Podcasts about neck medical oncology

In today's episode, supported by Summit Therapeutics, we had the pleasure of speaking with Xiuning Le, MD, PhD, about the use of ivonescimab (SMT112) in patients with PD-L1–positive non–small cell lung cancer (NSCLC). Dr Le is an associate professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at The University of Texas MD Anderson Cancer Center in Houston. The phase 3 HARMONi-2 trial (NCT05499390) investigated ivonescimab vs pembrolizumab (Keytruda) in patients with locally advanced or metastatic, PD-L1–positive NSCLC without sensitizing EGFR mutations or ALK translocations. At the preplanned interim analysis, at a median follow-up of 8.7 months (IQR, 7.1-10.3), the median progression-free survival was significantly longer in the ivonescimab arm (n = 198) vs the pembrolizumab arm (n = 200), at 11.1 months (95% CI, 7.3-not estimable) vs 5.8 months (95% CI, 5.0-8.2), respectively (stratified HR, 0.51; 95% CI, 0.38-0.69; 1-sided P < .0001). The objective response rates were 50% (95% CI, 43%-57%) and 39% (95% CI, 32%-46%) in these respective arms. In our exclusive interview, Dr Le discussed the rationale for the HARMONi-2 trial, key findings from the study, and where these findings position the potential role of ivonescimab in the PD-L1–positive NSCLC treatment paradigm.

In this episode of Lung Cancer Considered, host Dr. Stephen Liu leads a discussion on the FDA approval of perioperative nivolumab based on the Phase III CheckMate 77T study. Perioperative therapy has improved outcomes in patients with resectable NSCLC and is emerging as best practice but there is nuance to the delivery of this therapy. Guest: Dr. Tina Cascone is a Physician-Scientist and Associate Professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas and lead author of the CheckMate 77T manuscript in the New England Journal of Medicine Guest: Dr. Shun Lu is the Chief of Shanghai Lung Cancer Center and Shanghai Chest Hospital and Professor at Shanghai Jiaotong University. He is an executive board member of the Chinese Society of Clinical Oncology and past chair of Chinese Lung Cancer Association

The multicenter RAMOSE randomized clinical trial has found that doublet growth factor tyrosine kinase inhibitor therapy, when compared with standard osimertinib monotherapy, achieved a statistically significant improvement in progression-free survival in patients whose advanced non-small cell lung cancers were driven by mutated epidermal growth factor receptor. First author Xiuning Le, MD, PhD, Associate Professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center, has been discussing her group's findings with Peter Goodwin, an OncTimesTalk correspondent.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. 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 this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, Dr. Xiuning Le discusses new research on targeted therapy for non-small cell lung cancer presented at the 2022 North America Conference on Lung Cancer, held September 23-25 in Chicago, Illinois. Dr. Le is an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas. She is also a 2022 Lung Cancer Advisory Panelist on the Cancer.Net Editorial Board. You can view Dr. Le's disclosures at Cancer.Net. Dr. Le: Hi everyone. This is Xiuning Le. I'm an assistant professor here at MD Anderson in the Department of Thoracic/Head and Neck Medical Oncology department. I am a medical oncologist. I am a clinical investigator and also translational researcher. So today is a great opportunity to discuss some of the new meeting updates from 2022 North America Conference on Lung Cancer. Let me begin with the information about the meeting itself. So this conference, North America Conference on Lung Cancer, is organized by an organization called the International Association for the Study of Lung Cancer. As reflected in the name, this is an international organization for all the lung cancer researchers to get together to share our research, experience, and also patient advocates as well as patients participate in this fantastic organization. This organization also has meetings every year, including a World Lung Conference as well as the meeting we're going to talk a little bit about today, focusing on the progress we made in the North America. Therefore, it's called North America Conference on Lung Cancer. In this year's meeting, we had a very active agenda with multiple presenters from different parts of the U.S. And we also had international participants as well. We had exciting updates on some of the targeted therapy trials as well as updates from immunotherapy trials. So it was a very productive meeting. Let me start with some of the updates from the targeted therapy space. During the meeting oral presentation, there were 3 abstracts selected for oral presentations. The first talk I would briefly discuss today is an update study for ADAURA trial using osimertinib as an adjuvant therapy for resected lung cancer patients whose tumor has EGFR mutation. This was presented by Dr. Roy Herbst, key investigator on the trial from Yale Cancer Center. So ADAURA trial is a multicenter international trial taking patients whose lung cancer have EGFR classical mutation at the diagnosis, or stage 1B to 3A, and then undergoing chemotherapy as the initial adjuvant treatment. But after completion of those treatments, patients were offered opportunities to go on to the trial receiving either osimertinib for 3 years or best supportive care placebo. The primary report of this trial became available in year 2021, where the osimertinib-treated patient had a significant clinical benefit reflected as the disease-free survival was much higher in the patient population who received osimertinib. The results of the ADAURA trial led to the FDA approval of using osimertinib in the surgically resected EGFR-mutant non-small cell lung cancer. So that's the background of this year's update and presentation. Now, in the fall of 2022, after additional long follow-up, the data become more mature because although we still don't have overall survival results, we start to have 3-year disease-free survival. So in the study population, each is over 300 patients each arm, the 3-year disease-free survival rate was 84% for patients who receive osimertinib and then for placebo group is 34%. As you can see, this is a 2.5-fold significant benefit in the patient who received the treatment. The presentation was also a breakdown the patient population by their stage by different subgroup analysis across the board. The patient who received osimertinib derived benefit and then the hazard ratio remained to be between 0.2 to 0.3, depending which population we're looking at. Really, this data validated and confirmed the prior knowledge of this approach of offering adjuvant osimertinib really works and really should be offered to every single patient who qualifies for this study. One update on the subgroup analysis is the benefit for preventing brain metastasis to happen in the patients. Very impressive. We observe a hazard ratio of 0.24, meaning that if a patient goes on to osimertinib has a 4-fold benefit of not to develop brain metastasis. Overall, the conclusion of this presentation is that this data becoming more mature, and then the mature data reinforced that adjuvant osimertinib really should be the standard of care which we have been using pretty widely in the clinic. The second abstract I want to talk about is a presentation that's presented by Dr. Lyudmila Bazhenova from University of California, San Diego. So she presented a pooled updated analysis on a novel EGFR exon 20 insertion medication. And then this medication currently is under U.S. FDA evaluation with breakthrough therapy designation. The drug's chemical name is called DZD9008, and then the drug's brand name is sunvozertinib. This is a great addition to the treatment option that we already start to see for EGFR exon 20 as a new inhibitor coming at the horizon. EGFR, we now start to classify all the mutations into classical mutation versus exon 20 mutation, as we are using different targeted therapy for different patients. For EGFR exon 20 insertion, we have already 2 FDA-approved drugs. One is amivantamab, the other is mobocertinib. But we still need more options for our patients. And this new medication, DZD9008, is having a great potential of becoming the next-generation EGFR exon 20 drug, as it showed good efficacy and pretty low toxicity. So let's review the data that's presented here. In this meeting abstract, the authors combined 2 studies. One is called WU-KONG1. The other is called WU-KONG2. The first one was conducted in the U.S., and the second one was conducted in China. So there is a value of pooling different patient populations together and then not just getting the sample size greater but also understand different patient population, are they all having very similar benefit? Here the focus on analyzing the patient population that EGFR exon 20 lung cancer who have already received the chemotherapy. In the total of 71 patients analyzed here, in the subgroup of receiving 300 mg daily dose, the response rate was observed to be 40% to 45% depending on if you're using the central review system or you're using the investigator evaluation. But again, showing a very promising response. I want to put those numbers in the reference. For example, the currently FDA approved, the mobocertinib, in their population also had prior treatment. The response for mobocertinib was 28%. In the over 100 patient population, in these 71 patients, they see a 40% to 45% response. So potentially this one is having an even better efficacy really translate into clinic can be a great opportunity for the patients who had chemotherapy and needs something else. Also, we reviewed the toxicity profile. This drug is overall pretty well tolerated. We have to say that the population is relatively small. In order to truly understand toxicity, we usually want to look at the multi-hundred patients' experience, but I believe the data will mature over time. I would have to say the result here is very exciting. The third abstract I will be talking about today is presented by myself, Xiuning Le from MD Anderson. In this abstract, we evaluated tepotinib, which is a MET inhibitor, their efficacy and safety in MET amplified non-small cell lung cancer patients. As we already know, MET exon 14 skipping represents a molecular subgroup that can benefit from MET TKI, including tepotinib. But MET amplification without MET exon 14 is another patient subgroup that could potentially benefit from MET inhibition. As in those cancers, MET not using exon 14 skipping as driving events rather than amplify. So the gene makes many copies of itself, so that drives the tumor growth that way. In this abstract, in this analysis, MET amplified non-small cell lung cancer patients were identified and offered tepotinib. So in this group, there are 24 patients who were treated on the VISION trial cohort B, and we observe a response rate of 42%. For a targeted therapy, having a 42% of response is really pretty encouraging. And the duration of response also is expected at multiple months. We showed that the therapy was particularly beneficial for patients who are treatment-naive. In that setting, the response rate can be as high as 70%. This time, this year, we updated our molecular analysis for this patient cohort trying to understand deeper, do we have other signals to help us to decide which patient could benefit more and which patient might benefit less and then need something else? In the molecular analysis, we find that focal MET amplification is quite important. In another word, if MET amplification is the only event, then more likely this MET TKI will work in that patient population. However, if the tumor also has p53 or RB loss or certain other genetic alterations, then the response rate can be more inferior. So I think we are starting to understand each of the molecular-driven patient population group into even more molecular detail, understanding the co-mutations' impact to the clinical outcome. So I think this abstract is interesting in pointing directions of how to use an existing medication to patients to magnify the benefits that we can potentially achieve. So this year's North America Lung Conference was really productive. We had a lot of stimulating presentations and a lot of discussions. Other than the targeted therapy session, we have seen 2 exciting abstract on the immunotherapy updates. Other than that, we start to have more opportunities to learn about cancer screening, cancer prevention, smoking addiction, and then the cancer survivorship. There are 2 abstracts presented at the oral section for that topic as well. So this meeting is particularly interesting opportunity for North America investigators, especially in their junior stage, to network, to present their work, and then to have exposure to major investigators in the field as well. Dr. Le: Thank you, Dr. Le. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

David Stewart, MD; Head, Division of Medical Oncology, University of Ottawa; Author, A Short Primer on Why Cancer Still SucksDr. Stewart received his MD degree from Queen's University, Kingston, followed by training in internal medicine at McGill University and in medical oncology in the Department of Developmental Therapeutics at the UT MD Anderson Cancer Center. He first moved from MD Anderson to the University of Ottawa in 1980, and served as Chief of Medical Oncology at the Ottawa Civic Hospital from 1989 to 1999. He returned to the Department of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center from 2003 to 2011 where he served as Chief of the Section of Experimental Therapeutics (2003-2005), Chair Ad Interim (2005), Deputy Chair (2006-2009), and Director of Translational Research (2009-2011). He was also the Principle Investigator of MD Anderson' phase II N01 contract with the National Cancer Institute, and was the clinical leader of a number of other federally-funded translational research projects. In 2011, Dr. Stewart returned to Ottawa from the University of Texas MD Anderson Cancer Center (Houston, TX) in 2011 to assume the position of Head of the Division of Medical Oncology at The Ottawa Hospital and the University of Ottawa. John Marchica, CEO, Darwin Research GroupJohn Marchica is a veteran health care strategist and CEO of Darwin Research Group. He is leading ongoing, in-depth research initiatives on integrated health systems, accountable care organizations, and value-based care models. He is a faculty associate in the W.P. Carey School of Business and the graduate College of Health Solutions at Arizona State University.John did his undergraduate work in economics at Knox College, has an MBA and M.A. in public policy from the University of Chicago, and completed his Ph.D. coursework at The Dartmouth Institute. He is an active member of the American College of Healthcare Executives and is pursuing certification as a Fellow. About Darwin Research GroupDarwin Research Group Inc. provides advanced market intelligence and in-depth customer insights to health care executives, with a strategic focus on health care delivery systems and the global shift toward value-based care. Darwin's client list includes forward-thinking biopharmaceutical and medical device companies, as well as health care providers, private equity, and venture capital firms. The company was founded in 2010 as Darwin Advisory Partners, LLC and is headquartered in Scottsdale, Ariz. with a satellite office in Princeton, N.J.

The role of the pathologist in lung cancer treatment has dramatically evolved as our understanding of lung cancer biology has advanced. Lung Cancer Considered host Dr. Stephen Liu discusses that evolution with renowned lung cancer pathologists Dr. Dara Aisner from the University of Colorado and Dr. Ignacio Wistuba from MD Anderson Cancer Center. Dr. Wistuba is a Professor in the Department of Thoracic and Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston. He is the Head of the Division of Pathology and Lab Medicine and an expert in translational pathology. Dr. Aisner is an Associate Professor in the Department of Pathology at the University of Colorado in Aurora, CO. She has expertise in Anatomic as well as Molecular Genetic Pathology and is the Medical Director of the Colorado Molecular Correlates Laboratory.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. 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 this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, members of the Cancer.Net Editorial Board discuss new research in molecular testing, also known as biomarker testing or tumor marker testing, to help guide treatment for people with early-stage non-small cell lung cancer. This podcast is led by Dr. Ryan Gentzler, Dr. Xiuning Le, Dr. Brendan Stiles, and Dr. Vamsidhar Velcheti. Dr. Gentzler is the director of the Thoracic Oncology Clinical Research Program at the University of Virginia (UVA) and chairs the UVA Cancer Center's Lung Cancer Translational Research Team.  Dr. Le is an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at The University of Texas MD Anderson Cancer Center. Dr. Stiles is chief of thoracic surgery and surgical oncology at Montefiore and Albert Einstein College of Medicine. Dr. Velcheti is the director of thoracic medical oncology at New York University Langone's Perlmutter Cancer Center. View disclosures for Dr. Gentzler, Dr. Le, Dr. Stiles, and Dr. Velcheti on Cancer.Net. Dr. Gentzler: Thank you, everyone, for joining us. We've got a great group here today, and we're really going to focus on talking about molecular testing in lung cancer. This is a very hot topic. My name is Ryan Gentzler from the University of Virginia. I'm a thoracic medical oncologist. We have Drs. Le, Stiles, and Velcheti with us today. I'd like them to go ahead and introduce themselves, starting with Dr. Le. Dr. Le: My name is Xiuning Le. I'm an assistant professor. I'm at the MD Anderson Cancer Center here in Houston, Texas. I'm also a medical oncologist. Thank you, Ryan, for inviting us today. Dr. Stiles: Hey, everybody. I'm Brendan Stiles. I'm a thoracic surgeon. I'm chief of thoracic surgery at Albert Einstein College of Medicine in Montefiore Health System here in the Bronx in New York. Dr. Gentzler: All right, thanks for joining us. And Dr. Velcheti. Dr. Velcheti: Thank you, Ryan. I'm Vamsidhar Velcheti. I'm the director of the thoracic oncology program at NYU. Dr. Gentzler: All right, great. We hear a lot of terms thrown around about molecular testing, genomic testing, biomarkers, oncogenic drivers, and I thought it would be good to just define what exactly is molecular testing, so all of our listeners are aware of what we're talking about. Dr. Le, do you want to take this question? Dr. Le: Yeah. So we have many terms, as you described. In my eyes, there are 2 sets of testing, and then some of them also classify into actionable versus not actionable. So for clinical use, we usually ask the tumor to be tested for both the mutations as well as the immune marker. Usually, the panel of mutational testing is more than a field. Usually, it's depending on the platform we're using, oftentimes in the hundreds of things. And then the immune markers, usually, we refer to PD-L1 and the tumor mutational burden. Those are the 2 commonly used markers now in the clinic. Some of those markers, especially the hundreds in gene testing, not all of them can lead to a clinical decision because we're still in the phase of understanding the interactions of different genes. However, there is a subgroup of those mutations. Nowadays, we have targeted therapy for, we call those actionable mutations. So in the clinic, we push for testing for a panel of mutations as well as immune markers, hoping to look at the tumor comprehensively so that we can recommend a good treatment regimen precise to that particular tumor, precise to that particular patient. Dr. Gentzler: Yeah. Wonderful. This has also been termed precision medicine, where we really match a therapy to a specific genomic abnormality identified on these tests and maybe, Dr. Velcheti, if you could maybe elaborate on some of the different ways that these tests are performed and how we're using these in clinic today? Dr. Velcheti: Yeah, definitely. I think our understanding of the biology of lung cancer has evolved quite dramatically over the past several years and obviously it's led to a lot of advancements in terms of treatment opportunities for patients. Broadly, the way I look at biomarkers in lung cancer or, for that matter, any cancer, it's like you have biomarkers that actually kind of give us very deep insights into the biology of the cancer and giving us insights into how aggressive somebody's cancer is. Those are called prognostic biomarkers, kind of predicting outcome. And there are predictive biomarkers where there are certain biomarkers. If you do have some of these biomarkers in the tumor, then you could potentially use certain treatments that might work better for patients who have those biomarkers. So now we have a lot of different approaches in terms of how we kind of test for these biomarkers. Especially in lung cancer, now we have a lot of new therapeutics for certain genomically categorized types of lung cancer. And the challenge now is that we have so many different mutations we absolutely need that information to decide on treatment. So how do we test that? Until a few years ago, we've been doing a single gene testing. The problem with those approaches is that we have so many different genes we need to test and we kind of do sequential gene testing, a single gene testing, we won't get all the information we need to make the right decision for our patients. So the standard approach in most oncology practices, especially larger cancer centers and academic medical centers, is do comprehensive genomic profiling, and that's being widely accepted as a standard approach right now. Dr. Gentzler: Wonderful. And this has really been something that has fallen on the laps of thoracic medical oncologists as we've treated patients with advanced stage or stage 4 disease. And this is starting to become more and more important and relevant for surgeons. And Dr. Stiles, I just wanted to bring you into the conversation and see if this is something that, prior to some of the more recent data, which we'll discuss in a minute, is this something that as a surgeon, you've kept up with and think it's important in a surgical practice? Dr. Stiles: Yeah, definitely, Ryan. And I think now is probably the most exciting time for that, right? We used to just be sort of in the prognostic side, like Vamsi said, but now we really are in the predictive side in the early-stage disease. And I think that's why everybody is so excited. But that's why there's now this pressure about the timing of biomarker testing. What do you get? Do you get a whole panel? As we'll talk about some of the trials that have made their way into earlier stage disease, but it becomes inherent upon surgeons to really think about this and understand this, from the first time that they meet the patient I think, as we increasingly get better therapies in earlier stage disease. Dr. Gentzler: So as this has moved into earlier stage disease, a lot of this has been driven by some new data from clinical trials, and Dr. Velcheti, I thought maybe you could comment on the IMpower010 trial and its relevance and why molecular testing is important in the context of that trial. Dr. Velcheti: Yes, absolutely. I think the IMpower010 Trial is certainly a new shift in our approach to treating stage I, II curable non-small cell lung cancers. So we haven't had an approval in the adjuvant setting in a while. I mean, of course, we had approval with the osimertinib result of the ADAURA trial, but that's only for EGFR patients. Now we have approval for using immunotherapy in the postoperative adjuvant setting for patients with any level of PD-L1 expression. So this is a large randomized study looking at the role of adjuvant atezolizumab, which is a PD-L1 inhibitor in patients who have PD-L1 expression greater than 1%. Patients were randomized getting platinum doublet alone, which is a standard-of-care adjuvant assistant therapy for patients at stage I, II lung cancer. It is atezolizumab at a dose of 1,200 milligrams given every 3 weeks. Patients who received atezolizumab had significantly improved outcomes in disease-free survival. And the benefit was actually really striking for patients who had high PD-L1, patients with PD-L1 testing TPS score of greater than 50%. They had a really remarkable increase in terms of disease-free survival for those patients. So this is certainly very encouraging. And of course, we know it's now approved. We are still awaiting some overall survival results to mature. But given the extent of the benefits we're seeing with the disease-free survival, I think it's a very promising approach. Dr. Gentzler: Yeah, so obviously, immune therapy has had a tremendous benefit in the adjuvant setting from this trial and still some longer-term follow-up that's needed. But I think the important point here is that molecular testing may identify certain mutations that may make patients less likely to benefit or respond, or perhaps there's more appropriate treatments than immunotherapy within this group. And that brings us to the next trial that I think really shifted this discussion stage with the ADAURA trial. Maybe Dr. Le, if you could summarize this trial and give us your thoughts on why molecular testing is so important in the era of ADAURA. Dr. Le: Yeah. So ADAURA trial is also an adjuvant trial, meaning that the patient received additional treatment after the completion of surgery. So ADAURA trial looked at patients who have EGFR mutations. So it's a different biomarker. It's a gene biomarker, not the immune biomarker. So this is a large international trial, enrolled almost 700 patients and then randomized the patients after surgery, after standard chemo, the patient can go on to either receive 3 years of osimertinib, which is the standard-of-care therapy for EGFR mutant patients for metastatic setting, or the control group if the patient just received standard of care, which is to continue the monitoring. The trial actually showed that for people who had osimertinib before that prolonged time of 3 years, the risk of the disease coming back is almost 5 times lower than the patient who did not receive therapy. So based on that really striking benefit of after surgery, after chemotherapy, continue osimertinib in EGFR patients, FDA approved after the surgical resection and all the standard care patient can go on for osimertinib for a prolonged time, which we think currently the data is saying the disease is more likely not to come back. And hopefully, in the future, that result will translate into overall survival benefit. Dr. Gentzler: Okay, wonderful. And I think both of these trials, both the ADAURA and the IMpower010, are adjuvant trials. So these are trials that allow us adequate time to do molecular testing on a large surgical specimen, formulate our plans, and implement those plans up to a month or longer after surgery. Obviously, there's some new data that we've seen in a press release from the CheckMate 816 trial. This is a neoadjuvant trial of chemotherapy plus nivolumab. We've seen previous data from this trial showing some results, but this moves the conversation into the neoadjuvant space, and Dr. Stiles, I wonder if you could give us a summary of your thoughts on the CheckMate 816 and the relevance for molecular testing in that context of neoadjuvant therapy. Dr. Stiles: Yeah. Thanks, Ryan. I think, first of all, those are incredibly important adjuvant trials. I saw 2 patients each this week on adjuvant osimertinib and adjuvant atezo [atezolizumab], so it's real-life practice. Every day, it's going to benefit patients. But I think that's easy, like you said, these are big specimens that are taken out. You've got time to decide while the patient gets better. Now, we have to shift all this even earlier because CheckMate 816 really has some pretty impressive results. We, unfortunately, don't have the paper yet. I'm told it's going to be coming out soon, but the primary endpoint pathologic complete response 24% versus 2.2%. That's with chemo-nivo versus chemo alone. Obviously, people are questioning, does pathologic complete response correlate with outcomes? Certainly, we got a signal on a press release that the event-free survival is going to be the hazard ratio is 0.63, so it sounds like it does, and I think we'll see more data on that in the next couple of months. A difference in median event-free survival of 32 months versus 21 months in the report. So everybody is excited to see this. And I think it has some advantages over the adjuvant strategy. First of all, more patients are able to tolerate it. It's just 3 cycles, and so it's not given indeterminately for a year. And it worked across different subgroups. And we can talk about some of the nuances, but as where atezo [atezolizumab] was only looking good in the PD-L1-high. This sort of worked across different groups. The caveat to that is we don't really know what happens with these EGFR patients who are eligible and sort of, how do we then move that test? And all of a sudden, we've got to make a decision on neoadjuvant therapy. Now we need to know. It helps to know the PD-L1 maybe preoperatively, with the high PD-L1, maybe you could wait until adjuvant therapy, with the low to sort of medium PD-L1, maybe you want to give them their shot in the neoadjuvant space. But if they have an EGFR mutation, it's probably not the right thing. We don't really know the data on that and CheckMate 816 yet, but certainly, I'd be sort of hesitant to give them neoadjuvant chemoimmunotherapy. So then you have to teach surgeons all this too, and teach them to think about this and teach them to hold their horses on taking patients to the operating room while they wait for molecular testing. But that probably means we need to speed up the process somewhat either with sort of more rapid turnaround test, with consideration of liquid tests in some instances. It's just an incredibly fast-changing place that here we are speaking about a trial that hasn't even been published yet, so that tells you how fast things are happening. Dr. Gentzler: One last question. How can the results of these tests guide therapy after surgery? Do we incorporate a full NGS [next-generation sequencing] panel at the time of surgery? And we don't have data on adjuvant therapy for ALK or ROS1, or RET. Do we factor that into how we think about adjuvant chemotherapy, adjuvant immunotherapy, do we employ targeted therapies for some of these mutations? Any thoughts on that? Dr. Le: Ryan, I think you bring an important point in that EGFR is 1 of the 8 actionable mutations we have nowadays based on FDA and NCCN. The tumor biology between EGFR and ALK-fusion oncogenesis and potential response and benefits probably share some similarities. So we look forward to seeing trials reporting out the adjuvant setting with ALK inhibitors with ROS1. And the smaller target might require a multi-institutional or co-op group effort to really achieve the sample size for us to see. But as of now, we don't have the approval. We try to enroll patients to the oncogene trials, but I think currently we're practicing based on EGFR and PD-L1. Dr. Stiles: Yes, and I agree. I'm excited to see what comes out of some of those trials. They're slow to grow, but we'll eventually get some readouts. I think an interesting question sometimes is PD-L1. And we had an example recently where in the pre-op biopsy, the patient had a low PD-L1, and so not particularly enthusiastic. And the question sometimes arises, do you test that whole tumor to consider them as kind of an adjuvant to atezo [atezolizumab]and then the fully resected tumor, the PD-L1 was greater than 50%. And so I would sort of sound a caution that the small biopsy sample, they're incredibly helpful for many things, incredibly helpful for moleculars. It may not always be totally representative of the PD-L1 staining. Dr. Gentzler: And I think that's a good point. Even for molecular testing, sometimes if you have smaller biopsies, you may get a result that's negative, but it could be low levels of DNA and not sufficient to complete the full panel with high quality. So you really have to pay attention to the report and make sure that there's some confidence in the amount of DNA in some of these results. Well, I think that's all the time we have here, so I appreciate everyone's participation, and hopefully we're able to learn a little bit about genomic testing today. ASCO: Thank you, Dr. Gentzler, Dr. Le, Dr. Stiles, and Dr. Velcheti. Learn more about treating lung cancer at www.cancer.net/lung.  Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, experts will discuss targeted therapy for lung cancer, including 2 new treatments that target a specific type of mutation or change in the EGFR gene in some cancer cells, called an EGFR exon 20 insertion. They will explain how targeted therapy works to treat cancer, why this specific mutation is different from other, more common EGFR mutations, and what these 2 new treatments mean for people with this type of cancer. This podcast will be led by Dr. Charu Aggarwal, Dr. Xiuning Le, Dr. Vamsidhar Velcheti, and Marcia Horn. Dr. Charu Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine in Philadelphia, Pennsylvania. She is also the Cancer.Net Associate Editor for Lung Cancer.  Dr. Xiuning Le is an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at the University of Texas MD Anderson Cancer Center in Houston, Texas.  She is also a Cancer.Net advisory panelist for lung cancer.  Dr. Vamsidhar Velcheti is the director of thoracic medical oncology at NYU Langone's Perlmutter Cancer Center in New York, New York, and is also a Cancer.Net advisory panelist for lung cancer. Marcia Horn is the President and CEO of the International Cancer Advocacy Network and the executive director of the Exon 20 Group in Phoenix, Arizona.  View full disclosures for Dr. Aggarwal, Dr. Le, Dr. Velcheti, and Ms. Horn at Cancer.Net. Dr. Charu Aggarwal: Hello and welcome to this Cancer.Net podcast on new research in lung cancer. I'm Dr. Charu Aggarwal from the University of Pennsylvania. I'm also the Cancer.Net Associate Editor for Lung Cancer. I'm here today with my colleagues from the Cancer.Net Lung Cancer Panel. First is Dr. Xiuning Le from the University of Texas MD Anderson Cancer Center. Hi, Dr. Le. Dr. Xiuning Le: Hi, everyone. This is Xiuning Le from MD Anderson. I'm happy to be here as one of the discussants. Dr. Aggarwal: Next is Dr. Vamsi Velcheti from the NYU Langone Perlmutter Cancer Center. Vamsi? Dr. Vamsidhar Velcheti: Hi, this is Vamsi Velcheti. I'm so glad to be here with you. Dr. Aggarwal: And our special guest today is Marcia Horn, the president and CEO of the International Cancer Advocacy Network and the executive director of the Exon 20 Group. Hi Marcia. Marcia Horn: Hi, everyone. Wonderful to be here. Dr. Aggarwal: So good to have you all. Before we begin, we should mention that Marcia has consulted with both Takeda Oncology and Janssen on survey research for the Exon 20 Group. You can view full disclosures for this podcast at Cancer.Net. Our podcast today is going to be about targeted therapy for non-small cell lung cancer, and specifically, 2 new treatments that target a specific type of mutation or change in the EGFR gene in some cancer cells. This mutation is called an EGFR exon 20 insertion. Dr. Velcheti, I'll start off with you. What is targeted therapy, and how does it work? Dr. Velcheti: So thank you, Charu. Lung cancer is a very complex biological disease. There are a lot of genes in the tumor cells that could be mutated, and understanding the type of genetic changes or mutations in the DNA of these tumor cells helps us really develop treatments that are very focused on that particular patient's cancer. Having a specific gene alteration could render tumors more susceptible or vulnerable to certain treatments, and these are what we call targeted therapies. And in lung cancer, these are especially important because there are a lot of drugs developed for patients with certain unique genomic aberrations, or changes in the DNA, and it's ushered in a whole wave of new treatments for patients with lung cancer, and it's really an exciting time for patients with lung cancer. Dr. Aggarwal: That's terrific. And I would like to focus on the mutation aspect a little bit more. Dr. Le, can you talk to us [about] whether all mutations found in lung cancer, can all of them be treated? Dr. Le: Like Dr. Velcheti was talking about, lung cancer is really a complex disease. And oftentimes in 1 lung cancer, we can detect more than 1, multiple mutations. Some of them function as driving the cell growth. Some of them function as a brake. We call that a tumor suppressor to release the cell from being suppressed. Clinically, we usually classify all the mutations that can be detected in the lung cancer into the 2 groups. One is called actionable. The other group is called not actionable. Actionable, meaning when we detect a mutation, we, as clinicians, can actually offer a specific targeted therapy to act on the mutation. Therefore, detection of the actionable mutation oftentimes translates to the patient potentially having the opportunity to get targeted therapy targeting that potential actionable driver oncogene. As of today, we're talking, the development of lung cancer treatment has been so advanced. We have 9 actionable genetic alterations that can be detected in non-small cell lung cancer. Even since 2 years ago, there are 4 new additions, so a total of 9 as of today, and EGFR exon 20 is one of the newest being approved in 2021, so really good news. Dr. Aggarwal: I know we've come a long way, and EGFR exon 20 insertions have been known for a long time. However, we've also known that they are not perhaps as sensitizing as the other EGFR mutations. Dr. Velcheti, could you shed some light on what is unique about these mutations in terms of testing as well as application of therapies? Dr. Velcheti: We have known about EGFR mutations in lung cancer for a very long time, and there have been quite effective treatments for EGFR activating mutation-positive lung cancer patients. However, not all mutations in the EGFR gene are the same. Depending on the location of the sequence change in the gene, they could have a different degree of response to EGFR inhibitors. So when we talk about EGFR exon 20, we're talking about a subset of these EGFR gene mutations which is in an area of the EGFR gene, a change in the sequence of the EGFR gene, that doesn't necessarily respond so well to the novel EGFR inhibitors that we have been using for a long time. So the clinical implications, and it's something to kind of think about and remember, is that the way we test for these mutations is very different. You could do comprehensive genomic profiling, or in some cases, there are some tests that actually test for a specific type of gene mutation. So it's something we call “hotspot panels.” Those are tests using certain techniques that actually only pick up certain EGFR genes, and they don't pick up all the gene mutations that happen in the EGFR gene. So it is very important to kind of keep that in mind because now we have drugs approved for exon 20 mutations. If you don't actually pick them up on a test, then obviously, we can't identify those patients for treatment with these exciting new treatments. And also, just as a quick plug, given that we have so many new drugs approved for different types of gene alterations in lung cancer, it is even more important now to focus on doing really good biomarker testing with comprehensive genomic profiling looking at a wide panel of genes, rather than focusing on certain kinds of gene mutations. So this is what we call comprehensive genomic profiling. That's absolutely critical in order to identify patients for the right treatment with targeted therapy. So it's extremely important to do that upfront so that we have patients kind of matched up to the right treatment. Dr. Le: I do also want to add with Dr. Velcheti in that I fully agree that exon 20 is oftentimes not on the hotspot PCR-based testing, so please use a comprehensive, what we call, next-generation sequencing base. I also want to say that also, exon 20 can be detected in liquid biopsy. So it's not you have to do the tissue biopsy if the patient has the opportunity to get liquid biopsy. As long as it's a good, comprehensive panel, it should also be able to detect that. Dr. Aggarwal: Absolutely, can never underemphasize the benefits and importance of comprehensive testing. Marcia, I'll turn to you. You lead a large group called the Exon 20 Group. How common is the EGFR exon 20 insertion-- how common is this mutation in people with lung cancer? Marcia Horn: It's not at all common. In fact, EGFR exon 20 insertion mutations in non-small cell lung cancer are exceedingly rare, a total of about 2% of all NSCLC and about 9 to 10% of all EGFR mutations. And it's an insertion mutation that hits, for the most part, never-smokers and members of Asian populations, although we at the Exon 20 Group have seen diagnoses in virtually every racial and ethnic group imaginable. The Exon 20 Group was established in 2017 as a special project of ICAN. It was founded by an EGFR exon 20 insertion patient, Kevin Hamlin, and his brother, Bob Hamlin, who's a senior lecturer at MIT. What we all wanted to do was get an international working group put together, and before we knew it, we had this huge global coalition of not only many hundreds of patients for EGFR exon 20 insertion and HER2 exon 20 insertion representing about 54 countries, but we had care partners, family members, several hundred leading thoracic oncologists, medical oncologists, and members of the community oncology setting as well, plus biotechs, pharmas with drugs in the exon 20 pipeline, and members from molecular profiling labs and the basic sciences in exon 20 bench science. So altogether, we're working to turn this into a chronic and manageable disease, and for the last 4 and a half years, we've been connecting our patients to promising clinical trials, especially the 2 newly approved drugs, and our angel buddy program provides our patients with peer-to-peer counseling to help them through side effects. So we're all united in blasting this disease off the planet and making the patient journey far more manageable. Dr. Aggarwal: Incredible. I'm just so proud of what all you've achieved, and you serve such an important mission in terms of patient advocacy and, more importantly, support. Dr. Velcheti, there have been 2 new recently approved targeted therapies to treat non-small cell lung cancer that harbors an EGFR exon 20 insertion mutation, and really, these drugs have come to us within the last few months. How does the first drug, mobocertinib, work to treat this cancer? Dr. Velcheti: Yeah, definitely. I think this is a really exciting time for thoracic oncology as we have more to offer our patients, especially for exon 20 and EGFR exon 20 specifically. We have 2 drugs now, FDA-approved, and mobocertinib is a small-molecule inhibitor. It's an oral drug, and this has been approved for patients who have EGFR exon 20 mutation. This is for patients who have already had platinum-based chemotherapy, and they have progressed, and these patients could now be treated with mobocertinib. Certainly, the activity, it seems like a very active drug. It's very promising. It's kind of similar to the other small-molecule targeted therapies that we have, but it does have side effects. Patients could potentially have diarrhea, which is kind of similar to other EGFR small-molecule inhibitors or drugs in the class, so it's something to kind of know when patients are being treated with this drug. Certainly, it's really nice to have more treatment options for these patients. So I think now we haven't had any EGFR small-molecule inhibitors show significant efficacy in this patient population, so this is a really welcome approval for patients. And there's also a new drug, which I'm sure Dr. Le is going to be talking about, amivantamab, which could also be an option for these patients. Dr. Aggarwal: Speaking of, let's turn to Dr. Le about amivantamab. Can you tell us a little bit more? Dr. Le: Yeah, amivantamab, again, represents a very exciting approval. I think, like Dr. Velcheti was talking about, the small-molecule inhibitor, but amivantamab represents a brand-new class of potential agents for exon 20 and many other oncogene targets in lung cancer. So amivantamab, as the name signifies, is an antibody drug. It's not an oral drug. It's an IV drug. The antibody has 2 heads, basically. One is targeting EGFR. The other is targeting another oncogene called MET. So it's a bispecific antibody. The mechanism of action is also different than the small-molecule inhibitor such as mobocertinib in that it's not disabling the ATP-binding kinase activity of EGFR, rather than its antibodies to go after the EGFR on the cell surface and disable or internalize the receptor a different way. So I say that we're excited because it represents a really brand-new group of targeted therapy that we're probably going to see coming in the next decade, not just limited to the small-molecule inhibitor, of course, from the research, and also opens opportunity for future combinations. In terms of usage, so again, this medication is approved in patients who have EGFR exon 20 insertion, who had prior treatment. It's an IV treatment, and then the IV is rather frequent, every 2 weeks. The drug showed really great safety and then induced response in about 40% of the patients, a nice addition to the tools we have that we can battle the disease. Dr. Aggarwal: It's amazing that we have 2 drugs in this space. Can you talk, in your personal experience, pros and cons of each approach and if there is any data to guide using 1 drug versus another or in sequence? We'll start with you, Dr. Le, and then we'll go to Dr. Velcheti. Dr. Le: Yeah. So that's a very good question. I don't think we have the 1 perfect answer because we haven't conducted either head-to-head trials or sequential trials. When I'm in my clinic, I tell my patients that both of them are valid options. And most likely, 1 patient will be receiving 1 and the other because I think each of the medications also have a limit of after a certain time, the disease will continue to progress. So we shouldn't be ruling out either of them rather than thinking of them as being the sequential treatment. One thing I do also discuss with the patient is the drug administration - one is IV; one is oral - and then toxicity profile. The amivantamab, the most common issue is the infusion reaction in the first time that the patient's receiving it. However, after that's properly managed, the drug is really easy to tolerate down the line. So usually, I present both options to patients. I would have to say that numerically speaking, the response rate of amivantamab is higher than the reported of mobocertinib. So sometimes, together with the patients and family, we decide to go for amivantamab first and then save oral TKI as the next option, but really, there's no right or wrong. And then I tell the patient most likely, they will be receiving both in the end. Dr. Aggarwal: Your thoughts, Dr. Velcheti, on that approach? Anything different that you do? Dr. Velcheti: No, I completely agree with Dr. Le. Both of them are very different drugs. So Dr. Le mentioned they work in very different ways. They have, most importantly, very different adverse event profile. So we don't know about what the right sequencing should be. We don't have those studies to really inform us. But I do the same thing that Dr. Le just mentioned. Given slightly higher response rates, we tend to use amivantamab first, but again, it's really patient preference. I've had patients who said they don't want to have IV infusions. They prefer oral treatment. They don't want to come into the hospital that often. And there are some patients who are really concerned about the diarrhea. So it's really hard to kind of know what would be the perfect sequence, and especially, it's a rare population, so it's going to be really hard to do a trial, to kind of do a cross-trial comparison. That's all we have here in terms of making decisions. The other thing to also consider is, do we use these 2 drugs, one after the other, if they progress? I think given that they work in a very different way mechanistically, I do think if you progress on mobocertinib that doesn't necessarily mean you will not respond to amivantamab and vice versa. So I would encourage trying sequential approach. And also the other thing to also keep in mind is there are a lot of clinical trials with exciting drugs which are in the pipeline, and, of course, some of the data has already been presented and those look really promising. So I highly encourage patients to kind of consider participating in clinical trials. Dr. Aggarwal: That's such a fantastic summary. And Marcia, I will turn to you. What do these new drugs mean for patients with this rare subset of an actionable mutation? Marcia Horn: I totally agree with Dr. Le and Dr. Velcheti and their comments based on their deep, deep experience with EGFR exon 20 insertion patients. No question that, from the point of view of the Exon 20 Group, we were totally thrilled at the FDA approvals of both amivantamab and mobocertinib. And we, like everyone else, affectionately call both drugs as ami and mobo. These drugs are providing a concrete lifeline of hope, for the first time, that patients' lives can be extended and patient journeys can be manageable in terms of side effects. So what we're really excited about in the Exon 20 Group is not only the continuing clinical development of ami and mobo and other promising drugs in the pipeline, as Dr. Velcheti said, but we're looking forward to seeing ami and mobo in combination with second drugs. We're awaiting data down the road, obviously, from the ongoing amivantamab plus lazertinib trial that is recruiting, in part, EGFR exon 20 insertion patients, and we're really excited about drugs that can be combined with mobocertinib as well. We want a robust pipeline of numerous choices and good compounds. Dr. Aggarwal: And Marcia, given the amount of information in this subgroup, what questions should patients ask their doctors about these new treatments? Marcia Horn: We really think it's important for patients on diagnosis to ask their clinicians what the method of communication is going to be between patient and physician. This is not only important on diagnosis of EGFR exon 20 insertion mutated cancer, but it's really, really important when the patient is accessing either ami or mobo or a drug in clinical trials. So patients need answers on who is going to be answering their questions about side effects when they write those questions into a patient portal, and they have to have the sense that somebody is going to be listening to them in the event that the collateral medications that an oncologist may be giving them in conjunction with a clinical trial drug or in tandem with either ami or mobo-- if those collateral medications are not tamping down on side effects to the extent that we all want to see, we, for sure, want that patient to be talking to the treatment team, the study team, or whoever, and getting some quick answers because frankly, nothing is more tragic than a patient withdrawing from a drug for failure to manage toxicities, and we never want to see that happen. We do everything possible at the Exon 20 Group to make sure patients are outfitted with angel buddies who have lived, battle-hardened experience with that particular drug, and these drugs are manageable. Dr. Aggarwal: So much excitement going on in this space, and we are thrilled to be able to offer these approaches. But I will just summarize that we wouldn't be able to extend these benefits if we don't test, and comprehensive testing remains critical in diagnosing and delivering appropriate therapy. Thank you so much, Dr. Le, Dr. Vamsi Velcheti, as well as Marcia, for joining us today for this Cancer.Net podcast. You can learn more about lung cancer and how it's treated by visiting Cancer.Net. Thank you, everyone. Dr. Le: Thank you. Marcia Horn: Thank you. ASCO: Thank you, Dr. Aggarwal, Dr. Le, Dr. Velcheti, and Ms. Horn. Learn more about lung cancer at www.cancer.net/lung. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Dr. Lauren Byers, associate professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, highlights a new study published in Cancer Cell that features a transformative new framework to classify small-cell lung cancer into four subtypes based on gene expression, paving the way for personalized treatment options (DOI: 10.1016/j.ccell.2020.12.014).   Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for ASCO Daily News. My guest today is Dr. Lauren Byers, associate professor of Thoracic, Head, and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. Dr. Byers is the lead author of a new study published in Cancer Cell that features a transformative new framework to classify lung cancer into four small-cell lung cancer subtypes based on gene expression, and, for the first time, a personalized treatment option for the second most common type of lung cancer. Dr. Byers serves on advisory committees and receives research funding from AstraZeneca, Genmab, and Sierra Oncology, among other organizations. Her full disclosures and those relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Byers, welcome to the ASCO Daily News Podcast. Dr. Lauren Byers: Thank you, Geraldine. ASCO Daily News: Small-cell lung cancer is known for its aggressive growth and resistance to treatment with predictably poor outcomes. There has been some progress with immunotherapy and targeted therapy, but can you tell us why advances in small-cell lung cancer have been more modest in recent years?  Dr. Lauren Byers: We've seen incredible progress in personalizing treatment for patients with non-small cell lung cancer. And for those patients, we routinely use biomarkers, such as EGFR mutations, ALK fusions, or PD-L1 expression, to match our patients to the most effective targeted therapy or to immunotherapy. And this really allows us to have a more personalized approach to their treatment. And last year in the New England Journal of Medicine, there was a very encouraging report showing that deaths from lung cancer had gone down sharply (DOI: 10.1056/NEJMoa1916623). And this was in part because of those improvements in terms of targeted and personalized treatments. Unfortunately for patients with small-cell lung cancer, which makes up about 13% of newly diagnosed lung cancers, the advances have really been more modest. And to date, we have not had any validated biomarkers for small-cell lung cancer that we can routinely use in the clinical setting. And this means that currently patients are really treated with a one size fits all approach. And this could be chemotherapy in combination with radiation, or chemotherapy plus immunotherapy. But I think we really in the field had a growing appreciation that small-cell lung cancer was essentially more than one type of lung cancer, and that certain small-cell lung cancers can respond very differently to different treatments depending on what genes are turned on and what's driving the growth of these cancers. And we had had a few leads in terms of what some of the potential biomarkers might be. But we found that many small-cell lung cancers didn't fit into one of the groups or categories that we predicted might be some of the important subtypes. ASCO Daily News: Right. So can you tell us about the approach that you and your co-investigators used to identify the small-cell lung cancer subtypes based on gene expression data? Dr. Lauren Byers: So what our group did was we really used that data-driven approach where we took an unbiased computational approach to let the data tell us how many distinct molecular groups are there within small-cell lung cancer. And we did this by looking at gene expression data, so looking at what genes were turned on or off in different patient tumors. And based on this, we found that there were four major distinct molecular subtypes of small-cell lung cancer. Three of these were ones that we predicted were probably important players. And these are ones that are defined by expressing different transcription factors. These are master regulator genes, specifically the genes ASCL1, NeuroD1, and PALB2 F3. Those three made up three of the four groups that were identified in our study. But there was a novel fourth group that emerged from this analysis which had not been previously appreciated. And we called this group the small cell lung cancer inflamed subtype, because it really was distinct from the other small-cell cancers by having increased immune cell infiltration and increased expression of multiple immune markers, including higher levels of immune checkpoints. And so when we saw this, we predicted that this inflamed subtype might be the group that was responding better to immune checkpoint inhibitors, such as atezolizumab. And together with our collaborators on our publication, we had the opportunity then to test whether or not the small-cell inflamed subtype was in fact more responsive to immunotherapy. And we did this by looking at patient samples, gene expression data from over 250 patients who were treated on the randomized phase III IMpower133 clinical trial (NCT02763579). This was a trial that changed the standard of care for small-cell lung cancer and tested the question for patients with extensive stage disease, whether the addition of atezolizumab's immune checkpoint inhibition to standard front-line chemotherapy with platinum-etoposide could improve outcomes for patients. And so what we found in this retrospective analysis of the IMpower133 study was that, first, we again found these four major subgroups, including the inflamed group, which made up about 20% of patients. And then as we predicted, one of the really exciting findings from this analysis was that in fact the small-cell inflamed group did have improved survival with the addition of immunotherapy to chemotherapy. In patients that were in that small-cell inflamed group, their overall survival with the addition of the atezolizumab was approximately 18 months as compared to when the inflamed patients received the standard chemotherapy by itself. And importantly also, if we looked at across the four small-cell subtypes in terms of how patients did in the inflamed group as compared to the other three groups when there was the addition of the immunotherapy, the benefit really was enriched in that small-cell inflamed where, again, those patients had a much longer survival as compared to patients in the subtypes where their survival was around 10 months or similar to what was seen with the standard chemotherapy. So I think that was really an exciting finding and I think gives us a path forward to think about how we might start personalizing treatment. The other thing related to this was that the three subtypes that were not as responsive to immunotherapy, the ASCL1, NeuroD1, and PALB2 F23, in our paper we described certain targeted therapies that actually work quite well in preclinical models in those other groups. And so I think it gives us a path forward in terms of the potential to identify a personalized approach for each of the four groups. ASCO Daily News: Absolutely. Now, I understand in some cases you and your co-investigators observed more than one of the small-cell subtypes within a patient's tumor. Can you tell us about this? Dr. Lauren Byers: I think one of the really interesting things that we also found in the study was that in some cases we saw more than one of the small-cell subtypes present within an individual patient's tumor. So in a small-cell lung cancer tumor, there could be, for example, cells that were in ASCL1 group, and then others that were expressing markers of the NeuroD1 group. And when we did further investigation into this using some of our preclinical models, we found that one way that these cancers were becoming resistant to chemotherapy was by switching from one subtype to another. ASCO Daily News: Dr. Byers, did the subtype switching surprise you, and have other investigators seen this before? Dr. Lauren Byers: This subtype switching was not totally unexpected. There have been other groups that do work in the field of small-cell lung cancer that have also recently reported a similar type of subtype switching. And in the case of our publication, we also found that tumors could switch to the inflamed group. And I think, again, this provides us additional insights into how small-cell lung cancer adapt and what might be driving resistance. And I think, more importantly, also, as a medical oncologist, this gives us ideas about how we might potentially combine drugs that target more than one subtype to overcome resistance or also the importance of getting repeat biopsies after a patient has relapsed so that we can see what is their current subtype and, again, personalize the treatment to the subtype of their cancer at that time when we're making a treatment decision. The other thing that we've been very focused on is developing and also sharing ways that we will be able to test for the small-cell subgroups and biomarkers that can be used. So this can be done easily in clinic. And so I think that both from tumor as well as ultimately, hopefully, minimally invasive approaches, such as blood-based testing, will be ways that we'll be able to do this routinely, and then move us forward in terms of having more precision oncology approaches for our patients. ASCO Daily News: Yes, there are surely new tailored approaches on the horizon as the work continues to find ways to test for the small-cell subgroups in clinic. Dr. Byers, is there anything else you'd like to share before we wrap up our discussion today? Dr. Lauren Byers: I think I would just say that we're very excited, that we think that this work, together with a lot of the other very exciting work in this field, is opening the door to precision medicine for small-cell lung cancer. And I think this is a very exciting time for our patients and for hopefully seeing accelerated progress because of these findings. The other thing that I think will be really exciting is that ultimately I think we look forward to having trials where we do start matching patients to specific treatments based on their molecular classification. And I think that also will really help accelerate progress the same way that those types of studies in non-small cell lung cancer have. And then the last thing I wanted to say is I would just like to recognize Dr. Adi Gazdar, who was a world-renowned thoracic pathologist, and we dedicated our paper to--he really was the father of lung cancer pathology. And he always encouraged all of us in lung cancer research that small cell was not a single disease and that we needed to keep looking and refining what the small cell subtypes were. So I just want to acknowledge his contributions and give the role that he has played on the field for so many of us. ASCO Daily News: Well, thank you Dr. Byers for telling us about these exciting developments in small-cell lung cancer. I'll just remind listeners of the title of your study published in Cancer Cell is "Patterns of Transcription Factor Program and Immune Pathway Activation Defined for Major Subtypes of SCLC with Distinct Therapeutic Vulnerabilities." Thanks again, Dr. Byers. Dr. Lauren Byers: Thank you, Geraldine. I really appreciate you having me. ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us, wherever you get your podcasts.   Disclosures: Dr. Lauren Byers Consulting or Advisory Role: Abbvie, AstraZeneca, PharmaMar, Genmab, Bristol-Myers Squibb, Sierra Oncology, Pfizer, Merck, Jazz Pharmaceuticals, Genentech Research Funding: Tolero Pharmaceuticals, Sierra Oncology, AstraZeneca (institution), Genmab (institution)  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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Jack West is joined by Dr. Anne Tsao for a conversation on the state of treatment of mesothelioma in anticipation of the first IASLC 2019 Mesothelioma Meeting July 10-12, 2019 in New York, NY. Dr. Tsao is Professor in the Department of Thoracic Head and Neck Medical Oncology in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston. She is also Director of the Mesothelioma Program and Director of the Thoracic Chemo Radiation program.

John Heymach, MD, PhD, Chair and Professor of Thoracic/Head and Neck Medical Oncology introduces his Symposium session: Neoadjuvant Treatment for Lung Cancer Boris Sepesi, MD Targeting EGFR TKI Resistance and Novel Mutations John V. Heymach, MD, PhD New Approaches for Targeting KRAS Ferdinandos Skoulidis, MD, PhD Mechanisms of Resistance to PD1/PDL1 Pathway Blockade Don L. Gibbons, MD, PhD Targeting DNA Damage Repair in Lung Cancer Lauren A. Byers, MD Neoadjuvant and Surgical Approaches for HNSCC Jeffrey N. Myers, MD, PhD Immunotherapy for HNSCC Maura Gillison, MD

Lung cancer is being fought on three fronts at MD Anderson Cancer Center: prevention, early detection and treatment of advanced disease. John Heymach, M.D., Ph.D., professor in Thoracic/Head and Neck Medical Oncology at MD Anderson, talks about new developments in lung cancer research including advances in genetic mapping, molecular profiling, diagnostic imaging and lung cancer screening. With lung cancer being a part of the MD Anderson’s Moon Shots Program, we have a chance to make lung cancer history.

John Heymach, M.D., associate professor in MD Anderson Cancer Center's Thoracic/Head & Neck Medical Oncology department, details progress made in the first year of the Lung Cancer Moon Shot.

John Heymach, M.D., associate professor in MD Anderson Cancer Center's Thoracic/Head & Neck Medical Oncology department, details progress made in the first year of the Lung Cancer Moon Shot.

Advanced care planning is not about giving up, emphasizes Katherine Pisters, M.D., professor in Palliative Care and Rehabilitation Medicine, and Donna Zhukovsky, M.D., professor in Thoracic/Head and Neck Medical Oncology, both at MD Anderson Cancer Center. Rather, it’s a way for cancer patients to tell their loved ones what’s important to them as they approach the end of life. MD Anderson’s new advance care planning program makes the patient’s whole health care team aware of his/her goals, spiritual values and wishes. Pisters and Zhukovsky discuss this pilot initiative.