Podcasts about thoracic oncology program

In this episode of Lung Cancer Considered, host Dr. Narjust Florez leads a discussion of two of the most challenging thoracic malignancies – NUT carcinoma and mesothelioma. Listen to the episode to learn about the role of next-generation sequencing in diagnosis and treatment selection, as well as current and future targeted therapy in the management of both. Guests Melina Marmarelis, MD MSCE Assistant Professor Medical Director, UPenn Mesothelioma University of Pennsylvania Jia Luo, MD Medical Oncologist, Thoracic Oncology Program, Dana-Farber Cancer Institute Faculty, Brigham and Women's Hospital and Harvard Medical School

Host: Jacob Sands, MD Guest: Marina Garassino, MD Datopotamab deruxtecan (Dato-DXd) is a second-line antibody drug conjugate that could lead to improved progression-free survival in patients with advanced or metastatic non-small cell lung cancer. Given these potential benefits, it's important to identify biomarkers that may predict a patient's response to Dato-DXd, which was the focus of recent research presented at the 2024 World Conference on Lung Cancer. Here with Dr. Jacob Sands to discuss a new biomarker for TROP2 is Dr. Marina Garassino, Professor of Medicine and Director of the Thoracic Oncology Program at the University of Chicago.

In this special WCLC 2024 episode of Lung Cancer Considered, host Dr. Stephen Liu discusses daily highlights from the conference. Dr. Caicun Zhou discusses the results of ivonescimab versus pembrolizumab in the first-line HARMONi-2 study. Dr. Tina Cascone discusses preliminary outcomes from the perioperative NeoCOAST-2 study, and Dr. Marina Chiara Garassino outlines the potential QCS-NMR TROP2 biomarker using data from TROPION-Lung01. Dr. Matthew Smeltzer shares the results of the 2024 IASLC Global Survey on Biomarker Testing and how they compare to findings from the previous survey in 2018. Guests: Dr. Tina Cascone Physician-Scientist and Associate Professor, Department of Thoracic/Head and Neck Medical Oncology University of Texas MD Anderson Cancer Center in Houston, Texas Dr. Marina Chiara Garassino Director, Thoracic Oncology Program and Professor of Medicine University of Chicago Dr. Matthew Smeltzer Associate Professor, Division of Epidemiology, Biostatistics, and Environmental Health University of Memphis Professor Caicun Zhou Chief Physician and Director of the Department of Medical Oncology Tongji University in Shanghai Pulmonary Hospital

In this video capsule series, we discuss the first-line treatment strategies for the management of locally advanced metastatic urothelial carcinoma in Canada.This fifth episode of the series was recorded live from ESMO 2023 with Dr. Thomas Powles, who presented results of the EV-302 trial, and Dr. Normand Blais, Dr. Srikala Sridhar, and Dr. Bernie Eigl, who discussed the impact of new data from trials on 1L LA/mUC .Our Guests:Dr. Thomas Powles: Dr Thomas Powles is a Professor of Genitourinary Oncology and Director of the Barts Cancer Centre at St. Bartholomew's Hospital. He is also the Lead for Solid Tumour Research in London, England. Dr. Normand Blais: Dr  Blais is the co-founder of the Groupe d'Études en Oncologie du Québec & chair of the Thoracic Oncology Program of the CHUM Cancer center in Montreal. He is the president of Association des hémato-oncologues du Québec. He is interested in lung cancer – clinical trials & correlative science. His clinical research expertise is in lung & bladder cancer, and cancer associated thrombosis.Dr. Srikala Sridhar: Dr  Sridhar is a professor in the Department of Medicine at the University of Toronto & a Genitourinary Medical Oncologist & GU Site Lead at the Princess Margaret Cancer Center. She is chair of the Genitourinary Medical Oncologists of Canada & vice chair of the Medical Advisory Board of Bladder Cancer Canada. She has a particular focus on advanced urothelial cancers. Dr. Bernie Eigl: Dr. Eigl is a medical oncologist specializing in genitourinary oncology, with a special research interest in bladder and prostate cancers at BC Cancer. He ia alo a Clinical Associate Professor at the University of British Columbia.This podcast episode was sponsored by Seagen Canada.If you enjoy our podcast, please review and subscribe. For more podcasts and other medical education content, visit our website at: https://www.impactmedicom.com.

In this podcast series, we discuss the first-line treatment strategies for the management of locally advanced metastatic urothelial carcinoma in Canada. This second part of the series is based on a live webinar presented on September 12th, 2023 by Dr. Normand Blais from the CHUM Cancer center in Montreal, Dr. Terence Friedlander from the Zuckerberg San Francisco General Hospital, and Dr. Srikala Sridhar from the Princess Margaret Cancer Center in Toronto. In this first episode taken from the webinar, Dr. Normand Blais introduces the speakers and discusses the unmet needs of patients with locally advanced metastatic urothelial carcinoma in Canada. Our Guests:Dr. Normand Blais: Dr  Blais is the co-founder of the Groupe d'Études en Oncologie du Québec & chair of the Thoracic Oncology Program of the CHUM Cancer center in Montreal. He is the president of Association des hémato-oncologues du Québec. He is interested in lung cancer – clinical trials & correlative science. His clinical research expertise is in lung & bladder cancer, and cancer associated thrombosis.Dr. Terence Friedlander: Dr  Friedlander is a clinical & translational medical oncologist with a focus on urologic cancers, specifically cancers of the bladder and prostate. He serves as chief of the ZSFG Division of Hematology & Oncology, & his research is focused on understanding the basic biology of urologic malignancies & on developing novel therapeutic ways to treat diseases.Dr. Srikala Sridhar: Dr  Sridhar is a professor in the Department of Medicine at the University of Toronto & a Genitourinary Medical Oncologist & GU Site Lead at the Princess Margaret Cancer Center. She is chair of the Genitourinary Medical Oncologists of Canada & vice chair of the Medical Advisory Board of Bladder Cancer Canada. She has a particular focus on advanced urothelial cancers. The full webinar can be found on our website at: https://www.impactmedicom.com/video-capsules. This podcast episode was sponsored by Seagen Canada.If you enjoy our podcast, please review and subscribe. For more podcasts and other medical education content, visit our website at: https://www.impactmedicom.com.

In this podcast series, we discuss the first-line treatment strategies for the management of locally advanced metastatic urothelial carcinoma in Canada. This second part of the series is based on a live webinar presented on September 12th, 2023 by Dr. Normand Blais from the CHUM Cancer center in Montreal, Dr. Terence Friedlander from the Zuckerberg San Francisco General Hospital, and Dr. Srikala Sridhar from the Princess Margaret Cancer Center in Toronto.In this second episode taken from the webinar, Dr. Terrence Friedlander presents clinical data in the first-line setting and provides a US perspective on how he manages the treatment of locally advanced metastatic urothelial carcinoma.  Our Guests:Dr. Normand Blais: Dr  Blais is the co-founder of the Groupe d'Études en Oncologie du Québec & chair of the Thoracic Oncology Program of the CHUM Cancer center in Montreal. He is the president of Association des hémato-oncologues du Québec. He is interested in lung cancer – clinical trials & correlative science. His clinical research expertise is in lung & bladder cancer, and cancer associated thrombosis.Dr. Terence Friedlander: Dr  Friedlander is a clinical & translational medical oncologist with a focus on urologic cancers, specifically cancers of the bladder and prostate. He serves as chief of the ZSFG Division of Hematology & Oncology, & his research is focused on understanding the basic biology of urologic malignancies & on developing novel therapeutic ways to treat diseases.Dr. Srikala Sridhar: Dr  Sridhar is a professor in the Department of Medicine at the University of Toronto & a Genitourinary Medical Oncologist & GU Site Lead at the Princess Margaret Cancer Center. She is chair of the Genitourinary Medical Oncologists of Canada & vice chair of the Medical Advisory Board of Bladder Cancer Canada. She has a particular focus on advanced urothelial cancers. This podcast episode was sponsored by Seagen Canada.If you enjoy our podcast, please review and subscribe. For more podcasts and other medical education content, visit our website at: https://www.impactmedicom.com.

In this podcast series, we discuss the first-line treatment strategies for the management of locally advanced metastatic urothelial carcinoma in Canada. This second part of the series is based on a live webinar presented on September 12th, 2023 by Dr. Normand Blais from the CHUM Cancer center in Montreal, Dr. Terence Friedlander from the Zuckerberg San Francisco General Hospital, and Dr. Srikala Sridhar from the Princess Margaret Cancer Center in Toronto.In this third episode taken from the webinar, Dr. Srikala Sridhar presents a clinical case on the treatment of locally advanced metastatic urothelial carcinoma, highlighting the role of enfortumab vedotin plus pembrolizumab in the treatment plan. Our Guests:Dr. Normand Blais: Dr  Blais is the co-founder of the Groupe d'Études en Oncologie du Québec & chair of the Thoracic Oncology Program of the CHUM Cancer center in Montreal. He is the president of Association des hémato-oncologues du Québec. He is interested in lung cancer – clinical trials & correlative science. His clinical research expertise is in lung & bladder cancer, and cancer associated thrombosis.Dr. Terence Friedlander: Dr  Friedlander is a clinical & translational medical oncologist with a focus on urologic cancers, specifically cancers of the bladder and prostate. He serves as chief of the ZSFG Division of Hematology & Oncology, & his research is focused on understanding the basic biology of urologic malignancies & on developing novel therapeutic ways to treat diseases.Dr. Srikala Sridhar: Dr  Sridhar is a professor in the Department of Medicine at the University of Toronto & a Genitourinary Medical Oncologist & GU Site Lead at the Princess Margaret Cancer Center. She is chair of the Genitourinary Medical Oncologists of Canada & vice chair of the Medical Advisory Board of Bladder Cancer Canada. She has a particular focus on advanced urothelial cancers. This podcast episode was sponsored by Seagen Canada.If you enjoy our podcast, please review and subscribe. For more podcasts and other medical education content, visit our website at: https://www.impactmedicom.com.

In this podcast series, we discuss the first-line treatment strategies for the management of locally advanced metastatic urothelial carcinoma in Canada. This second part of the series is based on a live webinar presented on September 12th, 2023 by Dr. Normand Blais from the CHUM Cancer center in Montreal, Dr. Terence Friedlander from the Zuckerberg San Francisco General Hospital, and Dr. Srikala Sridhar from the Princess Margaret Cancer Center in Toronto.In this fourth and final episode taken from the webinar, Drs Normand Blais, Terence Friedlander, and Srikala Sridhar provide their perspective on the management of the first-line treatment locally advanced metastatic urothelial carcinoma, including a discussion of the optimal use of enfortumab vedotin plus pembrolizumab and management of associated adverse events. Our Guests:Dr. Normand Blais: Dr  Blais is the co-founder of the Groupe d'Études en Oncologie du Québec & chair of the Thoracic Oncology Program of the CHUM Cancer center in Montreal. He is the president of Association des hémato-oncologues du Québec. He is interested in lung cancer – clinical trials & correlative science. His clinical research expertise is in lung & bladder cancer, and cancer associated thrombosis.Dr. Terence Friedlander: Dr  Friedlander is a clinical & translational medical oncologist with a focus on urologic cancers, specifically cancers of the bladder and prostate. He serves as chief of the ZSFG Division of Hematology & Oncology, & his research is focused on understanding the basic biology of urologic malignancies & on developing novel therapeutic ways to treat diseases.Dr. Srikala Sridhar: Dr  Sridhar is a professor in the Department of Medicine at the University of Toronto & a Genitourinary Medical Oncologist & GU Site Lead at the Princess Margaret Cancer Center. She is chair of the Genitourinary Medical Oncologists of Canada & vice chair of the Medical Advisory Board of Bladder Cancer Canada. She has a particular focus on advanced urothelial cancers. This podcast episode was sponsored by Seagen Canada.If you enjoy our podcast, please review and subscribe. For more podcasts and other medical education content, visit our website at: https://www.impactmedicom.com.

On today's episode, meet Dr. Amy Cummings. Dr. Cummings is a thoracic oncologist and research scientist who practices in Santa Monica and Torrance California. In Santa Monica, she sees lung cancer patients, runs clinical trials, and is part of the virtual multidisciplinary Thoracic Oncology Program. Her clinical interests include immunotherapy, precision medicine, and providing equitable care to all patients regardless of race, ethnicity, sexual orientation, and gender identity. At the Jonsson Comprehensive Cancer Center she also serves as the Director for Justice, Equity, Diversity, and Inclusion (JEDI).Dr. Cummings received her medical degree from the Keck School of Medicine at the University of Southern California and completed both her internal medicine residency and her hematology and oncology fellowship at UCLA.

Hosts Chris Joyce and Stephanie Winn sit down with Dr. Jonathan Riess of the UC Davis Comprehensive Cancer Center. Dr. Riess is a medical oncologist and Associate Professor of Internal Medicine for Hematology and Oncology. Dr. Riess is also the Director of the Thoracic Oncology Program which is the largest and most comprehensive program in Northern California, providing a wide array of clinical and research services, ranging from prevention strategies to new diagnostic and therapeutic approaches. To learn more about the UC Davis Comprehensive Cancer Center, visit https://health.ucdavis.edu/cancer.

In this Virtual Tumor Board episode of Lung Cancer Considered, host Dr. Stephen Liu and his guests discuss the dynamic topic of managing resectable stage III NSCLC. Joining him are: Dr. Isabelle Schmitt-Opitz, Professor of Thoracic Surgery and Director of the Department of Thoracic Surgery at University Hospital of Zurich, Chair of the Lung Cancer Center of Zurich, and the President of the European Society of Thoracic Surgery. She received the IASLC Robert J Ginsberg Lectureship Award for Surgery at the 2022 World Conference on Lung Cancer. Dr. Jonathan Spicer, Medical Director of the Thoracic Oncology Program at McGill University in Montreal where he is the Advanced Thoracic and Upper GI Surgical Oncology Fellowship Program Director. He is also a co-author of the CheckMate 816 study. Dr. Tina Cascone, Assistant Professor and Thoracic Medical Oncologist at the University of Texas MD Anderson Cancer Center and Principal Investigator of the neoadjuvant NEOSTAR study.

Dr. Vamsi Velcheti and Dr. Benjamin Neel, of the NYU Langone Perlmutter Cancer Center, and Dr. John Heymach, of MD Anderson Cancer Center, discuss new therapeutic approaches for KRAS-mutant lung cancers and therapy options for RAS-altered tumors.   TRANSCRIPT Dr. Vamsidhar Velcheti: Hello, I'm Dr. Vamsidhar Velcheti, your guest host for the ASCO Daily News podcast today. I'm the medical director of the Thoracic Oncology Program at Perlmutter Cancer Center at NYU Langone Health. I'm delighted to welcome two internationally renowned physician-scientists, Dr. John Heymach, the chair of Thoracic-Head & Neck Medical Oncology at the MD Anderson Cancer Center, and my colleague, Dr. Benjamin Neel, the director of the Perlmutter Cancer Center at NYU Langone Health, and professor of Medicine at NYU Grossman School of Medicine. So, we'll be discussing new therapeutic approaches today for KRAS-mutant lung cancers, and we will talk about emerging new targeted therapy options for RAS-altered tumors. Our full disclosures are available in the show notes, and the disclosures of all the guests of the podcast can be found on our transcript at: asco.org/podcast. Dr. Heymach and Dr. Neel, it's such a great pleasure to have you here for the podcast today. Dr. John Heymach: My pleasure to be here. Dr. Benjamin Neel: Same here. Dr. Vamsidhar Velcheti: Dr. Neel, let's start off with you. As you know, RAS oncogenes were first discovered nearly four decades ago. Why is RAS such a challenging therapeutic target? Why has it taken so long to develop therapeutic options for these patients? Dr. Benjamin Neel: Well, I think a good analogy is the difference between kinase inhibitors and RAS inhibitors. So, kinase inhibitors basically took advantage of an ATP-binding pocket that's present in all kinases, but is different from kinase to kinase, and can be accessed by small molecule inhibitors. So, the standard approach that one would've thought of taking, would be to go after the GTP-binding pocket. The only problem is that the affinity for binding GTP by KRAS is three to four orders of magnitude higher. So, actually getting inhibitors that are GTP-binding inhibitors is pretty much very difficult. And then, until recently, it was felt that RAS was a very flat molecule and there weren't any surfaces that you could stick a small molecule inhibitor in. So, from a variety of biochemical and medicinal-pharmacological reasons, RAS was thought to be impervious to small molecule development. But as is often the case, a singular and seminal insight from a scientist, Kevan Shokat, really broke the field open, and now there's a whole host of new approaches to trying to drug RAS. Dr. Vamsidhar Velcheti: So, Dr. Neel, can you describe those recent advances in drug design that have enabled these noble new treatments for KRAS-targeted therapies? Dr. Benjamin Neel: So, it starts actually with the recognition that for many years, people were going after the wrong RAS. And by the wrong RAS, the overwhelming majority of the earlier studies on the structure, and for that matter, the function of RAS centered on HRAS or Harvey RAS. We just mutated in some cancers, most prominently, bladder cancer, and head & neck cancer, but not on KRAS, which is the really major player in terms of oncogenes in human cancer. So, first of all, we were studying the wrong RAS. The second thing is that we were sort of thinking that all RAS mutants were the same. And even from the earliest days, back in the late eighties, it was pretty clear that there were different biochemical properties in all different RAS mutants. But this sort of got lost in the cause and in the intervening time, and as a result, people thought all RASes were the same and they were just studying mainly G12V and G12D, which are more difficult to drug. And then, the third and most fundamental insight was the idea of trying to take advantage of a particular mutation in KRAS, which is present in a large fraction of lung cancer patients, which is, KRAS G12C. So, that's a mutation of glycine 12 to cysteine and Kevan's really seminal study was to use a library of covalently adducting drugs, and try to find ways to tether a small molecule in close enough so that it could hit the cysteine. And what was really surprising was when they actually found the earliest hits with this strategy, which was actually based on some early work by Jim Wells at Sunesis in the early part of this century, they found that it was actually occupying the G12C state or the inactive state of RAS. And this actually hearkens back to what I said earlier about all RASes being the same. And in fact, what's been recently re-appreciated is that some RAS mutants, most notably, G12C, although they're impervious to the gap which converts the active form into the inactive form, they still have a certain amount of intrinsic ability to convert from the inactive form. And so, they always cycle into the inactive form at some slow rate, and that allows them to be accessed by these small molecules in the so-called Switch-II Pocket, and that enables them to position a warhead close enough to the cysteine residue to make a covalent adduct and inactivate the protein irreversibly. Scientists at a large number of pharmaceutical companies and also academic labs began to understand how to access various other pockets in RAS, and also even new strategies, taking advantage of presenting molecules to RAS on a chaperone protein. So, there's now a whole host of strategies; you have a sort of an embarrassment of riches from an impoverished environment that we started with prior to 2012. Dr. Vamsidhar Velcheti: Thank you, Dr. Neel. So, Dr. Heymach, lung cancer has been a poster child for personalized therapy, and we've had like a lot of FDA-approved agents for several molecularly-defined subsets of lung cancer. How clinically impactful is a recent approval of Sotoracib for patients with metastatic lung cancer? Dr. John Heymach: Yeah. Well, I don't think it's an exaggeration to say this is the biggest advance for targeted therapies for lung cancer since the initial discovery of EGFR inhibitors. And let me talk about that in a little more detail. You know, the way that lung cancer therapy, like a lot of other cancer therapies, has advanced is by targeting specific driver oncogenes. And as Dr. Neel mentioned before, tyrosine kinases are a large percentage of those oncogenes and we've gotten very good at targeting tyrosine kinases developing inhibitors. They all sort of fit into the same ATP pocket, or at least the vast majority of them now. There are some variations on that idea now like allosteric inhibitors. And so, the field has just got better and better. And so, for lung cancer, the field evolved from EGFR to ALK, to ROS1 RET fusions, MEK, and so forth. What they all have in common is, they're all tyrosine kinases. But the biggest oncogene, and it's about twice as big as EGFR mutation, are KRAS mutations. And as you mentioned, this isn't a tyrosine kinase. We never had an inhibitor. And the first one to show that it's targetable, to have the first drug that does this, is really such an important breakthrough. Because once the big breakthrough and the concept is there, the pharmaceutical companies in the field can be really good at improving and modulating that. And that's exactly what we see. So, from that original insight that led to the design of the first G12C inhibitors, now there's dozens, literally dozens of G12C inhibitors and all these other inhibitors based on similar concepts. So, the first one now to go into the clinic and be FDA-approved is Sotoracib. So, this again, as you've heard, is inhibitor G12C, and it's what we call an irreversible inhibitor. So, it fits into this pocket, and it covalently links with G12C. So, when it's linked, it's linked, it's not coming off. Now, the study that led to its FDA approval was called the CodeBreak 100 study. And this was led in part, by my colleague Ferdinandos Skoulidis, and was published in The New England Journal in the past year. And, you know, there they studied 126 patients, and I'll keep just a brief summary, these were all refractory lung cancer patients. They either had first-line therapy, most had both chemo and immunotherapy. The primary endpoint was objective response rate. And for the study, the objective response rate was 37%, the progression-free survival was 6.8 months, the overall survival was 12.5 months. Now you might say, well, 37%, that's not as good as an EGFR inhibitor or the others. Well, this is a much harder thing to inhibit. And you have to remember in this setting, the standard of care was docetaxel chemotherapy. And docetaxel usually has a response rate of about 10 to 13%, progression-free survival of about 3 months. So, to more than double that with a targeted drug and have a longer PFS really is a major advance. But it's clear, we've got to improve on this and I think combinations are going to be incredibly important now. There's a huge number of combination regimens now in testing. Dr. Vamsidhar Velcheti: Thank you, Dr. Heymach. So, Dr. Neel, just following up on that, unlike other targeted therapies in lung cancer, like EGFR, ALK, ROS, and RET, the G12C inhibitors appear to have somewhat modest, I mean, though, certainly better than docetaxel that Dr. Heymach was just talking about; why is it so hard to have more effective inhibitor of KRAS here? Is it due to the complex nature of RAS-mutant tumors? Or is it our approach for targeting RAS? Is it a drug-related problem, or is it the disease? Dr. Benjamin Neel: Well, the short answer is I think that's a theoretical discussion at this point and there isn't really good data to tell you, but I suspect it's a combination of those things. We'll see with the new RAS(ON) inhibitors, which seem to have deeper responses, even in animal models, if those actually work better in the clinic, then we'll know at least part of it was that we weren't hitting RAS hard enough, at least with the single agents. But I also think that it's highly likely that since KRAS-mutant tumors are enriched in smokers, and smokers have lots of mutations, that they are much more complex tumours, and therefore there's many more ways for them to escape. Dr. Vamsidhar Velcheti: Dr. Heymach, you want to weigh in on that? Dr. John Heymach: Yeah, I think that's right. I guess a couple of different ways to view it is the problem that the current inhibitors are not inhibiting the target well enough, you know, in which case we say we get better and better inhibitors will inhibit it more effectively, or maybe we're inhibiting it, but we're not shutting down all the downstream pathways or the feedback pathways that get turned on in response, in which case the path forward is going to be better combinations. Right now, I think the jury is still out, but I think the data supports that we can do better with better inhibitors, there's room to grow. But it is also going to be really important hitting these compensatory pathways that get turned on. I think it's going to be both, and it seems like KRAS may turn on more compensatory pathways earlier than things like EGFR or ALK2, you know, and I think it's going to be a great scientific question to figure out why that is. Dr. Vamsidhar Velcheti: Right. And just following up on that, Dr. Heymach, so, what do we know so far about primary and acquired resistance to KRAS G12C inhibitors? Dr. John Heymach: Yeah. Well, it's a great question, and we're still very early in understanding this. And here, if we decide to call it primary resistance - meaning you never respond in the first place, and acquired - meaning you respond and then become resistant, we're not sure why some tumors do respond and don't respond initially. Now, it's been known for a long time, tumors differ in what we call their KRAS-dependence. And in cell lines and in mouse models, when you study this in the lab, there are some models where if you block KRAS, those cells will die immediately. They are fully dependent. And there's other ones that become sort of independent and they don't really seem to care if you turn down KRAS, they've sort of moved on to other things they're dependent on. One way this can happen is with undergoing EMT where the cell sort of changes its dependencies. And EMT is probably a reason some of these tumors are resistant, to start with. It may also matter what else is mutated along with KRAS, what we call the co-mutations, the additional mutations that occur along with it. For example, it seems like if this gene KEAP1 is mutated, tumors don't respond as well, to begin with. Now, acquired resistance is something we are gaining some experience with. I can say in the beginning, we all knew there'd be resistance, we were all waiting to see it, and what we were really hoping for was the case like with first-generation inhibitors with EGFR, where there was one dominant mechanism. In the first-generation EGFR, we had one mutation; T790M, that was more than half the resistance. And then we could develop drugs for that. But unfortunately, that's not the case. It looks like the resistance mechanisms are very diverse, and lots of different pathways can get turned on. So, for acquired resistance, you can have additional KRAS mutations, like you can have a KRAS G12D or V, or some other allele, or G13, I didn't even realize were commonly mutated, like H95 or Y96 can get mutated as well. So, we might be able to inhibit with better inhibitors. But the more pressing problem is what we call bypass; when these other pathways get turned on. And for bypass, we know that the tumor can turn on MET with MET amplification, NRAS, BRAF, MAP kinase, and we just see a wide variety. So, it's clear to us there isn't going to be a single easy to target solution like there was for EGFR. This is going to be a long-term problem, and we're going to have to work on a lot of different solutions and get smarter about what we're doing. Dr. Vamsidhar Velcheti: Yeah. Thank you very much, Dr. Heymach. And Dr. Neel, just following up on that, so, what do you think our strategies should be or should look like while targeting KRAS-mutant tumors? Like, do we focus on better ways to inhibit RAS, or do we focus on personalized combination approaches based on various alterations or other biomarkers? Dr. Benjamin Neel: Yeah. Well, I'd like to step back a second and be provocative, and say that we've been doing targeted therapies, so to speak, for a long time, and it's absolutely clear that targeted therapies never cure. And so, I think we should ask the bigger question, "Why is it that targeted therapies never cure?" And I would start to conceive of an answer to that question by asking which therapies do cure. And the therapies that we know do cure are immune therapies, or it's therapies that generate durable immune response against the tumor. And the other therapies that we know that are therapies in some cases against some tumors, and radiation therapy in some cases against some tumors. Probably the only way that those actually converge on the first mechanism I said that cures tumors, which is generating a durable immune response. And so, the only way, in my view, it is to durably cure an evolving disease, like a cancer, is to have an army that can fight an evolving disease. And the only army I know of is the immune system. So, I think ultimately, what we need to do is understand in detail, how all of these different mutations that lead to cancer affect immune response and create targetable lesions in the immune response, and then how the drugs we'd give affect that. So, in the big picture, the 50,000-foot picture, that what we really need to spend more attention on, is understanding how the drugs we give and the mutations that are there in the first place affect immune response against the tumor, and ultimately try to develop strategies that somehow pick up an immune response against the tumor. Now in the short run, I think there's also lots of combination strategies that we can think of, John, you know, alluded to some of them earlier. I mean one way for the G12C inhibitors, getting better occupancy of the drug, and also blocking this so-called phenomenon of adaptive resistance, where you derepress the expression of receptor tyrosine kinases, and their ligands, and therefore bypass through normal RAS or upregulate G12C into the GTP state more, that can be attacked by combining, for example, with the SHIP2 inhibitor or a SOS inhibitor. Again, the issue there will be therapeutic index. Can we achieve that with a reasonable therapeutic index? Also in some cases, like not so much in lung cancer, but in colon cancer, it appears as if a single dominant receptor tyrosine kinase pathway, the EGF receptor pathway, is often the mechanism of adaptive resistance to RAS inhibitors, and so, combining a RAS inhibitor with an EGF receptor inhibitor is a reasonable strategy. And then of course, some of the strategies they're already getting at, what I just mentioned before, which is to try to combine RAS inhibitors with checkpoint inhibitors. I think that's an expected and understandable approach, but I think we need to get a lot more sophisticated about the tumor microenvironment, and how that's affecting the immune response. And it's not just going to be, you know, in most cases combining with a checkpoint inhibitor. I think we ought to stop using the term immunotherapy to refer to checkpoint inhibitors. Checkpoint inhibitors are one type of immunotherapy. We don't refer to antibiotics when we mean penicillin. Dr. Vamsidhar Velcheti: Dr. Heymach, as you know, like, there's a lot of discussion about the role of KRAS G12C inhibitors in the frontline setting. Do you envision these drugs are going to be positioning themselves in the frontline setting as a combination, or like as a single agent? Are there like a subset of patients perhaps where you would consider like a single agent up front? Dr. John Heymach: So, I think there's no question G12C inhibitors are moving to the first-line question. And the question is just how you get there. Now, the simplest and most straightforward approach is to say, “Well, we'll take our standard and one standard might be immunotherapy alone, a PD-1 inhibitor alone, or chemo with the PD-1 inhibitor, and just take the G12C inhibitor and put it right on top.” And that's a classic strategy that's followed. That may not be that simple. It's not obvious that these drugs will always work well together or will be tolerated together. So, I think that's still being worked out. Now, an alternative strategy is you could say, “Well, let's get a foot in a door in the first-line setting by finding where chemotherapy and immunotherapy don't work well, and pick that little subgroup.” There are some studies there using STK11-mutant tumors, and they don't respond well to immunotherapy and chemotherapy and say, “Well, let's pick that first.” And that's another strategy, but that's not to get it for everybody in the first-line setting. That's just to pick a little subgroup. Or we may develop KRAS G12C inhibitor combinations by themselves that are so effective they can beat the standard. So, what I think is going to happen is a couple things; I think they'll first be some little niches where it gets in there first. I think eventually, we'll figure out how to combine them with chemotherapy and immunotherapy so it goes on top. And then I think over time, we'll eventually develop just more effective, targeted combos where we can phase out the chemo, where the chemo goes to the back of the line, and this goes to the front of the line. Dr. Vamsidhar Velcheti: And Dr. Heymach, any thoughts on the perioperative setting and the adjuvant/neoadjuvant setting, do you think there's any role for these inhibitors in the future? Dr. John Heymach: Yeah, this is a really exciting space right now. And so that makes this a really challenging question because of how quickly things are moving. I'll just briefly recap for everybody. Until recently, adjuvant therapy was just chemotherapy after you resected a lung cancer. That was it. And it provided about a 5% benefit in terms of five-year disease-free survival. Well, then we had adjuvant immunotherapy, like atezolizumab, approved, then we had neoadjuvant chemo plus immunotherapy approved; that's a CheckMate 816. And just recently, the AEGEAN study, which I'm involved with, was announced to be a positive study. That's neoadjuvant plus adjuvant chemo plus immunotherapy. So now, if you say, well, how are you going to bring a G12C inhibitor in there? Well, you can envision a few different ways; if you can combine with chemo and immunotherapy, you could bring it up front and bring it afterwards, or you could just tack it in on the back, either with immunotherapy or by itself, if you gave neoadjuvant chemo plus immunotherapy first, what we call the CheckMate 816 regimen. So, it could fit in a variety of ways. I'll just say neoadjuvant is more appealing because you can measure the response and see how well it's working, and we in fact have a neoadjuvant study going. But the long-term benefit may really come from keeping the drug going afterwards to suppress microscopic metastatic disease. And that's what I believe is going to happen. I think you're going to need to stay on these drugs for a long while to keep that microscopic disease down. Dr. Vamsidhar Velcheti: Dr. Neel, any thoughts on novel agents in development beyond KRAS G12C inhibitors? Are there any agents or combinations that you'd be excited about? Dr. Benjamin Neel: Well, I think that the YAP/TAZ pathway inhibitors, the TEAD inhibitors in particular, are potentially promising. I mean, it seems as if the MAP kinase pathway and the GAPT pathway act in parallel. There's been multiple phases which suggest that YAP/TAZ reactivation can be a mechanism of sort of state-switching resistance. And so, I think those inhibitors are different than the standard PI3 kinase pathway inhibitor, PI3 kinase mTOR inhibitor, rapamycin. I also think as we've alluded to a couple of times, the jury's still out in the clinic, of course, but it'll be very exciting to see how this new set of RAS inhibitors works. The sort of Pan-RAS inhibitors, especially the ones that hit the GTP ON state. So, the G12C inhibitors and the initial preclinical G12D inhibitors that have been recorded, they all work by targeting the inactive state of RAS, the RAS-GDP state. And so, they can only work on mutants that cycle, at least somewhat, and they also don't seem to be as potent as targeting the GTP or active state of RAS. And so, at least the Rev meds compounds, which basically use cyclophilin, they basically adapt the mechanism that cyclosporine uses to inhibit calcineurin. They basically use the same kind of a strategy and build new drugs then that bind cyclophilin and present the drug in a way that can inhibit multiple forms of RAS. So, it'll be interesting to see if they are much more efficacious in a clinic as they appear to be in the lab, whether they can be tolerated. So, I think those are things to look out for. Dr. Vamsidhar Velcheti: Dr. Heymach? Dr. John Heymach: Yeah, I agree with that. I'm excited to see that set of compounds coming along. One of the interesting observations is that when you inhibit one KRAS allele like G12C, you get these other KRAS alleles commonly popping up. And it's a little -- I just want to pause for a second to comment on this, because this is a little different than EGFR. If you inhibit a classic mutation, you don't get multiple other separate EGFR alleles popping up. You may get a secondary mutation in cyst on the same protein, but you don't get other alleles. So, this is a little different biology, but I think the frequency that we're seeing all these other KRAS alleles pop up tells us, I think we're going to need some pan-KRAS type strategy as a partner for targeting the primary driver. So for example, a G12C inhibitor plus a pan-KRAS strategy to head off these other alleles that can be popping up. So, I think that's going to be probably a minimum building block that you start putting other things around. And by partnering an allele-specific inhibitor where you might be able to inhibit it a little more potently and irreversibly with a pan-KRAS, you may solve some of these problems at the therapeutic window. You can imagine KRAS is so important for so many different cells in your body that if you potently inhibit all KRAS in your body, bad things are likely to happen somewhere. But if you can potently inhibit the mutant allele and then dampen the other KRAS signaling that's popping up, it's more hopeful. Dr. Benjamin Neel: There is a mouse model study from Mariano Barbacid's lab, which suggests that postnatal, KRAS at least, complete inhibition is doable. So, you could take out KRAS postnatally and the mice are okay. Whether that translates to human of course, is not at all clear. And you still have the other RAS alleles, the HRAS, the NRAS that you'd still have to contend with. Dr. John Heymach: Yeah, it's an interesting lesson. We've shied away from a lot of targets we thought weren't feasible. I did a lot of my training with Judah Folkman who pioneered targeting angiogenesis. And I remember hearing this idea of blocking new blood vessels. I said, "Well, everyone is just going to have a heart attack and die." And it turns out you can do it. You have to do it carefully, and in the right way but you can separate malignant or oncogenic signaling from normal signaling in an adult, pretty reasonably in a lot of cases where you don't think you could. Dr. Vamsidhar Velcheti: All right. So, Dr. Neel, and Dr. Heymach, any final closing comments on the field of RAS-targeted therapies, you know, what can we hope for? What can patients hope for, let's say five years from now, what are we looking at? Dr. John Heymach: Well, I'll give my thoughts I guess first, from a clinical perspective, I think we're already seeing the outlines of an absolute explosion in targeting KRAS over the next five years. And I think there's a really good likelihood that this is going to be the major place where we see progress, at least in lung cancer, over these next five years. It's an example of a problem that just seemed insolvable for so long, and here I really want to acknowledge the sustained support for clinical research and laboratory research focused around RAS. You know, the NCI had specific RAS initiatives and we've had big team grants for KRAS, and it shows you it's worth these large-scale efforts because you never know when that breakthrough is going to happen. But sometimes it just takes, you know, opening that door a little bit and everybody can start rushing through. Well, I think for KRAS, the door has been opened and everybody is rushing through at a frantic rate right now. So, it's really exciting, and stay tuned. I think the landscape of RAS-targeting is going to look completely different five years from now. Dr. Benjamin Neel: So, I agree that the landscape will definitely look different five years from now, because it's reflective of stuff that's been in process for the last five years. And it takes about that long to come through. I want to make two comments; one of which is to slightly disagree with my friend, John, about these big initiatives. And I would point out that this RAS breakthrough did not come from a big initiative, it came from one scientist thinking about a problem uniquely in a different way. We need a basic science breakthrough, it almost always comes from a single lab person, thinking about a problem, often in isolation, in his own group. What big initiatives can help with is engineering problems. Once you've opened the door, and you want to know what the best way is to get around the house, then maybe big initiatives help. But I do think that there's been too much focus on the big team initiative and not enough on the individual scientists who often promote the breakthrough. And then in terms of where I see the field going, what I'd really like to see, and I think in some pharmaceutical companies and biotechs, you're seeing this now, and also in academia, but maybe not enough, is that sort of breaking down of the silos between immunotherapy and targeting therapy. Because I agree with what John said, is that targeted therapy, is just sophisticated debulking. If we want to really make progress-- and on the other hand, immunotherapy people don't seem to, you know, often recognize that these oncogenic mutations in the tumor actually affect the immune system. So, I think what we need is a unification of these two semi-disparate areas of therapeutics in a more fulsome haul and that will advance things much quicker. Dr. Vamsidhar Velcheti: Thank you both, Dr. Neel and Dr. Heymach, for sharing all your valuable insights with us today on the ASCO Daily News podcast. We really appreciate it. Thank you so much. Dr. John Heymach: Thanks for asking us. Dr. Benjamin Neel: It's been great having us. Dr. Vamsidhar Velcheti: And thank you all to our listeners, and thanks for joining us today. If you value our insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe. 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. Vamsi Velcheti @VamsiVelcheti Dr. Benjamin Neel @DrBenNeel Dr. John Heymach Want more related content? Listen to our podcast on novel therapies in lung cancer.    Advances in Lung Cancer at ASCO 2022 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Vamsi Velcheti: Honoraria: Honoraria Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen 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. Benjamin Neel: None disclosed Dr. John Heymach: None disclosed    

Tanya Doan, 45, lung cancer, Braintree, with husband, Mark Rudolph, daughter, Rebecca, and Dr. David Jackman, Medical Director for Clinical Pathways, Dana-Farber ● Tanya was diagnosed with 4 EGFR adenocarcinoma of the lower lobe of right lung atthe beginning of 2021. After experiencing migraines, Tanya had an MRI and CT scanwhich showed the cancer.● Her father had been diagnosed with the same cancer the previous year.● EGFR lung cancer commonly affects non-smoking young Asians.● Tanya had surgery to remove two tumors, followed by radiation and immunotherapy.She is still on the immunotherapy and gets an infusion every three months for herbone metastases.● Tanya enjoys reading, exercising with her Peloton, cooking, travelling, and raising herHavanese puppy. She loves spending time with her family, including daughtersRebecca and Zoe.● Tanya feels Dana-Farber is special because every single person who works there --from the people who work in the coffee shop to the radiology techs, MAs and RNs --are kind and friendly.● She says that the physicians, PAs and NPs are phenomenal and that the nutritionistsand social workers have been especially helpful. For her, Dana Farber has become ahome away from home. ● She likes knowing her treatment is on the cutting edge and not having to worryabout researching treatment on her own. Lung cancer facts● Lung cancer is the uncontrolled growth of abnormal cells in one or both lungs.● These abnormal cells do not carry out the functions of normal lung cells and do notdevelop into healthy lung tissue. As they grow, the abnormal cells can form tumorsand interfere with the functioning of the lung, which provides oxygen to the body viathe blood.● Lung cancer is the second most common cancer (not counting skin cancer) in bothmen and women.● According to the American Cancer Society, there will be an estimated 236,740 newcases of lung cancer in the United States for 2022.● Lung cancer is the leading cause of cancer death in the United States, among bothmen and women. Lung cancer claims more lives each year than do colon, prostate,ovarian and breast cancers combined.● Overall, the chance that a man will develop lung cancer in his lifetime is about 1 in15; for a woman, the risk is about 1 in 1.7● People who smoke have the greatest risk of lung cancer, and about 80% of lungcancer deaths are thought to result from smoking, though lung cancer can also occurin people who have never smoked. The risk of lung cancer increases with the lengthof time and number of cigarettes you've smoked.● Lung cancer is divided into primary or secondary lung cancer.-Primary lung cancer starts in the lungs. The cancer cells are abnormal lung cells.-Secondary lung cancer is when people who have cancer travel from another part oftheir body or metastasize to their lungs. This is called secondary lung cancer because thelungs are a secondary site compared to the original primary location of the cancer.Dr. David Jackman● Dr. Jackman is a Senior Physician in the Thoracic Oncology Program at Dana-Farber,where he cares for patients with lung cancer, mesothelioma, and thymoma. He also serves as the Medical Director for Clinical Pathways, helping to create and oversee aweb-based platform in which doctors across the country and the world, can seekcare recommendations for their patients based on the expertise of Dana-Farber'sphysicians and researchers, extending the expertise of Dana-Farber physicians.

Guest host Dr. Vamsi Velcheti, of the NYU Langone Perlmutter Cancer Center, and Dr. Brian Henick, of the Columbia University Herbert Irving Comprehensive Cancer Center, discuss advances in KRAS-mutated lung cancer in the KRYSTAL-1 trial, and the association of ctDNA with overall survival in the NADIM trial, as well as other key advances in lung cancer presented at the 2022 ASCO Annual Meeting.   TRANSCRIPT   Dr. Vamsi Velcheti: Hello, everyone! This is Dr. Vamsi Velcheti, I'm your guest host for the ASCO Daily News podcast, today. I'm an associate professor and medical director for the Thoracic Oncology Program at Perlmutter Cancer Center at NYU Langone Health. My guest today is Dr. Brian Henick, an associate director of the Experimental Therapeutics Program, and assistant professor of Medicine at Columbia University's Herbert Irving Comprehensive Cancer Center. We'll be discussing key abstracts in lung cancer that were featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the notes and disclosures of all guests on the podcast can be found on the transcripts at asco.org/podcasts. Brian, it's great to speak with you today. Dr. Brain Henick: Thank you so much, Vamsi, and ASCO Daily News for letting me join you to discuss these abstracts. Dr. Vamsi Velcheti: So, let's dive in. So, it's an exciting ASCO Annual Meeting. And I hope you had a great time at the Meeting. So, let's start off with the LBA9009 and KRYSTAL-1 clinical trial. The study showed the activity of adagrasib in patients with KRAS-G12C mutant non-small cell lung cancer and active untreated brain mets. So, what is the key takeaway from this trial? Dr. Brain Henick: Well, Dr. Sabari presented some encouraging data on this important population. As we know, patients with active central nervous system (CNS) metastases represent a population of unmet medical need who are often excluded from clinical trials. So, it's a credit to the investigators for including this cohort. As Dr. Sabari noted, and as Dr. Goldberg emphasized in her discussion of the abstract, the measured CNS penetration of adagrasib compares favorably with other CNS active compounds from other settings. The overall response rate was 35%, with a disease control rate of 80%. But impressively, the median duration of intracranial response and progression-free survival (PFS) wasn't reached. This certainly seems to be a CNS active compound, and we'll need to see how sotorasib stacks up in their comparable cohort. Ideally, we'd have randomized data to prove superiority over the standard of care, but we may be a few steps away from that. Dr. Vamsi Velcheti: So, Brian, in terms of CNS mets, how big of a problem is it in patients with KRAS G12C mutant lung cancers? Dr. Brian Henick: We know that CNS metastases are a big problem for G12C mutant lung cancer. The rates have been quoted as high as up to 42% of patients. And in particular, as you know, Vamsi, a lot of times trials often don't include, specifically, cohorts with active untreated brain metastases. And so, this is a very unique cohort in that sense. Dr. Vamsi Velcheti: I just want to highlight that we really don't know the differential efficacy of sotorasib and adagrasib in the CNS met population because the trials were CodeBreak 100 and other trials and data readouts from sotorasib did not include patients with untreated brain mets. We did, however, [see] CNS progression-free survival data that go in line with sotorasib. So, it's really important to see that data from sotorasib. Dr. Brain Henick: I definitely look forward to seeing that. Dr. Vamsi Velcheti: So, let's talk about Abstract 8501. The primary endpoint that was presented at ASCO [Annual Meeting] was the pathologic complete response to chemotherapy and nivo vs. chemotherapy as a new adjuvant treatment for resectable stage 3, a non-small cell lung cancer. This was the phase 2 NADIM trial. So, what do you think about this study? And what's your key takeaway from the study? Dr. Brain Henick: Dr. Provencio from Spain presented data from this randomized study as you said, of nivo plus carbo taxol compared to carbo taxol as neoadjuvant therapy for potentially resectable stage 3-A and B non-small cell lung cancer. So, I did want to compare this to the randomized data that we have from Checkmate 816, which interestingly allowed for earlier-stage disease as low as 1-B. And they also allowed for more flexibility in the choice of platinum doublet regimens. This study, NADIM 2, employs 2:1 versus 1:1 randomization, which we saw in Checkmate 816. Another important difference was that NADIM 2 required adjuvant nivolumab for 6 months in the study arm, whereas Checkmate 816 didn't include any immunotherapy in the adjuvant setting, but they allowed for a standard of care chemotherapy. In NADIM 2, the control arm didn't include any adjuvant therapy. In keeping with the impressive improvements over historical pathologic complete response rates of about 5%, this chemotherapy-IO regimen yielded a path complete response (CR) rate of 36.8%. It also showed a major pathological response, which again is defined as less than 10% viable tumor of 52.6%, and an overall response rate of 75.4%. So, it looks like there's a benefit that's happening upfront with the immunotherapy and chemotherapy as opposed to this just being an adjuvant phenomenon. This is also in keeping with data that we saw with Checkmate 816, as well as neoadjuvant atezo plus chemotherapy in the phase 2 study that was led by Catherine Shu and colleagues here at Columbia a few years ago. Overall, this is more encouraging data for the neoadjuvant use of immunotherapy. The earlier immunotherapy marches into the treatment course of patients with lung cancer, the greater the cost of toxicity. So, I think an important thing for us to focus on going forward is trying to develop strategies to better identify the patients that are most likely to benefit. Dr. Vamsi Velcheti: So, Brian, I think from a practical standpoint, now that we have approval for neoadjuvant immunotherapy and adjuvant immunotherapy, we have some practical challenges in terms of how we manage our patients. Of course, the new adjuvant is very appealing because it's only 3 cycles of chemoimmunotherapy, but the challenge though, is a majority of the patients don't have a CR, or a significant proportion of the patients have an ongoing response or significant residual disease at the time of surgery. So, the question then would be what do you do after surgery if they're having an ongoing response? Do you think 3 cycles of immunotherapy are inadequate systemic therapy for these patients? Dr. Brian Henick: It's a really important question, Vamsi. I think until the data is mature, we're just kind of limited by the extent of what the data tells us so far, and then we have to kind of do our best as the treating doctor to navigate the patient's situation. So, tools that we'd still have available to us in the adjuvant setting that are approved are things like chemotherapy and radiation, leveraging things like circulating tumor DNA, I think maybe a promising path forward, as well to help guide strategies there, but I think until the data is mature, it has to be highly patient-focused to figure out what seems to be most appropriate there. How are you navigating those situations, Vamsi? Dr. Vamsi Velcheti: Yeah, as you said, it is very challenging. I think we need more data. And of course, the challenge now is like, if you use immunotherapy in the new adjuvant setting, it's very likely you're not going to get insurance authorization for 1 year of adjuvant atezolizumab. So, we really need studies to optimize treatment paradigms here. As you suggested, maybe circulating tumor DNA (ctDNA)-based approaches to look at residual disease, I think, that would be one great way to do it. Let's move on to the next abstract, Brian. I found Abstract 9001 really interesting. It's a U.S. Food and Drug Administration (FDA) pooled analysis that looked at outcomes of first-line immune checkpoint inhibitors, with or without chemotherapy based on the KRAS mutation status and PD-L1 expression. So, what is your take on this abstract and how do you think this is going to impact our practice? Dr. Brian Henick: So, Dr. Nakajima and colleagues explored the observation from individual trials that patients with KRAS-mutant lung cancer seem to have better responses than wild type with immunotherapy (IO) alone. But the favorability of these responses seems to be abrogated with chemotherapy-IO. We know that KRAS accounts for 25% of oncogene-driven non-small cell lung cancer predominantly at amino acid 12. And with the emergence of direct inhibitors of G12C, understanding the clinical features of these tumors may be critical to inform optimal integration of this new class of drugs and also to make sure that we've optimized treatment algorithms for KRAS patients in general. So, this study's authors at the FDA pulled data from 12 registrational clinical trials that were investigating first-line checkpoint inhibitor-containing regimens and they found no significant difference between KRAS wild type and mutant for overall survival regardless of the regimen used. The best outcomes were seen with chemoimmunotherapy regardless of KRAS status. This retrospective analysis does suggest that the notion of there being lesser benefit from chemoimmunotherapy from Dr. Gadgeel's study might not hold up in the overall population, but I think it raises important questions, like, are all KRAS mutations alike? The absence of KRAS mutation status for a majority of patients included in these studies limits the interpretation of the data. And also, the absence of commutation status makes it a little harder to interpret. And other important questions remain such as how G12C inhibitors will factor in? What were your thoughts, Vamsi? Dr. Vamsi Velcheti: No, I completely agree with you, Brian. I think we need more data and we know that commutation status is a very important aspect in terms of KRAS-directed therapies. And of course, with a lot of promising data from these KRAS inhibitors, there's an interest in moving these drugs into the front-line therapy for patients with KRAS mutations. But I think it's going to be quite challenging to incorporate them into the front-line therapies and we clearly will need better characterization of these patients with KRAS mutant [lung cancer] to further personalize treatment in the frontline setting for these patients. So, let's move on to the next abstract. This is the lung map study, Abstract 9004. This is a study sponsored by the National Cancer Institute (NCI), the lung map study, looking at overall survival from a phase 2 randomized study of ramucirumab and pembrolizumab, what's the standard of care in patients with advanced non—small cell lung cancer previously treated with immunotherapy. So, what were your key takeaway points here from this study? Dr. Brian Henick: So first of all, it's very exciting to see data from this very ambitious long map sub-study yield a positive result. Whereas many of the arms of this study were biomarker-guided, Dr. Reckamp presented the results from pembro plus ramucirumab as compared to the standard of care in unmarked patients with non-small cell lung cancer who had progressed after prior treatment with chemotherapy and immunotherapy. The data seems to suggest that pembro plus ramucirumab may be better tolerated than the standard of care chemo-containing regimens, as the experimental regimen had fewer serious adverse events. Pembro plus ramucirumab had a median overall survival of 14.6 months as compared to 11.6 months in the control arm and this was statistically significant. The PFS difference wasn't significant, but there was a late divergence in the curves. Dr. Bestvina nicely summarized some of the study's limitations such as the mixture of control regimens used, and there were really interesting signals that were found on subgroup analysis, such as benefit in those with mixed histology tumors, STK11 mutant tumors, and those who received chemotherapy prior to immunotherapy. The subgroups deserve further attention in the future. For now, this regimen may be an appealing option as an alternative to chemotherapy for the right patients. What do you think? Dr. Vamsi Velcheti: Yeah, I agree, Brian. I think it's a really promising combination. We've always seen some synergy with VEGF inhibitors and immunotherapy in multiple studies and multiple tumor types. So, we really need to develop better ways to select patients for VEGF combination-based approaches in lung cancer. So, let's move on to another interesting study. This is Abstract 9000. This explores the outcomes of anti-PD-L1 therapy with or without chemotherapy for first-line, metastatic non-small cell lung cancer with a PD-L1 score of greater than 50%. So, this is an FDA pooled analysis. So, what were your key takeaways from this abstract? Dr. Brain Henick: I thought this question was really well suited for a large pooled retrospective analysis and our colleagues at the FDA didn't let us down here. The question really was what's the optimal approach for patients with non-small cell lung cancer with greater than 50% PD-L1 in view of the absence of direct comparisons between these arms in prospective studies? I thought one of the most striking findings from Dr. Akinboro's presentation was the dismally low rate of underrepresented minority patients that were included in these registration trials. As far as the findings for the patients who were studied, although the Kaplan-Meier curves for overall survival showed early separation, the difference wasn't statistically significant. Subgroup analysis revealed a trend towards better outcomes for immunotherapy alone among patients who are [age] 75 and above, suggesting that this may need to be parsed out as a unique population in subsequent studies. But in all, our equipoise as a field on whether to include chemoimmunotherapy-based first-line regimens should persist and should be guided, in my opinion, largely by clinical considerations. Can the patient tolerate chemotherapy? Do you need a rapid response? Are there other things that you thought in hearing all this, Vamsi? Dr. Vamsi Velcheti: Yeah, absolutely. I think I am still struggling with the decision of whether to add chemotherapy for patients with greater than 50%. To a large extent, it's actually a clinical decision. In some patients who have a large disease burden, I tend to kind of opt for adding chemotherapy to immunotherapy in the front-line setting. But of course, we need more data here. And this is actually a very helpful piece of information from the FDA. And as you pointed out briefly, Brian, I think the fact that there are very few underrepresented patients in the pooled analysis, I think kind of speaks to the need for addressing increased diversity in clinical trial accruals. I think this is a great segue to also talk about Abstract 9012, talking about disparities in access to immunotherapy globally. This is a study from India looking at 15,000 patients who were checkpoint inhibitor eligible and who have very low rates of uptake of immunotherapy. This is something that reflects the global team of the ASCO Annual Meeting talking about disparities and improving access to treatments in underserved minority populations here in the United States, and also globally, in the developing world, the disparities in terms of access to care are humongous. So, what are your thoughts, Brian? And also, if you could highlight some of the work that you're doing at Columbia about disparities, I think that would be great. Dr. Brain Henick: Absolutely! I think access to medications is a really humbling topic for those of us who are involved in developmental therapeutics, particularly with the transformational impact we've seen with the advent of immunotherapy over the last decade-plus. Dr. Ravikrishna's presentation is therefore extremely important. He described very low rates of uptake of immunotherapy by indication. And perhaps most strikingly, the discrepancy in uptake by patients' ability to pay for therapy with the vast majority of immunotherapy received by those who are private is very concerning. Even if the definition of restricted access was permissive, for example, I didn't see mention of the cancer stage as an eligibility factor, the fact that this represents a single referral center's data doesn't bode well for uptake elsewhere. So, I think we need to continue to work as a field on prioritizing strategies to help overcome these gaps, but good quality data such as this study is an important first step. And to that point, Vamsi, I'm very excited to be working with you in collaboration on an observational study for patients with lung cancer from underserved minority populations with lung cancer in New York City so that we can better characterize access to care, efficacy, and toxicity in this population. Dr. Vamsi Velcheti: Thank you, Brian. I'd really like to thank you for sharing your valuable insights with us today on the ASCO Daily News Podcast. We really appreciate it. Brian, thank you so much for joining us. Dr. Brain Henick: My pleasure. Thanks for having me. Dr. Vamsi Velcheti: And thank you to all our listeners for joining in today. You will find links to all 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 so much.     Disclosures: Dr. Vamsi Velcheti: Honoraria: Honoraria Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen 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. Brain Henick: None disclosed. 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.

On this episode we hear from Thoracic Medical oncologist Dr. Thomas Stinchcombe. Dr. Stinchcombe is a member of Duke Cancer Institute, and Thoracic Oncology Program at Duke University in Durham, North Carolina. Dr. Stinchcombe explains whether or not they would recommend RET inhibitors as first line therapy for a RET-fusion positive metastatic Non-Small Cell Lung Cancer patient, what drugs are available to treat patients with Non-Small Lung Cancer and MET exon 14 skipping alterations, the significance of a metastatic Non-Small Cell Lung Cancer patient with a ERBB2 or HER2 alteration & whether there are specific mutations that are targetable for HER2. We conclude with a breakdown of the role of immune check point inhibitors in patients with resected Non-Small Cell Lung Cancer & the role of adjuvant therapy with atezolizumab. Visit www.precisca.com for more resources, content, and access to our entire catalogue of educational content. There you will have access to our complete library of educational videos. New episodes of the PrecisCa Oncology Podcast are released weekly. Please consider sharing our podcast, subscribing & turning on notifications to be the first to know about new releases. Together, we can raise the level of cancer care from diagnosis to recovery.

In this episode, we welcome Dr. Nagla Abdel Karim, director of the Thoracic Oncology Program at Augusta University at the Georgia Cancer Center. While overcoming stereotypical obstacles of being a gifted girl and immigrating from Egypt, her message is strong- to stay positive and make a difference; give back to the community. We also hear from Leah in our student voice segment who is a gifted program alum and studying to be a doctor.

On today's episode, meet Dr. Christopher Lathan. Dr. Lathan is Chief Clinical Access and Equity Officer at Dana-Farber Cancer Institute (DFCI), a new institutional leadership position that also adds him to Dana-Farber's Executive Leadership Team. Chris has been a member of the Dana-Farber staff since joining the Thoracic Oncology Program in 2005. He was appointed the first Faculty Director of Cancer Care Equity at Dana-Farber in 2010 and directs Dana Farber's clinical service at Whittier Street Health Center. Chris also serves as Medical Director for Dana-Farber Cancer Institute in Brighton and Associate Medical Director for the Dana-Farber Network. He is leading the effort to combat structural racism and improve health care outcomes for all patients and communities served by Dana-Farber.

Host: Jennifer Caudle, DO Guest: Tracey Evans, MD Small cell lung cancer (SCLC) is a highly aggressive, lethal, and widely metastatic lung cancer. While therapeutic progress in SCLC has been limited over the years, immunotherapy has made some meaningful advancements in the treatment landscape. Joining Dr. Jennifer Caudle to discuss key diagnostic and therapeutic considerations such as TECENTRIQ® (atezolizumab) for 1L ES-SCLC, is Dr. Tracey Evans, Director of Thoracic Oncology Research at Lankenau Institute for Medical Research and Co-Director of the Thoracic Oncology Program at Main Line Health. This program is intended for US Physicians. M-US-00010802(v1.0)

On today's episode, meet Dr. Leora Horn. Dr. Horn is the Global Clinical Head for Lung Cancer and Lung Cancer Strategy at AstraZeneca. She leads the company's global research and development in lung cancer. In her role, she partners with lung cancer teams from across AstraZeneca Oncology to rapidly progress their research and deliver on their commitment to cure more patients with the disease. Before coming to AstraZeneca, Dr. Horn was the Ingram Associate Professor of Cancer Research and Director of the Clinical Research Section of the Thoracic Oncology Program at Vanderbilt-Ingram Cancer Center.

Robert Figlin, MD, Steven Spielberg Family Chair in Hematology-Oncology, Cedars-Sinai Medical Center, and Edward Garon, MD, Director of Thoracic Oncology Program, Jonsson Comprehensive Cancer Center, Associate Professor of Medicine, David Geffen School of Medicine, UCLA, discuss promising agents in development for the management of NSCLC from ASCO20

Robert Figlin, MD, Steven Spielberg Family Chair in Hematology-Oncology, Cedars-Sinai Medical Center, and Edward Garon, MD, Director of Thoracic Oncology Program, Jonsson Comprehensive Cancer Center, Associate Professor of Medicine, David Geffen School of Medicine, UCLA, discuss promising agents in development for the management of NSCLC from ASCO20

This episode features Dr. Marty Edelman, Chair of the Department of Hematology/Oncology and a Professor, Department of Hematology/Oncology at Fox Chase Cancer Center. He is joined by Dr. Roy Herbst, a Professor of Medicine and Pharmacology, Chief of Medical Oncology, and Associate Director for Translational Research at Yale Cancer Center/ Yale School of Medicine; and Dr. Leora Horn, the Ingram Associate Professor of Cancer Research at Vanderbilt Ingram Cancer Center and Clinical Director, Thoracic Oncology Program. Together they discuss highlights from the 20th IASLC 2020 Lung Cancer Targeted Therapies conference in Santa Monica

Barry was diagnosed in 2012 with stage 3 lung cancer after experiencing swelling in his neck that had repeatedly showed up and disappeared several times. He went to see his primary care doctor and an oncologist. He was told he had 18 months to live in 2012. Barry went to see Dr. Lathan for a second opinion and wound up staying to be treated at Dana-Farber. Barry's treatment included chemotherapy, radiation, and a few clinical trials. In February 2014, he began a trageted gene therapy called immunotherapy. This saved Barry's life. He says this "is when my whole life began to change." Barry has been off treatment since February 2016 and healthy. He previously served as a certified risk manager and has two adult daughters. He is very active in church. Sang in church's choir and other volunteer work with church, prayer partner program, currently a lay servant at church, rides his bike, attends conferences with Dr. Lathan and Dr. Freeman. Barry is incredibly grateful to the entire team at Dana-Farber that he credits with saving his life. Barry had the oppotunity to meet Dr. Gordon Freeman, a researcher at Dana-Farber, who's work helped start the field of immunotherapy. Barry was so touched to meet the man whose work led to the creation of the treatment he is currently on.Dr. Lathan has been a member of the Thoracic Oncology Program at Dana-Farber since 2005 and was appointed as the first Faculty Director of Cancer Care Equity at Dana-Farber in 2010. He directs a successful Dana-Farber clinical service at Whittier Street Health Center in Boston where he developed a lung cancer screening pilot program with the support of a CVS pharmacy foundation grant. He is also a leading researcher in Dana-Farber's Population Sciences Center on issues of race and class disparities in cancer care and has published and lectured extensively on this topic. In addition to leading Dana-Farber at St. Elizabeth's, Dr. Lathan works at Whittier Street Health Center and sees patients in his thoracic oncology practice at Dana-Farber's Longwood campus. Dana-Farber Cancer Institute provides the latest hematology and medical oncology care to patients at St. Elizabeth's Medical Center. The partnership between Dana-Farber and St. Elizabeth's enables patients to receive the benefit of Dana-Farber's advances in care and research at their local hospital. Dana-Farber teams at St. Elizabeth's and in Boston collaborate to review cases and develop the optimal treatment plan for patients.

Lung cancer is the leading cause of cancer death in the U.S. At City of Hope, reducing this statistic is our top priority.Listen to City of Hope Radio as Dr. Dan Raz MD. co-director of City of Hope's Lung Cancer and Thoracic Oncology Program and director of the Lung Cancer Screening Program, sorts out facts about lung cancer and smoking, the benefits of and who qualifies for a new screening option, and what innovative treatments are available to treat this deadly disease.

Howard (Jack) West, MD, Medical Director of the Thoracic Oncology Program at the Swedish Cancer Institute and Founder of the cancer education nonprofit Global Resource for Advancing Cancer Education, discusses several models of successful online collaboration between patients and health care providers. His podcast is based on his article coauthored with Dave deBronkart and George Demetri, MD, "A New Model: Physician-Patient Collaboration in Online Communities and the Clinical Practice of Oncology."

Dr. Mark Socinski, medical oncologist and leader of the Thoracic Oncology Program at Univ. of North Carolina, answers questions about what treatments to recommend after first line therapy for advanced NSCLC and when they should be pursued.

Dr. Mark Socinski, medical oncologist and leader of the Thoracic Oncology Program at Univ. of North Carolina, answers questions about what treatments to recommend after first line therapy for advanced NSCLC and when they should be pursued.

Dr. Mark Socinski, medical oncologist and leader of the Thoracic Oncology Program at Univ. of North Carolina, summarizes the evidence and presents a current approach to managing treatment of advanced NSCLC after first line therapy.

Dr. Mark Socinski, medical oncologist and leader of the Thoracic Oncology Program at Univ. of North Carolina, summarizes the evidence and presents a current approach to managing treatment of advanced NSCLC after first line therapy.

Dr. Suresh Ramalingam, medical oncologist and leader of the Thoracic Oncology Program at Emory University, discusses questions about individualizing therapy choices for patients with advanced NSCLC.

Dr. Suresh Ramalingam, medical oncologist and leader of the Thoracic Oncology Program at Emory University, discusses questions about individualizing therapy choices for patients with advanced NSCLC.

Dr. Suresh Ramalingam, medical oncologist and leader of the Thoracic Oncology Program at Emory University, reviews the evolution of first line treatment of advanced non-small cell lung cancer to our current tailored approach for optimal outcomes.

Dr. Suresh Ramalingam, medical oncologist and leader of the Thoracic Oncology Program at Emory University, reviews the evolution of first line treatment of advanced non-small cell lung cancer to our current tailored approach for optimal outcomes.