home points that you think are the most important ones? Dr. Marc Braunstein: Sure, absolutely. So, the first abstract that we're going to discuss is an oral abstract being presented by Dr. Nooka regarding maintenance therapy in high-risk multiple myeloma patients. Outcomes of patients with multiple myeloma are clearly improving, yet those with high-risk cytogenetic abnormalities, which represent about 10-20% of all multiple myeloma, tend to have poorer survival, and worst among these are those with what's called ultra-high-risk or double-hit multiple myeloma who have more than 1 high-risk cytogenetic abnormality. So, this study looked at maintenance therapy following stem cell transplantation in 26 high-risk patients, about 59% of whom had double hit disease, representing very high-risk disease. This was a phase II study looking at using carfilzomib, pomalidomide, and dexamethasone in high-risk multiple myeloma patients who achieved at least a partial remission following stem cell transplant. There were 26 patients enrolled. The median age was 60. Of note, about 59% of patients were Black, which is important because these patients tend to be historically underrepresented in studies. And what they found was that at study entry, about 24% of patients were in a complete remission or better, and that deepened to 79% while on the study. And the median time to best response was 2 months, which is fairly brisk. With a median follow-up of about 26 months, the 36-month progression-free survival was 63%, and the overall survival was 72%, which is impressive, again in the context of patients who have very high-risk disease. So, although it remains to be determined what the optimal regimen or duration of maintenance should be in multiple myeloma, clearly, combination therapy is effective and should be used in patients who have high-risk or ultra-high-risk multiple myeloma. Dr. John Sweetenham: Great. Thanks, Marc. So, as you say, I mean, clearly the take-home message is around the effectiveness of this type of maintenance therapy. I just have a couple of quick follow-up questions for you. The first of those is, where do you see this going next? I mean, in your opinion, what would be the next logical study with this combination or similar combinations? And then secondly, what do you see on the horizon for those patients with very high-risk myeloma, particularly the double-hit population that you just mentioned? Dr. Marc Braunstein: It's a paradigm in multiple myeloma that combination therapy tends to be more effective as long as we're able to manage the adverse events that come with additional combinations. And we've been able to succeed in that regard with quadruplet regimens, even now that we have monoclonal antibodies that tend to be better tolerated and more targeted in nature. In terms of maintenance therapy, single-agent lenalidomide has been the long-standing agent of use for the majority of patients. But we now understand that the combination of an immunomodulator like lenalidomide and a proteasome inhibitor like bortezomib or carfilzomib is more effective for patients with higher risk disease.   We also have data from various upfront studies of quadruplet regimens, such as the FORTE study, which looked at carfilzomib and lenalidomide maintenance after transplant that shows that we can improve progression-free survival in all comers with multiple myeloma following transplants. So, I think down the road we're going to be looking at more use of combination therapies and maintenance. And as far as for high-risk patients, whether that's going to be using monoclonal antibodies in maintenance or combination proteasome inhibitors and immunomodulators or even other immunotherapies like bispecific antibodies as maintenance in the future remains to be determined, but clearly, for high-risk patients, we should be using combination therapies. Dr. John Sweetenham: Thanks, Marc. Let's change gears a little now and take a look at Abstract 7003, which addresses patients with myelodysplastic syndrome. This study addresses the efficacy and safety results from a study of luspatercept versus epoetin alfa in low-risk myelodysplastic syndrome. I wonder if you could describe this study and the results to us and maybe also for the benefit of our listeners, just mention quickly the mechanism of action of the experimental agent here.  Dr. Marc Braunstein: This is an oral abstract being presented by Dr. Garcia-Manero looking at a phase 3 study, as you mentioned, called the COMMANDS study, and this is looking at an agent called luspatercept in patients with low-risk myelodysplastic syndrome (MDS). So, patients with MDS can have inferior quality of life and survival when they become transfusion dependent. An earlier study called the MEDALIST study, which was published in the New England Journal of Medicine in 2020, randomized low-risk or intermediate-risk patients with MDS who were refractory or unlikely to respond to erythropoietin stimulating agents to either luspatercept, which is an agent that binds to TGF-beta family members and helps stimulate erythropoiesis. Patients were randomized in the MEDALIST study to luspatercept or placebo. And that study showed that luspatercept could improve a degree of anemia and lead to transfusion independence in certain patients. So, the COMMANDS study is a randomized controlled study that randomized 354 patients with low-risk MDS who were transfusion dependent and naive to an erythropoietin stimulating agent to receive either luspatercept or the erythropoietin stimulating agent erythropoietin alfa with the primary endpoint of transfusion independence at some time between 12 to 24 weeks. So, patients were randomized 1:1 to receive either luspatercept or epoetin alfa, and the primary endpoint again was transfusion independence. So, 354 patients were randomized in the study and the median treatment durations were 42 weeks of luspatercept and 27 weeks of epoetin alfa. And transfusion independence occurred in greater quantity in the patients who got luspatercept. For example, in the patients who received luspatercept at 8 weeks, transfusion independence was achieved in 74 versus 51% in the epoetin alfa group. So, in terms of treatment-related adverse events, they were fairly similar between the groups and consistent with the classes -  they were reported in 30% in the luspatercept group and 17% in the erythropoietin group, with no difference in patients who progressed to acute myeloid leukemia.  So, I think when it comes to MDS in low-risk patients, it's really important to preserve their quality of life by limiting their transfusion burden. And I think this study demonstrates that luspatercept continues to be an important part of the management in these low-risk patients. And whether or not you would start a patient with low-risk transfusion-dependent MDS on an erythropoietin stimulating agent or luspatercept is really addressed by this study showing that you can achieve greater rates of improvement in anemia and transfusion independence with luspatercept.  Dr. John Sweetenham: Great. Thanks, Marc. A really interesting study. And I do have one question for you about this study, which I think will make it clear to you that I am an expert neither in myelodysplastic syndrome nor in erythropoiesis. But my question is based on the mechanism of action. Is there any rationale for combining these 2 agents in future studies?  Dr. Marc Braunstein: Yes, it would potentially make sense to use 2 synergistic mechanisms to improve erythropoiesis. We would have to see what the potential for adverse events are. I think epoetin alfa tends to be a fairly low burden in terms of its side effect profile. Luspatercept can have some potentially dose-limiting side effects, such as GI side effects, but you can make dose adjustments to both of these medications. So we may need to find the correct doses of either of them in combination. But from a theoretical standpoint, it makes sense that these could potentially be synergistic, especially in patients who are likely to respond to erythropoietin by having a baseline lower erythropoietin level. Dr. John Sweetenham: Okay, let's move on in another change of gear now. And for the rest of the podcast, we're going to be talking about some studies in lymphoid malignancy, beginning with Abstract 7535, which is a follow-up of the phase 2 CAPTIVATE study which now has significantly extended follow-up from the original report. So Marc, can you walk us through this study and the outcomes to date? Dr. Marc Braunstein: Absolutely. So this is a poster being presented by Dr. Barr and it is looking at CLL, which is a field that is really moving away from chemotherapy for newly diagnosed patients, thanks to the development of novel targeted agents. The CLL14 trial, which was published in the New England Journal of Medicine in 2019, showed that fixed-duration venetoclax plus obinutuzumab improved progression-free survival and rates of negativity of minimal residual disease, or MRD, when compared to chlorambucil and obinutuzumab. So building on the success of that study, combining a monoclonal antibody and a BCL2 inhibitor, the CAPTIVATE study is a phase II study, which examines venetoclax with ibrutinib, the BTK inhibitor, and previously untreated CLL. So it's kind of combining 2of the novel targeted therapies in a fixed duration, similar to what was done in the CLL14 study where patients received 1 year of therapy and then stopped treatment.   So in the CAPTIVATE study, 154 patients were enrolled. This was a phase 2 study that included about 56% of higher-risk patients who had unmutated IGHV, and the median time on the study was 50 months, with a CR rate of 58% at a 4-year follow-up and an overall response rate of 96%, which is quite high, especially considering that more than half of patients had high-risk disease. The progression-free survival was 79% and the overall survival rate was 98% at 4 years. And when they looked at patients who had undetectable minimal residual disease, the 4-year overall survival rate was 100%, which also suggests that MRD can help serve as a predictive marker of longer-term survival. So I think we have to also consider what the side effects are of combining these 2 agents and the most common adverse events were hematologic, which is expected based on what we know about the 2 classes. So I think the implication of the study is that giving 2 oral agents for a fixed period of treatment for 12 cycles is a rational approach that may spare patients indefinite therapy and can lead to positive outcomes, including in patients who have high-risk features with CLL.  Dr. John Sweetenham: Yeah, the other interesting observation that was made in the abstract, which I found to be really encouraging, was the fact that a number of these patients apparently have been re-treated successfully upon progression with ibrutinib again, which seems to be somewhat reassuring as well.  Dr. Marc Braunstein: That's right. There were 4 patients who started re-treatment in the study and perhaps we'll see the outcomes of that small subgroup are at the poster presentation. But I think when we discuss fixed-duration treatment, it also opens the door to potentially re-challenging patients when they relapse. We know that when we stop single-agent BTK inhibitors, which are historically given indefinitely in patients with CLL, those patients who stop, many will relapse, but you can potentially re-challenge them with the BTK inhibitor. So this study with the CAPTIVATE trial gives us some liberty to discontinue therapy, but also considering re-challenging upon relapse.   Dr. John Sweetenham: Yeah, absolutely. Moving on to aggressive B-cell lymphoma, now, the next abstract I'd like to discuss with you is Abstract 7525. I find this one particularly interesting as the continued excitement around CAR T cell therapy for relapsed aggressive lymphoma remains high at the moment. It's intriguing that t cell-engaging antibodies also have been reported, at least, to have remarkable activity in this set of diseases. So can you take us through Abstract 7525 and what they're reporting?  Dr. Marc Braunstein: Absolutely. Bispecific antibodies represent an emerging field in multiple hematologic malignancies, and this is a class of antibodies that bind to both the tumor cell as well as T-cells, and activate T-cell immunity against the tumor cell. So epcoritamab is a bispecific antibody that binds to CD3, which is expressed on T cells, and CD20, which is expressed on B cells. And Thieblemont et al published results in the Journal of Clinical Oncology last year in a phase I/2 study that looked at epcoritamab in patients with diffuse large B cell lymphoma following 2 prior lines of therapy, and this was given subcutaneously until progression of disease. In that study, at a median follow-up of about 11 months, the overall response rate was 63% with 39% complete remissions.   So the EPCORE NHL-1 study, which is being presented at this year's ASCO meeting, is presenting the updated results of that study looking at patients with diffuse large B cell lymphoma that includes a small population as well of patients with high-grade B cell lymphomas and primary mediastinal B cell lymphomas who had at least 2 prior lines of therapy. In this presentation, 157 patients were included in this study, and 61% had primary refractory disease, and actually, 39% had prior CAR T-cell therapy, of whom 75% progressed within 6 months. So these were patients who were not only refractory to treatment but also had prior T-cell therapy.   So at a median follow-up of 20 months, the overall response rate was 63% and the complete response rate was again about 39%, and the median duration of complete remission was 21 months. In terms of overall survival, the median was about 19 months, which is substantial for this group of patients who really wouldn't be expected to respond very well to conventional therapies.   As we know, T-cell-engaging therapies, such as these bispecific antibodies or CAR T-cells have the potential risk for certain immune-related adverse events, including cytokine release syndrome or icons, and a neurologic syndrome related to the therapy. And it's worth noting that the CRS in this study was predominantly low-grade. There were only 3% of patients who had grade III CRS, and 9 patients, or 6% had grade I to II icons. I think that also reflects how we're better managing those side effects and intervening earlier. So I think the results are impressive from the standpoint of the population studied, who were quite refractory to treatment and show relatively high rates of response. In fact, the median overall survival was not reached in the overall population.   So I think what we take away from this abstract is that bispecific antibodies are going to play a vital role in the relapse-refractory setting for large cell lymphoma and may also offer an alternative to patients who aren't necessarily fit for CAR T-cell therapy, which plays a vital role in patients who are both refractory to first-line therapy or relapse-refractory to subsequent disease. So these are very encouraging results, and I'm sure we'll see randomized data as well in the future, further supporting the use of bispecific antibodies like epcoritamab.  Dr. John Sweetenham: Yeah, I agree. Thanks, Marc. I think that's a great summary. And it's particularly exciting to me that the investigators were able to achieve this kind of level of response and progression-free survival with a subcutaneous treatment. It's really quite remarkable and really exciting to see that.  We're going to wind up with our final abstract today, which is looking at the utilization of circulating tumor DNA in, again, in patients with aggressive B cell lymphoma. This is Abstract 7523, so maybe you could walk us through this one, Marc.  Dr. Marc Braunstein: Absolutely. So this is a poster being presented by Dr. Herrera looking at a, I guess you could call it a biomarker in the blood using circulating tumor DNA in patients with newly diagnosed diffuse large B cell lymphoma in the POLARIX study. So the results of the phase 3 POLARIX study were published last year in the New England Journal of Medicine and showed improvement in progression-free survival with the addition of these anti-CD79b antibody polatuzumab to standard R-CHOP chemotherapy compared to R-CHOP alone. And this study actually led to the approval of first-line treatment that includes polatuzumab.   In the abstract being presented by Dr. Herrera, the investigators looked at the value of circulating tumor DNA as a potential marker to serve as a guide for prognosis and predicting longer-term responses, particularly when the blood is cleared of circulating tumor DNA. So the study involved 654 patients who had ctDNA results both at baseline and then with longitudinal assessment, and they used an assay called the CAPP-Seq assay to assess circulating tumor DNA and assess for its clearance. In the study, undetectable circulating tumor DNA was achieved in 57% of patients who got the polatuzumab R-CHP combination and 59% of the patients who got R-CHOP by cycle 5 and then 6% in the polatuzumab group at 67% in the R-CHOP group.  So the rates of circulating tumor DNA clearance were similar between the 2 arms. But what's notable is that patients in the polatuzumab arm who achieved a complete response at the end of treatment plus cleared their circulating tumor DNA had superior progression-free and overall survival compared to patients who achieved a CR but retained circulating tumor DNA in their blood.   And this has implications because it might help gauge, for example, if patients may need additional cycles to clear the circulating tumor DNA, although we still need more data to answer whether that's necessary or not. And it may help serve as a predictive marker for longer-term remission, particularly in patients who perhaps have higher risk factors at baseline. So I don't think this is necessarily ready for primetime to use in clinical practice, but it is intriguing to know that we could finally have a tumor-specific biomarker in the blood to help monitor patients and potentially predict their longer-term remissions.  Dr. John Sweetenham: Thanks, Marc. I agree. Great summary, and obviously there's still something to learn about the kinetics of the response and so on. And also, I suppose it raises the question of whether those patients who still have detectable levels should be switched at the end of therapy to some kind of preemptive second-line therapy. And these are obviously all questions for the future, but it's going to be very interesting to watch this space, I think, and see how this story develops. Dr. Marc Braunstein: Absolutely. And my colleagues in the solid tumor space are already using circulating tumor DNA, for example, in colon cancer, to help with surveillance. So perhaps this could be a tool to use to predict relapse also in patients who are on surveillance after their treatment. But again, as you alluded to, we need more data to address that.  Dr. John Sweetenham: Well, thanks so much, Marc, for sharing your insights with us today on a really interesting set of abstracts coming up at the June meeting. And thanks for joining us on the ASCO Daily News Podcast. Dr. Marc Braunstein: Thank you for inviting me.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in a transcript of this episode. Join us again after the annual meeting for key takeaways on the late-breaking abstracts and other key advances from the ASCO Annual Meeting. And 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 speakers:  Dr. John Sweetenham 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 OncologyResearch Funding (Institution): Janssen, Celgene/BMS

To stay up to date with new treatments and standards of care medical oncologists in the United States are required to take the ABIM Maintenance of Certification exam, a ten-hour test, every ten years. This ASCO education podcast focuses on the Longitudinal Knowledge Assessment. An alternative test that offers more flexibility in medical certification.     Our guests are Dr. Suresh Nair Physician-in-Chief of Lehigh Valley Cancer Institute in Allentown, Pennsylvania and Chair of the ABIM Medical Oncology Board and Dr. Olatoyosi Odenike, Associate Professor of Medicine at the University of Chicago and member of the ABIM Medical Oncology Board.   Speaker Disclosures  Dr. Suresh Nair:   Research Funding - Bristol-Myers Squibb Recipient; Merck; Nektar Therapeutics; Mirati Therapeutics; Strata Oncology   Dr. Olatoyosi Odenike:   Consulting / Advisory Role – Abbvie; Impact Biomedicines; Celgene Recipient; Novartis; BMS; Taiho; CTI Biopharma; Threadwell therapeutics; Blueprint Medicines; SERVIER; Kymera; Bristol-Myers Squibb/Celgene  Research Funding - Celgene; Incyte; Astex Pharmaceuticals; NS Pharma; Abbvie; Janssen Oncology; Oncothyrapy; Agios; AstraZeneca; CTI BioPharma Corp Recipient; Kartos; Aprea AB; Bristol-Myers Squibb; Daiichi Sankyo; Loxo; Novartis  Resources  To find out more about the ABIM LKA, go to https://www.abim.org/lka/  For a video walk-through, visit https://www.youtube.com/watch?v=C0-qaUQmQXc  Sign in to the ABIM Physician Portal to sign up for LKA by June 30, 2023: https://portal.abim.org/   To find out more about how ASCO supports physicians engaged in ABIM MOC, go to https://old-prod.asco.org/meetings-education/continuing-education-moc  If you are interested in joining the ABIM Item Writing Task Force for Medical Oncology, find out more and submit your application at: https://www.abim.org/about/boards-and-committees/openings/medonc-iwtf-physician/  If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT Disclosures for this podcast are listed in the podcast page.  Dr. Suresh Nair: The medical profession is one where new treatments and standards of care are being discovered and applied frequently, especially in oncology. Staying up to date with such practices allows the physician to provide the highest quality of care. How is this accomplished? By taking part in the Maintenance of Certification, or MOC. The traditional MOC assessment takes about 10 hours to complete and gives you ten years to be reported as certified before your next assessment is due. But given today's world where new treatments and standards of care are advancing rapidly, a more continuous assessment approach is warranted to help oncologists stay up to date.  This ASCO Education Podcast explores a new alternative to the every decade MOC exam for medical oncology. It's known as the Longitudinal Knowledge Assessment or LKA. I'm Suresh Nair MD, the Physician Chief of the Lehigh Valley Topper Cancer Institute in Allentown, Pennsylvania, and Chair of the American Board of Internal Medicine Medical Oncology Board. I will guide you through a general overview of the LKA, what it is, how it works, what the advantages are, and top-level need-to-know information. Joining me is my medical oncologist colleague, Dr. Olatoyosi Odenike, who's a professor of medicine and director of the Leukemia Program at the University of Chicago and serves as a fellow member of the ABIM Medical Oncology Board.  To begin, here are the essential differences between the ten-year maintenance of certification exam or MOC exam and the Longitudinal Knowledge Assessment, the LKA. Both are being used to help medical professionals maintain a working knowledge of the latest treatments and standards in use in their field. The MOC is administered every ten years at specified locations, lasts about 10 hours, and the results are available after two months. The LKA is another option. It has a five-year cycle during which you answer questions on an ongoing basis and receive regular feedback on how you're performing. Dr. Odenike has taken the LKA and the MOC.  Toyosi, please describe the preparation and the actual experience of taking the traditional MOC test. How much time did you take to prepare for the exam and how did you fit that prep time into your busy schedule? Dr. Olatoyosi Odenike: Thank you so much, Dr. Nair. For the traditional MOC, I started preparing about six months ahead of time and it was challenging to find time to prep and to fit that into an already busy schedule. It came down to blocking out any available time, particularly on the weekends, in the few weeks leading up to the actual examination date. It was also challenging to find time to dedicate a whole day to taking the exam and traveling down to the test site to do so. Dr. Suresh Nair: Today, the LKA is another option for busy oncologists. In 2022, the American Board of Internal Medicine launched the LKA after years of working with and listening to the physician community to understand their needs. As long as you're meeting the LKA participation requirement and other MOC requirements you'll continue to be publicly reported as certified for your entire five-year LKA cycle. The LKA is designed to provide greater flexibility, more convenience, and more immediate feedback, helping physicians stay current. Dr. Odenike, what has been your experience so far with the LKA? Dr. Olatoyosi Odenike: So far, I have found the process far easier to navigate than the MOC. Registering for the LKA on the ABIM physician portal was very easy. There are 30 questions per quarter, and I chose to get weekly reminders of the due date, along with a link to access the portal and the LKA questions. I find this to be so convenient, I can determine when to access and complete the questions, which I have often done on block closer to the due date. You are able to do this and fit this in your schedule any way you choose, which is a big improvement on the traditional MOC. Dr. Suresh Nair: Is the LKA a big time commitment for you? 30 questions per quarter seems like a lot. How does it compare to the traditional ten-year model?  Dr. Olatoyosi Odenike: There's a four-minute time limit per question. So technically, you can answer all 30 questions in one afternoon. Some physicians report doing this in two hours. Data gathered over the last year have shown that most participants answer questions in under two minutes. And how they approach it is unique to each person. Some set aside a little time each week to answer questions until they're finished. Others, like me, will do it all at once or over the course of one week near the end of the quarter. You could do one a day with your morning coffee if you wanted to. We have found the structure to be significantly more flexible than the traditional MOC.  We have a question for you, Dr. Nair. Can physicians sign up for the LKA now, even if they're not due for an assessment? Dr. Suresh Nair: You can only sign up in the year that you're due, or rather, starting in the December prior to your due year. So, physicians due for an assessment in 2023 were able to enroll starting December 1, 2022. Physicians who are recently certified or who are not due for a few more years have to wait until their due year to sign up for the LKA. Dr. Olatoyosi Odenike: What is the last date to sign up for the LKA? Dr. Suresh Nair: The last day to enroll in 2023 is June 30. If you missed the enrollment date for the LKA this year, you can still opt to take the MOC exam in the fall without letting your certification lapse. MOC registration closes August 15.   Dr. Olatoyosi Odenike: What happens if you don't pass after five years? Dr. Suresh Nair: If you don't pass after five years, you enter the grace period as long as you're meeting your other MOC requirements and will continue to be reported as certified during that time. You'll have one calendar year to pass the traditional MOC exam. In some ways, this is somewhat risk-free going with the LKA in that regard. Can physicians still take the MOC exam if they prefer to? Dr. Olatoyosi Odenike: The MOC exam is still available in spring and fall each year for most certificates, including med ONC and hematology, the LKA is just another option. Many physicians prefer to take the traditional exam or if they're certified in multiple specialties, they use both the exam and the LKA to balance their time and areas of expertise better. Some physicians take the LKA in hematology and/or medical oncology while using the exam to remain certified in internal medicine, for instance, or vice versa.  I have a question for you, Dr. Nair. Who is eligible to take the LKA? How can physicians know if they're eligible? Dr. Suresh Nair: LKA is offered in 15 specialty areas. All board-certified physicians in their assessment due year, except those in a grace period, are eligible. All physicians certified before 1990, all physicians with a lapsed certification. In fact, I had trained in both hematology and oncology 30 years ago, and I practiced medical oncology at two academic community hospital systems. I actually signed up for the LKA this past year to regain certification in hematology that had lapsed after my first 10 years, and I've had a great experience. I have finished a year of taking the test. I've gotten assessments. I see what my strong points and weak points are. I've actually ordered the ASH_SAP and I'm reading up on my weak points and I'm continuing this process. It really starts growing on you.  I'd like to thank Dr. Odenike for sharing your real-time experience in taking both the MOC and the LKA. I would like to extend an opportunity for all listeners interested in keeping their certifications through the LKA by going to the ABIM Physician portal www.abim.org. That's www.abim.org or go to the notes on the podcast page to access the link, as well as other resources. There you can keep track of assessment deadlines and progress, and it allows you to set reminders for assessments, points, and payments.  I want to thank all of you for listening to this ASCO Education Podcast. The ASCO Education Podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncology well-being and professional development. If you have an idea for a topic or guest you'd like to see on the show, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, please visit education.asco.org. Thank you.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

In this episode of ASCO Educational podcasts, we'll explore how we interpret and integrate recently reported clinical research into practice. The first scenario involves a 72-year old man with high-risk, localized prostate cancer progressing to hormone-sensitive metastatic disease.  Our guests are Dr. Kriti Mittal (UMass Chan Medical School) and Dr. Jorge Garcia (Case Western Reserve University School of Medicine). Together they present the patient scenario (1:12), review research evidence regarding systemic and radiation therapy for high-risk localized disease (5:45), and reflect on the importance of genetic testing and (10:57) and considerations for treatment approaches at progression to metastatic disease (16:13).  Speaker Disclosures Dr. Kriti Mittal:  Honoraria – IntrinsiQ; Targeted Oncology; Medpage; Aptitude Health; Cardinal Health  Consulting or Advisory Role – Bayer; Aveo; Dendreon; Myovant; Fletcher; Curio Science; AVEO; Janssen; Dedham Group  Research Funding - Pfizer Dr. Jorge Garcia:  Honoraria - MJH Associates: Aptitude Health; Janssen Consulting or Advisor – Eisai; Targeted Oncology Research Funding – Merck; Pfizer; Orion Pharma GmbH; Janssen Oncology;  Genentech/Roche; Lilly  Other Relationship - FDA Resources  ASCO Article: Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019 ASCO Course: How Do I Integrate Metastasis-directed Therapy in Patients with Oligometastatic Prostate Cancer? (Free to Full and Allied ASCO Members) If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT Dr. Kriti Mittal: Hello and welcome to this episode of the ASCO Education Podcast. Today we'll explore how we interpret and integrate recently reported clinical research into practice, focusing on two clinical scenarios: localized prostate cancer progressing to hormone-sensitive metastatic disease; and a case of de novo metastatic hormone-sensitive prostate cancer progressing to castration-resistant disease.   My name is Kriti Mittal and I am the Medical Director of GU Oncology at the University of Massachusetts. I am delighted to co-host today's discussion with my colleague, Dr. Jorge Garcia. Dr. Garcia is a Professor of Medicine and Urology at Case Western Reserve University School of Medicine. He is also the George and Edith Richmond Distinguished Scientist chair and the current chair of the Solid Tumor Oncology Division at University Hospital's Seidman Cancer Center. Let me begin by presenting the first patient scenario.  Case 1: A 72-year-old male was referred to urology for evaluation of hematuria. A rectal exam revealed an enlarged prostate without any nodules. A CT urogram was performed that revealed an enlarged prostate with bladder trabeculations. A cystoscopy revealed no stones or tumors in the bladder, but the prostatic urethra appeared to be abnormal looking. Transurethral resection of the prostate was performed. The pathology revealed Gleason score 4+5=9 prostate cancer, involving 90% of the submitted tissue. PSA was performed one week later and was elevated at 50. Patient declined the option of radical prostatectomy and was referred to radiation and medical oncology.   So I guess the question at this point is, Dr. Garcia, in 2023, how do you stage patients with high-risk localized prostate cancer and how would you approach this case? Dr. Jorge Garcia: That's a great question and a great case, by the way, sort of what you and I in our practice will call ‘bread and butter'. Patients like this type of case that you just presented come from different places to our practice.  So either they come through urology or oftentimes they may come through radiation oncology. And certainly, it depends where you practice in the United States, at ‘X', US, they may come through medical oncology.   So I think that the first question that I have is in whatever role I'm playing in this case, where the patient has seen a urologist or a rad onc or me first, I think it's important for us in medical oncology, at least in the prostate cancer space, to talk about how do we think of their case and put those comments into context for the patient. It's very simple for you to tell a patient you can probably have surgery, radiation therapy, but at the end of the day, how do you counsel that patient as to the implications of the features of his disease is going to be really important. I use very simple examples that I relate to my patients, but really this patient is a patient that has very high-risk prostate cancer based upon the NCCN guidelines and how we actually stratify patients into what we call low-risk, intermediate-, and high-risk, and between those very low and very high risk.  So his PSA is high, very high, I would argue. His Gleason score, now, what we call group grading is high. He has high-volume disease. So the first question that I would have is, what are the choices for treatment for a patient like this? But even before you and I may talk about treatment options, we really want to understand the volume of their disease and whether or not they have localized prostate cancer with high-risk features or whether or not they have locally advanced or hopefully not metastatic disease. So back in the days prior to the FDA approval for PSMA PET imaging, we probably will have a Technetium-99 whole-body bone scan, and/or we probably will actually use CT scanning. Most people in the past, we used to do just a CT of the abdomen and pelvic region. As you know, with the movement of oral agents in the advanced setting, I think most of us will do a chest CT, abdomen and pelvic region, and certainly we also probably will have a Technetium-99 bone scan.  Now, with the utility and the use of PET imaging, I think most people like him will probably undergo PET PSMA, where you use F-18 PSMA or Gallium-68 PSMA. I think the importance depends on how you look at the approval of these two technologies. I think that PET PSMA imaging is here to stay. It's probably what most of us will use. And based upon that, we will define yet the truest stage of this patient. So right now, what we know is he has high-risk features. Hopefully, their disease is localized. We'll probably put the patient through an imaging technology. If you don't have access to a PET, then obviously CT and a bone scan will do. But if you do, the PET will actually help us define if the patient has disease outside of the prostate region, in the pelvic area, or even if they have distant metastases. Dr. Kriti Mittal: I would agree with that approach, Dr. Garcia. I think in the United States, we've been late adopters of PSMA scans. I think this patient with high-risk localized disease, if insurance allows at our institution, would get a PSMA for staging. There are still some patients where insurance companies, despite peer-to-peer evaluations, are not approving PSMAs. And in those situations, the patient would benefit from conventional CTs and a bone scan. So let's say this patient had a PSMA and was found not to have any regional or distant metastases. He decided against surgery, and he is seeing you as his medical oncologist together with radiation. What would your recommendations be?  Dr. Jorge Garcia: I think the bigger question is, do we have any data to suggest or to demonstrate that if in the absence of metastatic disease with conventional imaging or with emerging technologies such as PSMA PET, there is no evidence of distant disease, which I think you probably agree with me, that would be sort of unlikely with a patient with these features not to have some form of PSMA uptake somewhere in their body. But let's assume that indeed then the PSMA PET was negative, so we're really talking about high-risk localized prostate cancer. So I don't think we can tell a patient that radical prostatectomy would not be a standard of care. We never had a randomized trial comparing surgery against radiation therapy. This patient has already made that decision and surgery is not an option for him. If he, indeed, had elected radiotherapy, the three bigger questions that I ask myself are where are you going to aim the beam of that radiation therapy? What technology, dose, and fractionation are you going to use? And lastly, what sort of systemic therapy do you need, if any, for that matter? Where we do have some data maybe less controversial today in 2023 compared to the past? But I think the question is, do we do radiation to the prostate only or do we expand the field of that radiation to include the pelvic nodes?  Secondly, do we use IMRT? Do you use proton beam or not? Again, that's a big question that I think that opens up significant discussions. But more important, in my opinion, is the term of hypofractionation. I think the field of radiation oncology has shifted away from the old standard, five, seven weeks of radiation therapy to more hypofractionation, which in simple terms means a higher dose over a short period of time. And there was a concern in the past that when you give more radiation on a short period of time, toxicities or side effects would increase. And I think that there is plenty of data right now, very elegant data, demonstrated that hypofractionation is not worse with regards to side effects. I think most of us will be doing or supporting hypofractionation. And perhaps even to stretch that, the question now is of SBRT. Can we offer SBRT to a selected group of patients with high-risk prostate cancer? And again, those are discussions that we will naturally, I assume, in your practice, in your group, you probably also have along with radiation oncology.  Now, the bigger question, which in my mind is really not debatable today in the United States, is the need for systemic therapy. And I think we all will go back to the old data from the European EORTC data looking at the duration of androgen deprivation therapy. And I think most of us would suggest that at the very least, 24 months of androgen deprivation therapy is the standard of care for men with high-risk prostate cancer who elect to have local definitive radiation therapy as their modality of treatment. I think that whether or not it's 24 or 36, I think that the Canadian data looking at 18 months didn't hit the mark. But I think the radiation oncology community in the prostate cancer space probably has agreed that 24 months clinically is the right sort of the sweetest spot.  What I think is a bit different right now is whether or not these patients need treatment intensification. And we have now very elegant data from the British group and also from the French group, suggesting, in fact, that patients with very high-risk prostate cancer who don't have evidence of objective metastasis may, in fact, benefit from ADT plus one of the novel hormonal agents, in this case, the use of an adrenal biosynthesis inhibitor such as abiraterone acetate. So I think in my practice, what I would counsel this patient is to probably embark on radiotherapy as local definitive therapy and also to consider 24 months of androgen deprivation therapy. But I would, based upon his Gleason score of group grading, his high-volume disease in the prostate gland, and his PSA, to probably consider the use of the addition of abiraterone in that context. Dr. Kriti Mittal: That is in fact how this patient was offered treatment. The patient decided to proceed with radiation therapy with two years of androgen deprivation. And based on data from the multi-arm STAMPEDE platform, the patient met two of the following three high-risk features Gleason score >8, PSA >40, and clinical >T3 disease. He was offered two years of abiraterone therapy. Unfortunately, the patient chose to decline upfront intensification of therapy. In addition, given the diagnosis of high-risk localized prostate cancer, the patient was also referred to genetic counseling based on the current Philadelphia Consensus Conference guidelines. Germline testing should be considered in patients with high-risk localized node-positive or metastatic prostate cancer, regardless of their family history. In addition, patients with intermediate-risk prostate cancer who have cribriform histology should also consider germline genetic testing.  Access to genetic counseling remains a challenge at several sites across the US, including ours. There is a growing need to educate urologists and medical oncologists to make them feel comfortable administering pretest counseling themselves and potentially ordering the test while waiting for the results and then referring patients who are found to have abnormalities for a formal genetics evaluation. In fact, the Philadelphia Consensus Conference Guideline offers a very elegant framework to help implement this workflow paradigm in clinical practice. And at our site, one of our fellows is actually using this as a research project so that patients don't have to wait months to be seen by genetics. This will have implications, as we will see later in this podcast, not only for this individual patient as we talk about the role of PARP inhibitors but also has implications for cascade testing and preventative cancer screening in the next of kin. Dr. Jorge Garcia: Dr. Mittal, I think that we cannot stress enough the importance of genetic testing for these patients. Oftentimes I think one of the challenges that our patients are facing is how they come into the system. If you come through urology, especially in the community side, what I have heard is that there are challenges trying to get to that genetic counsel. Not so much because you cannot do the test, but rather the interpretation of the testing and the downstream effect as you're describing the consequences of having a positive test and how you're going to counsel that patient. If you disregard the potential of you having an active agent based upon your genomic alteration, is the downstream of how your family may be impacted by a finding such as the DNA repair deficiency or something of that nature. So for us at major academic institutions because the flow how those patients come through us, and certainly the bigger utilization of multi-disciplinary clinics where we actually have more proximity with radiation oncology urology, and we actually maybe finesse those cases through the three teams more often than not, at least discuss them, then I think that's less likely to occur. But I think the bigger question is the timing of when we do testing and how we do it.  So there are two ways -- and I'd love to hear how you do it at your institution -- because there are two ways that I can think one can do that. The low-hanging fruit is you have tissue material from the biopsy specimen. So what you do, you actually use any of the commercial platforms to do genomic or next-generation sequencing or you can do in-house sequencing if your facility has an in-house lab that can do testing. And that only gets you to what we call ‘somatic testing', which is really epigenetic changes over time that are only found in abnormal cells. It may not tell you the entire story of that patient because you may be missing the potential of identifying a germline finding. So when you do that, did you do germline testing at the same time that you do somatic testing or did you start with one and then you send to genetic counseling and then they define who gets germline testing? Dr. Kriti Mittal: So at our site, we start with germline genetic testing. We use either blood testing or a cheek swab assay and we send the full 84-gene multigene panel. Dr. Jorge Garcia: Yeah, and I think for our audience, Dr. Mittal, that's great. I don't think you and I will be too draconian deciding which platform one uses. It's just that we want to make sure that at least you test those patients. And I think the importance of this is if you look at the New England Journal paper from many years ago, from the Pritchard data looking at the incidence of DNA repair deficiency in men with prostate cancer in North America, that was about what,  around 10% or so, take it or leave it. So if you were to look only for germline testing, you only will, in theory, capture around 10% of patients. But if you add somatic changes that are also impacting the DNA pathway, then you may add around 23%, 25% of patients. So we really are talking that if we only do one type of testing, we may be missing a significant proportion of patients who still may be candidates, maybe not for family counseling if you had a somatic change, rather than germline testing, the positivity, but if you do have somatic, then you can add into that equation the potential for that patient to embark on PARP inhibitors down the road as you stated earlier. It may not change how we think of the patient today, or the treatment for that matter. But you may allow to counsel that patient differently and may allow to sequence your treatments in a different way based upon the findings that you have. So I could not stress the importance of the NCCN guidelines and the importance of doing genetic testing for pretty much the vast majority of our patients with prostate cancer. Dr. Kriti Mittal: Going back to our patient, three years after completion of his therapy, the patient was noted to have a rising PSA. On surveillance testing, his PSA rose from 0.05 a few months prior to 12.2 at the time of his medical oncology appointment. He was also noted to have worsening low back pain. A PSMA scan was performed that was noteworthy for innumerable intensely PSMA avid osseous lesions throughout his axial and appendicular skeleton. The largest lesion involved the right acetabulum and the right ischium. Multiple additional sizable lesions were seen throughout the pelvis and spine without any evidence of pathologic fractures. So the question is, what do we do next? Dr. Jorge Garcia: The first question that I would have is, the patient completed ADT, right? So the patient did not have treatment intensification, but at the very least he got at least systemic therapy based upon the EORTC data. And therefore, one would predict that his outcome will have been improved compared to those patients who receive either no ADT or less time on ADT. But what I'm interested in understanding is his nadir PSA matters to me while he was on radiation and ADT. I would like to know if his nadir PSA was undetectable, that's one thing. If he was unable to achieve an undetectable PSA nadir, that would be a different thought process for me.   And secondly, before I can comment, I would like to know if you have access to his testosterone level. Because notably, what happens to patients like this maybe is that you will drive down testosterone while you get ADT, PSAs become undetectable. Any of us could assume that the undetectability is the result of the radiation therapy. But the true benefit of the combination of radiation and ADT in that context really comes to be seen when the patient has got off the ADT, has recovered testosterone, and only when your testosterone has normalized or is not castrated, then we'll know what happens with your serologic changes. If you rise your PSA while you recover testosterone, that is one makeup of patient. But if you rise your PSA while you have a testosterone at the castrated level, that would be a different makeup of a patient. So do we have a sense as to when the patient recovered testosterone and whether or not if his PSA rose after recovery?  Dr. Kriti Mittal: At the time his PSA rose to 12, his testosterone was 275. Dr. Jorge Garcia: Okay, perfect. You and I would call this patient castration-naive or castration-sensitive. I know that it's semantics. A lot of people struggle with the castration-naive and castration-sensitive state. What that means really to me, castration-naive is not necessarily that you have not seen ADT before. It's just that your cancer progression is dependent on the primary fuel that is feeding prostate cancer, in this case, testosterone or dihydrotestosterone, which is the active metabolite of testosterone. So in this case, recognizing the patient had a testosterone recovery and his biochemical recurrence, which is the rising of his PSA occur when you have recovery of testosterone, makes this patient castration-sensitive. Now the PET scan demonstrates now progression of his disease. So clearly he has a serologic progression, he has radiographic progression. I assume that the patient may have no symptoms, right, from his disease?  Dr. Kriti Mittal: This patient had some low back pain at the time of this visit. So I think we can conclude he has clinical progression as well. Dr. Jorge Garcia: Okay, so he had the triple progression, serologic, clinical, and radiographic progression. The first order of business for me would be to understand the volume of his disease and whether we use the US CHAARTED definition of high volume or low volume, or whether we use the French definition for high volume from Latitude, or whether we use STAMPEDE variation for definition, it does appear to me that this patient does have high-volume disease. Why? If you follow the French, it's a Gleason score of >8, more than three bone metastases, and the presence of visceral disease, and you need to have two out of the three. If you follow CHAARTED definition, we did not use Gleason scoring, the US definition. We only use either the presence of visceral metastases or the presence of more than four bone lesions, two of which had to be outside the appendicular skeleton. So if we were to follow either/or, this patient would be high-volume in nature.  So the standard of care for someone with metastatic disease, regardless of volume, is treatment intensification, is you suppress testosterone with androgen deprivation therapy. And in this case, I'd love to hear how you do it in Massachusetts, but here, for the most part, I would actually use a GnRH agonist-based approach, any of the agents that we have. Having said that, I think there is a role to do GnRH antagonist-based therapy. In this case, degarelix, or the oral GnRH antagonist, relugolix, is easier to get patients on a three-month injection or six-month injection with GnRH agonist than what it is on a monthly basis. But I think it's also fair for our audience to realize that there is data suggesting that perhaps degarelix can render testosterone at a lower level, meaning that you can castrate even further or have very low levels of testosterone contrary to GnRH agonist-based approaches.  And also for patients maybe like this patient that you're describing, you can minimize the flare that possibly you could get with a GnRH agonist by transiently raising the DHT before the hypothalamic-pituitary axis would shut it down. So either/or would be fine with me. Relugolix, as you know, the attraction of relugolix for us right now, based upon the HERO data, is that you may have possibly less cardiovascular side effects. My rationale not to use a lot of relugolix when I need treatment intensification is quite simple. I'm not aware, I don't know if you can mitigate or minimize that potential cardiovascular benefit by adding abiraterone or adding one of the ARIs, because ARIs and abiraterone by themselves also have cardiovascular side effects. But either/or would be fine with me. The goal of the game is to suppress your male hormone.  But very important is that regardless of volume, high or low, every patient with metastatic disease requires treatment intensification. You can do an adrenal biosynthesis inhibitor such as abiraterone acetate. You can pick an androgen receptor inhibitor such as apalutamide or enzalutamide if that's the case. The subtleties in how people feel comfortable using these agents, I think, none of us – as you know, Dr. Mittal - can comment that one oral agent is better than the other one. Independently, each of these three oral agents have randomized level 1, phase III data demonstrating survival improvement when you do treatment intensification with each respective agent. But we don't have, obviously, head-to-head data looking at this.  What I think is different right now, as you know, is the data with the ARASENS data, which was a randomized phase III trial, an international effort looking at triple therapy, and that is male hormone suppression plus docetaxel-based chemotherapy against testosterone suppression plus docetaxel-based chemotherapy plus the novel androgen receptor inhibitor known as darolutamide. This trial demonstrated an outcome survival improvement when you do triple therapy for those high-volume patients. And therefore, what I can tell you in my personal opinion and when I define a patient of mine who is in need of chemotherapy, then the standard of care in my practice will be triple therapy. So if I know you are a candidate for chemotherapy, however, I make that decision that I want you to get on docetaxel upfront. If you have high-volume features, then the standard of care would not be ADT and chemo alone, it would be ADT, chemo, and darolutamide.  What I don't know, and what we don't know, as you know, is whether or not triple therapy for a high-volume patient is better, the same, equivalent, or less than giving someone ADT plus a novel hormonal agent. That is the data that we don't have. There are some meta-analyses looking at the data, but I can tell you that at the very least, if you prefer chemo, it should be triple therapy. If you prefer an oral agent, it certainly should be either apalutamide, abiraterone acetate, and/or enzalutamide. But either/or, patients do need treatment intensification, and what is perplexing to me, and I know for you as well, is that a significant proportion of our patients in North America are still not getting treatment intensification, which is really sub-optimal and sub-standard for our practice.  Dr. Kriti Mittal: Thank you, Dr. Garcia, for a terrific discussion on the application of recent advances in prostate cancer to clinical practice. In an upcoming podcast, we will continue that discussion exploring management of de novo metastatic prostate cancer.   The ASCO Education Podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncologists' well-being and professional development. If you have an idea for a topic or a guest you'd like to see on the ASCO Education Podcast, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, please visit education.asco.org. 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