Podcasts about egfr tki

JCO Editorial Fellow Dr. Ece Cali Daylan and JCO Associate Editor Dr. Thomas Stinchcombe discuss the ASCO 2025 Simultaneous Publication paper "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small-Cell Lung Cancer." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series, where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, JCO Editorial Fellow, and I am joined by JCO Associate Editor, Dr. Tom Stinchcombe. In this episode, we will discuss the Journal of Clinical Oncology article and abstract presentation "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer.” NeoADAURA is a randomized global phase III study investigating the efficacy of neoadjuvant osimertinib-containing regimens in patients with resectable EGFR-mutated stage II to IIIB non–small-cell lung cancer. 358 patients were randomized 1:1:1 to receive osimertinib plus chemotherapy, osimertinib monotherapy, or placebo plus chemotherapy in the neoadjuvant setting. The primary endpoint was major pathological response. Osimertinib plus chemotherapy and osimertinib alone demonstrated MPR rates of 26% and 25%, respectively, compared to 2% in the chemotherapy plus placebo arm with a p-value of less than 0.001. Tom, can you please explain to our listeners how you interpret this data? Dr. Thomas Stinchcombe: Great question. Yeah, I think to give a little context, obviously, chemotherapy and immunotherapies preoperatively is becoming the standard of care. However, patients with EGFR-mutant lung cancer generally have not responded to immunotherapy, and many of the trials excluded patients with known EGFR mutation. There have been smaller phase II trials that had looked at EGFR TKIs preoperatively, but none of these were definitive. So I think that this trial is a big trial, and I think some of the strengths are that it has osimertinib alone and chemotherapy with osimertinib arms as compared to the standard of chemotherapy. I think it's going to be really interesting at the meeting to see how this is discussed by the discussant and also what the reaction is to its public presentation. And I think that's largely because there's an alternative paradigm now, surgical resection adjuvant osimertinib, that's available to patients. So I think this will be interesting to see what the reaction is to the induction therapy. For patients with known N2 disease, I've generally given some form of induction therapy prior to surgical resection. So I think that's the subgroup of patients that I'm most likely to employ this approach with based on the results. Dr. Ece Cali: So, in this trial, more than 90% of the patients on the osimertinib-containing regimens underwent curative-intent surgery. So, this speaks to the feasibility of the approach, and the higher MPR rate with osimertinib-containing regimens is encouraging. Event-free survival data is currently immature. You have already touched upon some of the strengths of the trial, but what are the weaknesses and the strengths of this trial? Dr. Thomas Stinchcombe: So, I mean, I think there are some weaknesses. A major pathological response was chosen as an endpoint, and there could be an argument that path CR is more of a prognostic marker. However, the rates of path CR are relatively low, so it would have been very hard to design a trial such as that. And then I think the trial started off as a preoperative trial but effectively became a perioperative trial with preoperative EGFR-TKI, postoperative osimertinib. And so I think it's going to be very hard to determine what the contribution of the components are. And then you've hit on another part that I think is very important when we interpret the data that the maturity on the event-free survival is only 15%, and most people are still on therapy. So the event-free survival, which is an important endpoint, is very immature right now. Dr. Ece Cali: And this trial was designed to compare the neoadjuvant approaches, hence the comparator arm here is neoadjuvant chemotherapy followed by surgery. So, considering the ADAURA trial results with upfront surgery followed by osimertinib as adjuvant, so how do you see this trial's impact on the current clinical practice? Dr. Thomas Stinchcombe: Well, very good question, I think one that we're still struggling with as we kind of look at this data. I think, for me, stage II patients will most likely go to surgery and then get adjuvant osimertinib, and then maybe the N2 patients will get an osimertinib-containing regimen as an induction therapy. I think one of the questions is does it really matter when you get the osimertinib as long as you get it at some point? And I think that's going to be the critical interpretation of some of the data at this point. Dr. Ece Cali: And how do you think this trial shapes the future research for patients with resectable EGFR-mutated lung cancer? Dr. Thomas Stinchcombe: Well, I mean, I think it shows that chemotherapy was really modestly active with an MPR rate of 2%, no pathological responses. And then I think you're going to have to look at an osimertinib plus another targeted therapy component. I think, you know, when I looked at the osimertinib versus the chemo-osimertinib arm, I also was sort of surprised that the MPR rate and the path CR rate were very, very similar. So I think that the question is would a double targeted therapy approach or some other approach matter? And I think it also sets a safety standard. And you touched on this in your comments, that there was not a disparity in terms of the rate of going to surgery or R0/R1 resections. So patients were not having progressive disease events or toxicities that prevented surgery. So I think it does give us good safety data. Dr. Ece Cali: Tom, thank you so much for sharing your insights on the JCO article, "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting, and please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. John Sweetenham shares highlights from Day 3 of the 2025 ASCO Annual Meeting, including new research for the treatment of advanced renal cell carcinoma and 2 studies on novel approaches in non-small cell lung cancer. Transcript Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast, with my takeaways on selected abstracts from Day 3 of the 2025 ASCO Annual Meeting. Today's selection features studies addressing the treatment of advanced renal cell carcinoma and 2 studies exploring novel approaches in non-small cell lung cancer. My disclosures are available in the transcript of this episode. The first abstract is number 4505. This study, led by Dr. Toni Choueiri of the Dana-Farber Cancer Institute, describes the final analysis of the CheckMate 214 trial, which compared the combination of nivolumab and ipilimumab with sunitinib for the first-line treatment of advanced renal cell carcinoma. The ipi-nivo combination is approved for the frontline treatment of intermediate and poor-risk advanced renal cell carcinoma based on the primary analysis of the CheckMate 214 trial, which demonstrated a higher response rate and longer overall survival compared with sunitinib. Today's presentation provided the final safety and efficacy results for the trial with long-term follow-up of more than 9 years.  The intent-to-treat (ITT) population in this trial comprised 550 patients randomized to nivo and ipi versus 546 who received sunitinib. The final analysis showed sustained long-term benefit for the combination therapy. Patients given nivolumab plus ipi had a 29% reduction in the risk for death compared with sunitinib. For patients with intermediate or poor-risk disease, there was a 31% reduction in the risk of death.   The probability of remaining in response through 8 years was more than doubled with nivolumab plus ipilimumab versus sunitinib in the ITT population at 48% versus 19%, and in the intermediate and poor-risk population at 50% versus 23%. The other important observation is that patients with favorable-risk disease appeared to have a 20% reduction in the risk for death at 9 years and more durable responses. This suggests a possible delayed benefit for ipi and nivo in this group since these differences were not seen in the earlier analysis.   No new safety signals emerged with longer follow-up, and the results confirm the use of ipi and nivo as a standard front-line combination therapy in this disease. Since this combination has been in widespread use for some years, the results are not surprising although the subgroup analysis suggesting benefit in favorable-risk patients is likely to inform practice in the future.   Today's second abstract is number is 8506, which was presented by Dr. Tony Mok from the Chinese University of Hong Kong, describing results from the phase 3 HERTHENA-Lung02 trial. This trial compared the antibody-drug conjugate patritumab deruxtecan with platinum-based chemotherapy in patients with EGFR-mutated advanced non-small cell lung cancer following a third-generation tyrosine kinase inhibitor (TKI).  Patritumab deruxtecan, also known as HER3-DXd, comprises a fully human anti-HER3 IgG3 monoclonal antibody conjugated to a topoisomerase 1 inhibitor payload, and showed activity in a previous phase 2 trial in patients relapsing after EGFR TKI and chemotherapy.   In this phase 3 study, this agent was compared with platinum-based chemotherapy in eligible patients with an EGFR-activating mutation who had previously received 1 or 2 EGFR TKIs, at least one of which was a third-generation drug, with relapse or progression after this therapy. Five hundred and eighty-six patients were enrolled, with progression-free survival as the primary endpoint.  The primary analysis showed a 9-month progression-free survival of 29% for the experimental arm compared with 19% for platinum-based chemotherapy, for a hazard ratio of 0.77 and a P value of 0.011. With higher progression-free survival rates at 6 months and 12 months, HER3-DXd also had a better objective response rate (35.2% versus 25.3%) compared with platinum-based chemotherapy (PBC), and HER3-DXd also extended intracranial progression-free survival compared with PBC in patients with brain metastases, with a hazard ratio of 0.75. Grade 3 or more treatment-related adverse events occurred in 73% of patients treated with HER3-DXd and 57% of patients who received PBC. HER3-DXd had a higher rate of grade or more 3 thrombocytopenia, and drug-related interstitial lung disease occurred in 5% of patients in the HER3-DXd arm.   The follow-up will need more time to mature since no overall survival data are currently available, but definitely an agent to watch with interest. Moving on to today's final abstract, 8500, was presented by Dr. Pasi Jänne from the Dana-Farber Cancer Institute, describing results from the phase 2 portion of the KRYSTAL-7 study. This study is exploring the use of a potent KRAS inhibitor, adagrasib, in combination with pembrolizumab in patients with advanced or metastatic KRASG12C- mutated non-small cell lung cancer.  Adagrasib has already received accelerated approval in the U.S. for previously treated locally advanced or metastatic NSCLC with a KRASG12C mutation. A previous report from the KRYSTAL-7 study demonstrated encouraging activity in combination with pembrolizumab in the frontline setting for this patient group who also had more than 50% expression of PD-L1. The presentation today described efficacy and safety data for this drug combination across all PD-L1 expression levels.  One hundred and forty-nine patients with a median age of 67 years were treated with the combination, 104 of whom had PD-L1 expression level results available, representing the so-called biomarker population in this trial. The overall response rate for the entire study population was 44%. In the biomarker population, the overall response rate ranged from 36% in those with less than 1% PD-L1 expression to 61% for those with more than 50% expression. For all patients, the median response duration was just over 26 months, and the median progression-free and overall survival rates were 11 and 18.3 months respectively.    For the biomarker population, the median progression-free and overall survival were highest in those patients with more than 50% PD-L1. No new safety issues emerged from this analysis; the most frequent toxicities were nausea, diarrhea, and increases in transaminases. Immune-related toxicities included pneumonitis, hypothyroidism, and hepatitis. These are important results and the results of the phase 3 portion of KRYSTAL-7, which compares first-line therapy with adagrasib plus pembro versus pembro alone in the KRASG12C mutated/PD-L1 more than 50% group, will be informative. For those patients with lower levels of PD-L1 expression, the authors suggest that the treatment escalation may be beneficial, possibly including the addition of chemotherapy.  That concludes today's report. Thanks for listening and I hope you will join me again tomorrow to hear more top takeaways from ASCO25. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speaker:    Dr. John Sweetenham    Follow ASCO on social media:     @ASCO on Twitter    @ASCO on Bluesky    ASCO on Facebook    ASCO on LinkedIn     Disclosures:   Dr. John Sweetenham:    No relationships to disclose

Dr. Jyoti Patel is back on the podcast to discuss the updates to the living guideline on therapy for stage IV NSCLC with driver alterations. She shares updated recommendations in the first- and second-line settings for patients with stage IV NSCLC and classical EGFR mutations, and the impact of these updates for clinicians and patients. We also look to the future to discuss ongoing developments in the field. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02785     Brittany Harvey: Welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows including this one at asco.org/podcasts.   My name is Brittany Harvey and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.” It's great to have you back on the show today, Dr. Patel. Dr. Jyoti Patel: Thanks so much. Happy to be here. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline and in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this update, Dr. Patel, this clinical practice guideline for systemic therapy for patients with stage IV non small cell lung cancer with driver alterations is living, meaning that it's continuously reviewed and updated. So what data prompted this latest change to the recommendations? Dr. Jyoti Patel: Thanks so much. So it's really been an exciting time in the treatment of EGFR lung cancer, particularly this past year has required us to rethink approaches to front- and second-line therapy. In this particular update, we examined what patients in the front-line setting may be offered by their clinicians. And so we're talking about the population of classical EGFR mutations, so exon 19 and exon 21 L858R substitution. And so certainly for this population, osimertinib has a high level of evidence and should be offered to all patients at the time of diagnosis when they present with advanced disease. Our last update included a recommendation that patients could also get platinum doublet chemotherapy with osimertinib or osimertinib alone. This current recommendation also introduces another alternative therapy and that's the combination of amivantamab plus lazertinib. And so now, clinicians are faced with three really good options for their patients with EGFR exon19 deletion or L858R. Brittany Harvey: It's great to hear that there's this advance in the space, particularly for patients with these classical EGFR mutations that you mentioned. So what should clinicians know as they implement these new first-line recommendations? Dr. Jyoti Patel:  I think it's become more complex than ever. Certainly, we know again that patients should get osimertinib in the frontline setting. But we've been kind of stuck at progression-free survival that's between a year and a half and two years. And so we've really been looking at opportunities to intensify therapy. So one could certainly be with chemotherapy or switching over to amivantamab, the bispecific antibody that targets EGFR and MET plus lazertinib, an oral TKI that's very similar in structure to osimertinib. And when you're talking to a patient, it's really a conversation about balancing efficacy with toxicity. Unfortunately, as we know, there aren't that many free lunches. And so if we think about what a patient is hoping for in their therapy and how we can further personalize treatment options, really is important to look at some of the analyses for this study. So in the study of amivantamab plus lazertinib, we know that there were increased toxicities with a combination of both therapies. In fact, up to 75% of patients had over grade 3 toxicities, versus about 43% of patients with osimertinib monotherapy. And we know if we look back at FLAURA2, almost two thirds of patients with osimertinib and chemotherapy had grade 3 toxicities, compared to 27% of patients with osimertinib alone. So we certainly see an increase in toxicities. Then we have to ask ourselves, are those paper toxicities or ones that really impact patients? And we know that amivantamab, for example, causes significant cutaneous toxicities. With both of these therapies, whether it's chemotherapy or adding amivantamab, there's the burden of infusional visits and increased time in the doctor's office. Certainly with chemotherapy, there can be an increased incidence of myelosuppression. And so when we're thinking about advising our patients, certainly we need to talk about the toxicities. But one thing that we've been able to do is to look at the patients that were included in this trial. And what we really find is that in higher risk cohorts, particularly those that we know historically have done less well with standard osimertinib, so patients, for example, with CNS metastasis, for those patients with co-mutations, it may be that that additive benefit is significant. And so one example I think would be from the MARIPOSA study, again, the study of amivantamab and lazertinib versus chemotherapy. What we can say is that patients who had co-mutations, so patients with EGFR mutations as well as TP53, lazertinib and amivantamab led to a hazard ratio of 0.65 compared to osimertinib alone. So that was 18.2 months versus 12.9 months. And so this may be really important to patients. And we also see conversely that patients with wild type TP53, so those patients who didn't have the mutation, probably had equivalent survival regardless of therapy. So certainly, we need to prospectively study some of these high-risk cohorts. We've only seen progression-free survival in these studies. And so at this juncture, we can advise our patients about toxicity, the improvements in certain categories of progression-free survival, but we really still don't know how this pans out in overall survival. In many of these studies, all patients do not necessarily cross over to the study arm and so they may have lost the benefit of subsequent therapy. Brittany Harvey: Absolutely. It's very important to talk about that balance of benefits and risks and particularly those toxicities that you discussed. So I appreciate reviewing that recommendation and the considerations for clinicians for first-line therapy. This update also included a second-line treatment update. What is that update for patients with EGFR alterations? Dr. Jyoti Patel: So this is where it gets super tricky because we have a frontline option with amivantamab and now we've had an update in the second line option. So what we said is that for patients who have progressed on an EGFR TKI, and in the United States, certainly that's predominantly osimertinib, or those in other parts of the world that may have gotten an earlier generation TKI, but do not have evidence of T790M or other targetable mutations, we can offer patients chemotherapy with or without amivantamab. And so certainly we have seen that this again leads to improved survival. There have also been a number of studies looking at incorporation of PD-L1 and anti-VEGF therapies. And what we can say, I think pretty clearly is that multiple phase 3 trials have really shown no benefit of the addition of PD-1 to platinum chemotherapy. But there are some emerging bispecific antibodies that may target PD-1 as well as VEGF, or combinations of antibodies that target both of those pathways that may improve outcome. At this juncture, I think we feel that the evidence surrounding chemotherapy plus amivantamab is strongest, but there is certainly work in this space that will be of interest. Now, what happens if your patient received amivantamab and lazertinib in the frontline setting and then has progression? And so we're trying to understand resistance mechanisms and opportunities for treatment. What the panel decided to recommend, based on the available evidence, was that certainly those patients should get platinum-based chemotherapy, but there may also be a role for antivascular endothelial growth factor targeting therapy such as bevacizumab in patients in whom it would be safe. Brittany Harvey: Great. I appreciate you detailing those recommendations when it gets complicated in the second-line setting. So what should clinicians know as they implement these second-line recommendations too? Dr. Jyoti Patel: So certainly the frontline setting matters significantly. So if a patient gets osimertinib in the frontline setting, we generally suggest that patients undergo repeat testing to see if they have another targetable mutation. If they don't, then I think preferred therapy would be chemotherapy with or without amivantamab. And amivantamab leads to a significant improvement in progression-free survival and response rate at the cost of increased risk of toxicity. For patients who get FLAURA2 in the frontline setting, chemotherapy plus osimertinib, it's a little bit of an unclear space. Those patients most likely would get docetaxel with or without ramucirumab. But there are other agents that we hope to have available to our patients in the near future. For patients who receive amivantamab and osimertinib, we recommend that those patients get chemotherapy probably with anti-VEGF as demonstrated by multiple trials that have shown the improved progression-free survival with introduction of an anti-VEGF agent. And we've seen evidence of amivantamab in the third line setting, so it is likely that this question about sequencing really takes center stage in our next set of trials. When you're talking to a patient, I think again, it's absolutely important to discuss: What are their goals? How symptomatic or how fast is their progression? Are there ways in which patients may benefit from spot treatment oligoprogression such as radiation? When is the right time for introduction of amivantamab and when do we think patients need chemotherapy? Is it up front or predominantly in the second-line setting? Brittany Harvey: Definitely. And then you've just touched on the goals of treatment for individual patients. So in your view, what does this update mean for patients with stage IV non-small cell lung cancer and an EGFR alteration? Dr. Jyoti Patel: For patients, this is a time in which shared decision making really needs to take center stage. So our best patients are those patients that are best informed not only about their disease but also have a good understanding about what is important to them and their families in terms of care. And so bringing that shared understanding to the table again helps us think about this particular cancer as more of a journey rather than just a one off treatment. Therapy will hopefully be prolonged, and so it's absolutely important that we address toxicities, make therapies more tolerable, again, with the shared goal of living long and living well. Brittany Harvey: Absolutely. Those are key points to making sure that patients are living both longer and have a good quality of life during that time as well. So then, before you mentioned the possibility of future sequencing trials and other ongoing developments. What additional studies or future directions is the panel examining for future updates to this living guideline? Dr. Jyoti Patel: So certainly we're thinking about trials that look at, for example, cfDNA clearance. So are there patients that do well and can we detect that early on without having to intensify therapy on day 1 so it may be that we add chemotherapy a little bit later. I think really exciting are some of the new bispecific. The HARMONi-A trial was a trial in China of a novel bispecific, ivonescimab. And this drug targets both PD-1 and VEGF and it was combined with chemotherapy. And this trial found almost a doubling of progression-free survival with this drug in combination chemotherapy in an EGFR patient population. That study is being planned and being run in the United States to see if we have similar outcomes with a more diverse population. So certainly that's exciting. There are a number of antibody drug conjugates that are being studied in the post-chemotherapy setting as well. And I think we'll likely soon see a better understanding of what co-mutations and burden of disease really mean when we're thinking about assigning treatment. So which patients, again, need intensification of therapy and which patients may do really well on just an oral agent that they're taking at home with more tolerable toxicity than dual treatment. Brittany Harvey: Yes, we'll look forward to continued developments in these fields and seeing some of those studies come to fruition. So with that, I want to thank you for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Patel. Dr. Jyoti Patel: Thanks so much, Brittany. It's really an exciting time for lung cancer and we hope that these updates really help physicians decide the best treatments for their patients. Again, it's a rapidly evolving landscape which is fantastic, but it does become more cumbersome to stay ahead of the literature. Brittany Harvey: Definitely. And so we appreciate your time and the panel's time spent reviewing this literature and providing this much needed information to clinicians everywhere. So finally, thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the  Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

CME credits: 0.75 Valid until: 17-12-2025 Claim your CME credit at https://reachmd.com/programs/cme/expert-peer-discussion-integrating-novel-her3-directed-adcs-upon-disease-progression-following-egfr-tki-and-platinum-chemotherapy/26455/ This 6-episode program will guide healthcare professionals who treat advanced non-small cell lung cancer (NSCLC) through the biology of HER3 overexpression to broaden their understanding of its potential as a therapeutic target in EGFR-resistant advanced NSCLC. Tune in to enhance your confidence in applying scientific evidence to the creation of effective treatment strategies and develop evidence-based approaches for implementing novel HER3-directed antibody-drug conjugates (ADCs). Our experts also focus on the adoption of a team-based approach to help you monitor and manage treatment-related adverse events associated with HER3-directed ADCs.

Dr. Lyudmila Bazheova share the latest updates to the ASCO living guideline on therapy for stage IV non-small cell lung cancer with driver alterations. She discusses changes for patients with EGFR driver alterations in both the first- and second-line setting, and reviews the evidence supporting these updated recommendations, from trials such as MARIPOSA, MARIPOSA-2, CheckMate 722, and KEYNOTE-789. Stay tuned for future updates to this continuously updated guideline. Read the full update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2.” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02133   Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.   My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, lead author on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2.” Thank you for being here, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It is my pleasure. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bazhenova, who has joined us on this episode today, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes. So then, to kick us off on the content here, Dr. Bazhenova, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer with driver alterations is being updated routinely as a living guideline. So what prompted the update to the recommendations in this latest version? Dr. Lyudmila Bazhenova: Living ASCO Guidelines are developed to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. In this recently published guideline, we reviewed new evidence for patients with metastatic lung cancer harboring driver alterations. We reviewed evidence from four published studies, MARIPOSA, MARIPOSA-2, CheckMate 722 and KEYNOTE-789 that resulted in updated guidelines. Brittany Harvey: Great. And then based off those four trials that you just mentioned, what are the updated recommendations for patients with stage IV non-small cell lung cancer and an EGFR exon 19 deletion or exon 21 L858R substitution? Dr. Lyudmila Bazhenova: In the previous guideline, we detailed FLAURA 2 study which was presented and published in the past. In this guideline, we specifically highlighted a phase 3 MARIPOSA trial which took patients with untreated advanced non-small cell lung cancer which harbored classical EGFR mutations such as EGFR deletion 19 and L858R. In this study, patients were randomly assigned to receive amivantamab plus lazertinib or osimertinib or lazertinib alone. And the study showed that the primary endpoint which was progression-free survival was longer with amivantamab plus lazertinib compared to osimertinib, and numerically the progression free survival was 23.7 months with ami-lazertinib versus 16.6 months with osimertinib which was statistically significant. The challenge that we have to face when discussing that option with our patients is increased toxicity with amivantamab and lazertinib combination. For example grade 3 treatment adverse events were 75% with amivantamab and lazertinib and 43% with osimertinib. So this will require shared decision making between our patients and ourselves. We also noticed in the guidelines that there was a subgroup analysis of that study showing that the patients with a higher disease burden, central nervous metastasis or brain metastasis as well as disease which considered to be a higher risk such as commutation, for example, p53 and liver metastasis, they might benefit from intensified therapy. However, another thing that we are highlighting in the guideline is that at this point we do not know how the intensification of therapy will change overall survival of our patients. So one needs to take into account increased toxicity with that combination. Brittany Harvey: So then Dr. Bazhenova, in addition to those updates for first line therapy, what are the updated recommendations for second line therapy? Dr. Lyudmila Bazhenova: For patients who have progressive disease on osimertinib or other EGFR tyrosine kinase inhibitors, we also updated our guidelines highlighting MARIPOSA 2 study. In the MARIPOSA 2 study, patients were assigned to chemotherapy versus amivantamab plus lazertinib plus chemotherapy versus amivantamab plus chemotherapy. And both of the amivantamab arms showed superiority in progression-free survival compared to chemotherapy alone arm and therefore this becomes an additional treatment option for our patients who develop resistance to osimertinib. In addition, we also updated the results which highlight the lack of efficacy of immunotherapy in the patients who progressed on osimertinib. There were two studies that we highlighted. One of them was a CheckMate 722 which randomly assigned patients with metastatic non-small cell lung cancer whose cancer has progressed on EGFR tyrosine kinase inhibitor to receive either chemotherapy or chemotherapy plus nivolumab which is an immune checkpoint inhibitor. And the second study was KEYNOTE-789 which had a very similar study design. Again, patients who progressed on EGFR TKI also were assigned to receive chemotherapy plus pembrolizumab or chemotherapy alone and in both of those studies there was no improvement in progression-free survival when adding immunotherapy to chemotherapy. So for all your patients who are progressing on EGFR tyrosine kinase inhibitors and you're thinking if additional immunotherapy is necessary, we now have two randomized phase 3 studies telling us that immunotherapy should not be used in addition to chemotherapy for patients who develop progression on osimertinib. Brittany Harvey: Understood. I appreciate you talking about the evidence that supports these latest recommendations from the expert panel. So then you've already touched on this a little bit in mentioning shared decision making and discussing toxicity with these new therapies, but what should clinicians know as they implement these new recommendations and how do these new recommendations fit into the previous recommendations made by the panel? Dr. Lyudmila Bazhenova: Our previous recommendations did not include a MARIPOSA trial, so did not include amivantamab and lazertinib. So in our current guidelines for patients with newly diagnosed treatment-naive EGFR classical mutations, we have three options. Number one is osimertinib, number two is osimertinib plus chemotherapy based on the FLAURA study that we highlighted in the prior version of the guidelines. And the third is amivantamab plus lazertinib. At this point, we do not have any randomized head-to-head studies of those combinations with an exception of FLAURA 2 which is osimertinib plus chemo versus osimertinib. And so the decisions will have to be made on a cross-trial comparison, taking into account patient wishes if they would like to receive chemotherapy or amivantamab plus lazertinib, understanding that this combination will result in increased toxicity. Brittany Harvey: Absolutely. I appreciate you detailing those considerations. So then finally, what do these new options mean for patients with non-small cell lung cancer and an EGFR alteration? Dr. Lyudmila Bazhenova: As a patient, it is important to also be aware of what options we have and have a direct dialogue with the physician, with the treating physician, trying to understand what option will fit with each individual patient's goals, life goals, as well as toxicity concerns. Brittany Harvey: Definitely. It's always great to have more options for patients and it's also important to discuss all of those options with their clinician as well. So I want to thank you so much for your work on this update and thank you for your time today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: My pleasure. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

CME credits: 0.50 Valid until: 13-09-2025 Claim your CME credit at https://reachmd.com/programs/cme/targeting-resistance-in-egfrm-nsclc-with-her3-directed-adcs-in-the-community-setting/24489/ The treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC) that has progressed on EGFR TKI therapy remains a clinical challenge, as traditional therapies have yielded only modest results. However, recent findings show that targeting HER3 can produce dramatically improved clinical outcomes. Data are rapidly emerging from late-phase trials evaluating HER3-directed antibody-drug conjugate therapies, and it is thus crucial for community-based oncologists and interprofessional care team members to be aware of these findings so they can be prepared to integrate these therapies into practice once they are available. In this activity, expert faculty in the field of NSCLC will evaluate recent data supporting the use of HER3-directed ADCs in the treatment of locally advanced and metastatic EGFR-mutated NSCLC that has progressed on EGFR TKI therapy, optimal management strategies for treatment-emergent adverse events related to these therapies, and the potential role of these agents in the current treatment paradigm. Faculty will also discuss best practices for a successful multidisciplinary approach and for optimized shared decision-making with the patient. Finally, case discussions will conclude the program to reinforce key learnings from the didactic section of the activity. =

The discovery of EGFR as a driver mutation and the development of medications to take advantage of this mutation changed the treatment of non-small cell lung cancer (NSCLC) forever. Not only did it vastly improve outcomes for patients with this subset of cancers, it opened the door for the likes of alectinib, lorlatinib and sotorasib to carve out niches for their own driver mutations. However, the treatment remains imperfect and people much smarter than Josh and Michael have been hard at work trying to improve on the current standard of care, osimertinib. This brings us to MARIPOSA, a study that combined the dual EGFR-MET bispecific antibody amivantamab with the CNS-penetrant anti-EGFR TKI lazertinib, and uniquely compared it to osimertinib. Will this combination dethrone the king and rule the roost in EGFRmut NSCLC? Or will excessive toxicity and logistical concerns consign it to a niche at best? Listen on to find out!Links to studies discussed in this episode (subscription may be required):MARIPOSA: LinkFor more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comOncology for the Inquisitive Mind is recorded with the support of education grants from Pfizer, Gilead Pharmaceuticals and Merck Pharmaceuticals. Our partners have no editorial rights or early previews, and they have access to the episode at the same time you do.Art courtesy of Taryn SilverMusic courtesy of AlisiaBeats: https://pixabay.com/users/alisiabeats-39461785/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice. Hosted on Acast. See acast.com/privacy for more information.

In this JCO Article Insights episode, Rohit Singh provides summary on two articles published in the April 10th issue of the Journal of Clinical Oncology. The first article, "Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)" describes a randomized, open-label, multicenter, phase III study evaluating the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. The second is the accompanying Oncology Grand Rounds. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Rohit Singh: Hello and welcome to JCO Article Insights. I'm your host, Dr. Rohit Singh. Today I will provide a summary of a Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04), by Dr. Park and colleagues from Seoul, Korea. The purpose of this study was to evaluate the efficacy and safety of the ABCP regimen based on IMpower150 in patients with EGFR or ALK mutated non-small cell lung cancer who had progressed on prior targeted treatment.   I will also discuss an Oncology Grand Round case titled "Management of Treatment Resistance in Patients with Advanced EGFR Lung Cancer: Personalization, Parsimony, and Partnership", by Dr. Vallillo and colleagues from Lahey Hospital Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Oncology Grand Round cases help us to give a clinical context to the clinical trial.   While TKIs are the established standard of care for non-small cell lung cancer harboring driver mutations, most patients will develop resistance to these treatments. Immune checkpoint inhibitors, with or without chemo, have shown clinical benefits of immune checkpoint monotherapy in patients with EGFR-mutated non-small cell lung cancer. Consequently, platinum-based chemo is the standard of care for patients with EGFR TKI failure. This was a phase III, multicenter, open-label, randomized trial conducted at 16 hospitals across the Republic of Korea. Patients diagnosed with stage four non-small cell lung cancer with sensitizing EGFR mutation or ALK translocation were included in the study. Patients were randomly assigned to the ABCP arm or chemo-only arm in a 2:1 ratio. Eligible patients were stratified on the mutation type (EGFR mutation vs. ALK translocation) and the presence of brain metastasis. No crossover to atezolizumab was permitted.  The recruitment with T790M mutation was capped at 30%. Patients who responded continued to receive maintenance with atezolizumab until disease progression or unacceptable toxicities occurred. If a patient was identified to have an acquired T790M mutation after the failure of a first or second-generation EGFR TKI, the patient had to be treated with a third-generation EGFR TKI before enrollment. The primary endpoint was investigator-assessed objective response rate according to research criteria. The secondary endpoints included overall survival and progression-free survival at one and two years, and the duration of response, along with a safety analysis. Investigators also did an exploratory biomarker analysis based on PD-L1 expression and its correlation with the response. They also analyzed the distribution of tumor-infiltrating lymphocytes, and a cut-off of 20% inflamed score was used to compare the two arms. Overall, 228 patients were enrolled, 154 in the ABCP arm and 74 in the chemo-only arm. Most patients were female at 56.1% and never smokers at 62.7%. Brain metastasis was present in 42.7% of patients. Most patients had previously received EGFR TKI therapy, however, only 8% and 30% received third-generation TKI as first-line therapy in the ABCP arm and  chemo-only arm, respectively. The majority of the patients were EGFR at  90%.  The median duration of follow-up for the study population was 26 months. The objective response rate in the ABCP arm was significantly higher at 69.5% compared to 42% in the chemotherapy alone arm. The median PFS was significantly longer in the ABCP arm at 8.48 months versus 5.6 months, and the duration of response was similar at around seven months in both arms. The median overall survival was also similar at around 20 months in both arms, with a hazard ratio of 1.01. In the subgroup of patients with brain metastasis at the time of study enrollment, PFS was significantly longer in the ABCP arm at 8.4 months compared to 4.4 months in the chemotherapy-only arm. In contrast, no difference in PFS was observed in the subgroup without brain metastasis. Regarding EGFR mutation status, there was no difference in PFS or OS between the two arms in the EGFR deletion 19 subgroup. However, a favorable PFS was observed in the EGFR L858R subgroup. For those with acquired EGFR T790M mutation, there was no difference in PFS between groups, whereas a favorable PFS was observed in the subgroup without EGFR T790M mutation.  In the exploratory biomarker analysis, interestingly, the impact on PFS was correlated with PD-L1 expression. The study found that the higher the PD-L1 expression, the better the PFS. In patients with PD-L1 expression of more than 50%, the hazard ratio was 0.24 for PFS. This is an interesting observation. As in previous studies, we have seen that PD-L1 expression does not have a strong association with response to checkpoint inhibitors in patients with driver mutations. Based on the distribution density of tails in the tumor bed, the inflamed score was calculated using artificial intelligence. For patients with 20% of the imflamed score, the ABCP arm has significantly prolonged PFS at 12.9 months compared to 4.8 months. The median number of ABCP treatment cycles was 4, with 12 for atezolizumab and 8 for bevacizumab as maintenance therapy, pemetrexed maintenance was administered for a median of 10 cycles. The incidence of grade 3 or higher side effects was 35.1% in the ABCP arm compared to 15% in the chemotherapy-only arm. Peripheral neuropathy, alopecia, and myalgias were the most prevalent side effects. Interesting notably, 54% of patients in the ABCP arm required treatment interruption or dose modification, and there were three reported deaths in the ABCP arm, two due to pneumonia and one due to cerebral embolic infarction. Around 10 patients or 13.5% of patients in the chemotherapy-only arm required dose interruption or modification.   In conclusion, patients with EGFR-mutated or translocated non-small cell lung cancer who had failed prior TKI ABCP regimen showed a statistically significant prolongation of PFS and response rate compared to chemo alone. Patients in the subgroup with EGFR L858R, without acquired T790M mutation, and presence of brain met showed more benefit. There was no difference in overall survival, though we need more mature data. Adverse events were higher in the ABCP arm. Interestingly, in the exploratory analysis, a high PD-L1 and an inflamed score of more than 20% showed PFS benefits. Though we need to take into consideration that this trial was done and all the patients were grouped from a single country considering Asian ethnicity. And most importantly, the majority of patients were treated with first- and second-generation TKIs, whereas third-generation TKIs are the standard of care in the United States.  Coming to the Oncology Grand Round, in this case, we will discuss the management of treatment resistance in patients with advanced EGFR-mutated lung cancer. A patient with a 20-pack-a-year history of tobacco use presents with weight loss and hip pain, found to have a lung mass, skeletal mets, and brain mets, and was diagnosed with lung adenocarcinoma. The patient goes with palliative radiotherapy for the brain mets. Comprehensive tumor Merkel profiling demonstrated an EGFR mutation exon 19 and alteration P53. The patient was started on third-generation EGFR TKI osimertinib. However, after 17 months, the patient has symptomatic disease progression. Usual approach, if feasible, re-biopsy at the time of progression to evaluate for possible new mutations which can guide treatment options. As mentioned earlier, in the trial, acquired resistance to the TKI is inevitable and heterogeneous. There were various mechanisms which have been proposed regarding resistance, including a second-site EGFR alteration, upregulation of bypass pathway, histological transformation to small cell histology, or suboptimal drug penetration.  There are various approaches after disease progression on EGFR TKI. Combining EGFR-directed therapies to address resistance is an option. Prime results from the MARIPOSA-2 study showed amivantamab plus chemotherapy with or without lazertinib in EGFR-mutated non-small cell lung cancer after disease progression showed a better objective response rate at 64% compared to 36% in the chemo-alone arm. It also showed improved PFS with a median of 6.3 compared to 4.2 in the chemo-alone arm. Combining immune checkpoint inhibitors, EGFR-mutated non-small cell lung, I say has been disappointing in advance of EGFR-mutated non-small cell lung, and combination therapy studies are needed to improve outcomes. Studies, as I discussed ATTLAS, have shown that combining a VEGF inhibitor with ICIs and chemotherapy can lead to a better objective response rate and PFS. However, further clinical trials are needed to figure out the better subgroup of patients who can benefit from this combination.   Should the TKI be continued beyond progression in EGFR-mutated advanced non-small cell lung cancer? Continuing the primary EGFR TKI treatment beyond progression may be considered for patients with indolent or asymptomatic progression or localized progression. We can consider radiation, surgery, or ablation. This approach will potentially delay the need to change systemic therapy in patients. However, for patients with multifocal disease progression requiring chain systemic therapy it may be more beneficial to switch to next-line systemic therapy options like platinum doublet with or without immunotherapy and VEGF inhibitors. In the case presented, the decision was made to continue osimertinib along with platinum doublet, deferring the addition of immunotherapy and VEGF inhibitor. This choice was based on factors like the patient's history of brain metastases and intracranial control. There is also a high risk of toxicity, especially pneumonitis, with immune checkpoint inhibitors after using targeted therapy, the patient showed clinical and radiographic improvement while on this treatment regimen.  The decision to continue or change therapy at cancer progression is based on factors like drug tolerability, patient preferences, and specific subgroups with different outcomes, such as those with brain metastasis or specific EGFR mutation subtypes. Choosing between combination therapy strategies that concept progression involves personalized decision-making to optimize treatment outcomes. Ultimately, the approach to management should be tailored to individual patient needs, preferences, and eligibility for different treatment modalities.  This is Rohit Singh. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You will find all the ASCO shows at asco.org/podcasts. Thank you. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions ofASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.        

Check out this week's QuadCast as we highlight best management of locally advanced cervical cancer, hypofractionated proton therapy in post-mastectomy patients, the safety of EGFR-TKI therapy with thoracic RT, and more. @QuadShotNewswww.quadshotnews.com

Dr. Shannon Westin and her guest, Dr. Helena Yu discuss the paper "HERTHENA-Lung01, a Phase 2 Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC Following EGFR TKI Therapy and Platinum-Based Chemotherapy" published in the JCO during the World Conference on Lung Cancer in Singapore.  TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Dr. Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. And as always, it's my pleasure to review an incredibly exciting manuscript.  Today, we're going to be talking about “HERTHENA-Lung01: A Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-mutated NSCLC Following EGFR TKI Therapy and Platinum-based Chemotherapy.” And this is exciting. This is a simultaneous publication in the JCO on September 10th, 2023 at the same time it's being presented at the World Conference on Lung Cancer in Singapore.  I am joined today by the first author and overall outstanding physician, Helena Yu. She's an Associate Attending Physician, Thoracic Oncologist, and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center in New York, New York.  Welcome, Dr. Yu.  Dr. Helena Yu: Thank you. I'm glad to be here, and thanks for having me.  Dr. Shannon Westin: So we're so excited to have you, and we love doing these simultaneous podcasts because I think not everyone can go to Singapore and be with you today. So it's awesome that we'll be able to give people the data that they want to see as soon as possible.  So first, let's just level set. Coming from the GYN Oncology standpoint, I always like to get down to the basics of the cancer. So, can you speak just a little bit about the incidence and mortality of lung cancer overall and what have been some recent trends in the treatment of this disease?  Dr. Helena Yu: Everyone knows somebody that has been touched by lung cancer. It's the second most common cancer that is diagnosed in men and women in the US today. It is the leading cause of cancer-related deaths, with 25% of cancer deaths really being attributable to lung cancer. Historically, prognosis with lung cancer has been poor, with five-year survivals around 10%. What's really interesting is over the last couple of years, there have been some improvements in survival with lung cancer. And I think that that can largely be attributed to the advent of immunotherapies as standard of care, as well as targeted therapies for driver mutation-positive lung cancer.  Dr. Shannon Westin: So that leads right into the next question: What is the role of the EGFR pathway in lung cancer? How common are these aberrations and how successful have prior treatments targeting this pathway been?  Dr. Helena Yu: Yes. So we, in lung cancer, have this mutation pie, which really describes the different oncogenes that we see in lung cancer. And probably now two-thirds of patients actually have a detectable driver mutation when their tumors undergo next generation sequencing. EGFR is probably one of the first mutations that was identified. About 15% to 20% of patients diagnosed with lung cancer in the US have mutations in EGFR. It is both activating and sensitizing. So, obviously mutations in EGFR cause cancer and they are sensitizing to different EGFR targeted therapies we have.   Right now, the standard of care for first-line treatment for EGFR mutant lung cancer are EGFR tyrosine kinase inhibitors. And those are oral therapies that actually are very successful at managing EGFR mutant lung cancer. They're not curative, but they do kind of control disease for a long period of time. But unfortunately for all patients, at some point their cancer does progress on these targeted therapies. And the most common one we use today is one called osimertinib, which is a third-generation EGFR TKI. And we do not have any approved targeted therapies after osimertinib. And so that kind of is the setting for this new drug, patritumab-deruxtecan.  Dr. Shannon Westin: So tell us a little bit about HER3-DXd and why you prioritize targeting this particular part of the EGFR pathway in this population.  Dr. Helena Yu: Yes. So HER3 is actually part of the HER EGFR family, and it is a protein that, when expressed, really portends a poor prognosis. It kind of tells us cancers that are more likely to recur and cancers where overall survival is shorter. So HER3-DXd is an antibody drug conjugate. There are a slew of new medicines in lung cancer that are ADCs. Historically, we looked at HER3 monoclonal antibodies in EGFR mutant lung cancer and they actually were not successful, not efficacious. And so it's really interesting that using these antibodies as part of an ADC construct has led to better efficacy.  The HER3-DXd has that HER3 monoclonal antibody, there is a linker and then there is a chemotherapy payload. So for the deruxtecan family of which there are a few ADCs has a topoisomerase 1 chemotherapy, and in part, we know that HER3 is sort of more significantly expressed in these EGFR mutant lung cancers. And because HER3 is part of the EGFR family and heterodimerizes with EGFR, it was sort of a natural initial population to study this drug.  Dr. Shannon Westin: Why don't you briefly highlight the design of the trial and your key eligibility for our listeners? Dr. Helena Yu: So this phase II study came off the heels of an initial phase I study that helped us identify the appropriate dose of HER3-DXd for patients with EGFR mutant lung cancer. And so this study enrolled patients with metastatic EGFR mutant lung cancer. All patients had to have received EGFR TKI, most of them received osimertinib and that's first line standard of care globally. And then also patients had to receive platinum doublet chemotherapy, which is really our second line standard of care treatment. The initial study randomized patients to two cohorts. One, which was all patients received 5.6 milligrams per kilogram every three weeks intravenous. The other cohort was an uptitration cohort, where they actually started with lower doses and then kind of sequentially over cycles increased the dose to see if that mitigated toxicity based on emerging phase I data that really showed that the 5.6 milligram per kilogram had the better efficacy as well as better toxicity profile. Pretty soon after the study started, all patients received that 5.6 mg per kilogram.  And I think the other important thing to say is that patients with asymptomatic brain metastases were allowed. Lung cancer, in general, has a very high incidence or frequency of brain metastases. But in EGFR mutant lung cancer that number is north of 50%. So having a therapy that is effective in the CNS is especially important for this population. Dr. Shannon Westin: So let's talk a little bit more about this population. The group that you enrolled and treated, is it representative of the general population that we might see in the community?  Dr. Helena Yu: Yes, I think so. I think that one thing to highlight are these patients were pretty heavily pretreated. The median prior lines of therapy were three lines prior to study enrollment, but I think that went up to eleven for certain patients. And so that is one thing that I think is unique about this population, where they're able to sort of receive several sequential therapies. I think it was unique in allowing those asymptomatic brain metastases and then EGFR mutant lung cancer has certain demographic tendencies. And so we see women, Asian, never smokers, which may not kind of represent the typical demographic for lung cancer, but certainly is the typical demographic for EGFR mutant lung cancer. Dr. Shannon Westin: Got it. And let's hear about your primary results. What did you discover? Dr. Helena Yu: To set the stage, this is really an unmet need where post EGFR TKI and post chemotherapy, we really don't have exciting efficacious therapies. When you look at real world studies, the response rate to third line and beyond treatments are less than 10% PFS less than three months. And so really searching for something in this treatment landscape. And so for the study, the primary endpoint was confirmed overall response which was 30% for this patient population. Duration of response was 7.4 months and the median progression free survival was 5.5 months. Looking at sort of prespecified subgroups, there really did not seem to be a particular subgroup that had enhanced benefit.  Dr. Shannon Westin: So that is a really impressive improvement in the expected standard of care results. So I congratulate you and I'm so excited.  I was also really excited to see that you included patients with the asymptomatic brain meds for the recent ASCO-Friends guidelines. Can you speak a little bit about the efficacy in this population specifically? Dr. Helena Yu: Absolutely. As I mentioned before, for these novel targeted therapies, we really do need to look specifically at CNS efficacy because that is absolutely an area where we often see disease progression. And so having studies that allow those patients really is more representative, of course, of the clinical practice that we actually treat. And so when you look at the subgroup that had a history of brain metastases, which in this group was actually, I believe, 51%, so the majority of patients, the response rate was really similar to the patients that did not have brain metastases. I believe it was 29% response rate for patients with brain metastases and 30% for patients without.  And I think what is especially useful that we did was we had specific neuroradiologist look for measurable target lesions within the CNS that had not received prior radiation or prior local therapy to look at intracranial response rate. And so there were a subgroup of patients, 30 patients that had measurable target lesions within the CNS and the confirmed intracranial response rate was 33.3% in those patients with measurable target lesions in the CNS and disease control rate was 77%. So, I think, it's really exciting to see that the response rate in the CNS was really comparable to what we see with systemic disease. Dr. Shannon Westin: That is awesome. I don't think I've ever seen anything quite like that. So really, you and your co-authors are to be congratulated for including this really important population.  I guess the next natural question is, how was HER3 expression? Did you look at that? How was it associated with response to therapy? And did you find any other intriguing genomic alterations associated with benefit from the HER3-DXd?  Dr. Helena Yu: That is a super interesting topic because I think in lung cancer we are well familiar with these driver mutations that really are the biomarker for targeted therapy. It is less clear what the appropriate biomarkers are for some of these antibody drug conjugates. We absolutely looked at HER3 expression, pretreatment tissue was required for this point specifically. And actually within EGFR mutant lung cancer, almost all patients have some degree of HER3 expression. And so we're already looking at a population that is enriched for potential response.  But we actually looked at H-scores, looking at membrane HER3 expression and really did not find differences in the degree of HER3 expression when you compare patients with response versus stable disease versus progressive disease. So I don't think the degree of HER3 expression really is an appropriate biomarker. And I think we're still figuring out with ADCs, I think you actually might need very little of the surface protein for these ADCs to be internalized and be effective. So, right now, the disease population of interest is EGFR mutant lung cancer, where we think there's reasonable efficacy. Dr. Shannon Westin: And that makes sense. And with this particular drug, is there a bit of bystander effect as well, like we've seen with some of the other ADCs?  Dr. Helena Yu: There absolutely is a little bit. And I think what is interesting for this drug too is there are a few ADCs that are in development. So there is trastuzumab-deruxtecan, which is already approved for HER2 positive lung cancer; and then there is also datopotamab-deruxtecan, which is a TROP2 ADC. And so I think there really will be a wave of these different ADCs which are studied in slightly different populations. But I think understanding what the biomarker is for these and then, will there be cross resistance because of the similar chemo backbone, is something that we will need to find out in the future.  Dr. Shannon Westin: Yeah, these are definitely unmet needs in this space.   I guess one other question just around safety signals, anything unique for this particular agent? Kind of take us through the dose interruptions and dose reductions?  Dr. Helena Yu: Absolutely. So I think that it is important to remember, and I do remind all of my patients that have consented to this study, that ADCs are a hybrid chemotherapy agent. So they will have some of the typical chemotherapy adverse events like cytopenias. We did see a little bit of alopecia with this as well. So I think there's thrombocytopenia and neutropenia that actually is more front-loaded and actually weren't necessarily associated with significant clinical sequelae like bleeding or neutropenic fever.  The rate of treatment discontinuation from adverse events was actually pretty low at 7%; but about 20% of patients did require a dose reduction, and many of the side effects do appear to be dose-dependent. So I think those dose reductions are helpful. And then a really important side effect of this class of drugs is ILD or interstitial lung disease or pneumonitis. And we've seen kind of varying ranges of pneumonitis with these drugs. So far it really looks to be the highest with trastuzumab-deruxtecan with an ILD rate north of 15%; but with this drug, the independently adjudicated rate of ILD was 5%. So present, but maybe not as high as some of the other drugs in this class.   Dr. Shannon Westin: Well, that's great news. Well, congratulations on these exciting results and your presentation and your paper.  The last question I have for you is what's next for this agent? What do you see? Where do you see it going? Dr. Helena Yu: Absolutely. So I hope that with these promising results in an area of unmet need, that we will get approval for this drug so that we can get access to our patients. The other interesting thing that we are looking at is combining HER3-DXd with osimertinib, which is the standard of care EGFR inhibitor. So the idea of combining this novel therapy with the standard targeted therapy for this type of cancer, I think, is really interesting to see if we'll get even sort of greater efficacy and in particular greater CNS efficacy by combining two CNS active agents. So those are results that I'm looking forward to seeing, too. Dr. Shannon Westin: That's great. Well, thank you so much for being here, Dr. Yu. And congratulations again on these incredible results and your incredible success in the lung cancer space.   And thank you all of you for listening in to JCO After Hours, again, discussing the “HERTHENA-Lung01: Phase II Trial of of HER3-DXd in EGFR Mutated Non-Squamous Cell Lung Cancer.” We are always excited to have you. Please check out our other podcasts, reach out and let us know how we did. And until then, we'll see you next time.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Drs. Vamsi Velcheti and Jack West discuss ADAURA, KEYNOTE-671, and KEYNOTE-789 trials in NSCLC and the first pivotal study of sunvozertinib for the treatment of NSCLC with EGFR exon 20 insertion mutations. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast. I'm a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. My guest today is Dr. Jack West, a thoracic oncologist and associate professor in medical oncology at City of Hope Comprehensive Cancer Center. Today, we'll be discussing practice-changing studies and other key advances in lung cancer that were featured at the 2023 ASCO Annual Meeting.   Our full disclosures are available in the transcript of this episode and disclosures of all guests on the ASCO Daily News podcast are available at asco.org/DNpod.   Jack, there was a lot of exciting new data that emerged from the ASCO Annual Meeting, and it's great to have you back on our podcast today to talk about all the key updates in lung cancer.   Dr. Jack West: Absolutely. Thanks so much. It's always a high-energy meeting, and there was a lot to talk about in the lung cancer sessions this year for sure.  Dr. Vamsi Velcheti: Let's begin with LBA3, the ADAURA trial. This was presented in the Plenary Session at ASCO; we've heard previously the DFS updates from previous meetings, and overall survival updates were presented at the ASCO 2023 Annual Meeting. So, Jack, what was the highlight of the presentation for you? And could you put things in context for us? We have known about the DFS data for a while now. What gets you so excited about this study?  Dr. Jack West: Well, we've actually been focused on this trial for literally 3 years, since Dr. Herbst presented it at another Plenary presentation back in the ASCO Meeting in 2020 when we saw tremendous differences in the DFS data. Again, this was a trial of patients with resected stage 1b to 3a EGFR mutation-positive non-small cell lung cancer. Nearly 700 patients were randomized to after-surgery, and for many, but not all, patients undergoing chemotherapy, it wasn't mandated. But after that, they were randomized to get adjuvant, placebo, or osimertinib for up to 3 years. And we saw huge differences in the disease-free survival from the first presentation, with a hazard ratio in the range of 0.2.   We have notably seen significant improvements in disease-free survival before with other EGFR TKIs for this population after surgery, but nothing in this range. And it's also notable that in the various other trials of other EGFR inhibitors in the postoperative setting, we've seen a DFS benefit, but that didn't translate to an improvement in overall survival. So, seeing a press release that this was associated with a significant and, in fact, highly significant by report, improvement in overall survival, as well as DFS, was really notable.   What's also, I think, particularly important as a focus of this is that in the later presentations of this work, with longer follow-up last year, we saw that the DFS curves showed a drop in the DFS starting after these patients had completed 3 years of treatment. So, really suggesting that at least some, if not many or most of these patients who had been on adjuvant osimertinib were subject to a higher risk of relapse once they completed that. So, again, making the endpoint of overall survival particularly important. It's always been to me the endpoint we should care about most in a curative setting. Although the DFS was the primary endpoint of the study and it was powered and built around specifically focusing on the DFS difference, so overall survival was reassuring, I think, when we actually saw it, but not what the trial was centered around.    And what we saw was a very dramatic improvement in overall survival with a hazard ratio of 0.49. That was essentially the same for the patients with stage 2 to 3a disease, as well as the broader population with stage 1b to 3a disease. When we look at the absolute numbers for overall survival at 5 years, there was an improvement from 73% to 85% with osimertinib, and in the population from 1b to 3a, an improvement from 78% to 88%. So, many things to comment on here. Really remarkable to see an 88% 5-year survival in the osimertinib arm that includes patients with stage 3a disease.    I would say that there's still some controversy, some questions about this, and it really centers around a few things. One is, like many global trials, this one enrolled patients from many places that did not have the same standard of care staging that we follow in the U.S. There wasn't any specification or mandate for PET scans, which would be very routine in the U.S. And brain MRIs were not mandated either. And so there were almost certainly some patients with more advanced disease that was not detected that would be a big advantage for the osimertinib arm, but really not characterized. And also, the crossover was made possible to osimertinib starting in April of 2020, but only 38.5% of the patients on the control arm actually received osimertinib at the time of relapse. And even though many of the other patients who had a relapse did get another EGFR inhibitor, I don't think there's much question that osimertinib is the preferred and optimal EGFR TKI.   And so there were a couple of important factors kind of going for this trial. One is the long, long, long duration of treatment at 3 years, though with a drop-off, I think some questions about whether even that is enough, and we might be tempted to treat beyond 3 years. And then how much did the inability of most of the patients on the control arm to get osimertinib later contribute? My personal view is that it is a troubling aspect of this trial. But also so many other trials that they're run globally in places where we arguably perpetuate these disparities by running these trials that, in part, magnify the differences between the two arms because some patients just will not have access to what is our best standard of care in the U.S., or many other parts of the world, but weren't necessarily available to many of the patients on the control arm where it was conducted. So, I think that's always a concern. It's definitely an issue of this trial, but I would not say it's unique to this one.  Dr. Vamsi Velcheti: Very good points, Jack, and I completely agree with you. I think those certainly are concerns. But on the other hand, this is a pragmatic trial and that's the real-world scenario in terms of access issues, in terms of osimertinib globally, correct, in the stage 4 setting, even though we all agree that osimertinib is the best option for patients with metastatic EGFR-mutated lung cancer, I think that's obviously a reflection of global access issues and global disparities and changes in standard of care in terms of workup as well. So, it's somewhat of a pragmatic trial in some ways and I completely agree with you, I think that may have potentially had some impact on the overall survival.  Dr. Jack West: Well, I would clarify that I don't think that this really highly significant difference in overall survival is undermined completely by this. There's no question in my mind that with the huge difference in disease-free survival that we'd already seen for 3 years, it has become our standard of care really for this population at least to offer it, if not to strongly recommend it. But I would say that most of us have been quite inclined to recommend it, perhaps with caveats. And I would say that this overall survival benefit mostly corroborates that, even if there are some concerns about how these trials are done, but it's still an impressive difference that would lead me to only cement my practice of pursuing it in this setting. I just would love to re-examine how we conduct these trials and potentially potentiate disparities that exist and don't want to have our trials be more positive by capitalizing on that.   Dr. Vamsi Velcheti: Let's move on to the next abstract, LBA100; this is the KEYNOTE-671 trial. This was featured during the meeting's Clinical Science Symposium. This is a study of pembrolizumab or placebo plus platinum doublet followed by surgical resection and pembrolizumab or placebo for early-stage non-small cell lung cancer. Jack, what was the key message from this trial, and do you consider this as practice-changing?  Dr. Jack West: This has been an area where we've seen really dramatic evolution in our practice patterns, specifically, at least for patients who don't have a tumor harboring an EGFR mutation or ALK rearrangement. I would say that there has been some momentum toward preoperative neoadjuvant therapy, specifically based on the CheckMate-816 trial that gave chemo with nivolumab versus placebo and showed a significant improvement in the pathologic complete response rate at surgery as well as event-free survival. The overall survival looks encouraging but is still early and hasn't met the threshold for statistical significance, and that's FDA-approved.   But we still question whether there's a value to doing anything in the postoperative setting. And the CheckMate-816 trial did not include that as part of the trial. It allowed postoperative management at the judgment of the treating physician but didn't really prescribe anything. We now have the results of several trials in the last few months that have added a component in the postoperative setting in addition to three or four cycles of preoperative chemoimmunotherapy. And the first one that gave us a glimpse was the AEGEAN trial presented by Dr. John Heymach at AACR in April of this year that looked at chemo and durvalumab versus chemo placebo and then followed by a year of durvalumab versus placebo after surgery. That showed results in terms of major pathologic response and event-free survival that are significantly better with immunotherapy. Not clearly superior to what we would see with CheckMate-816.   And then even more recently, we saw a monthly Plenary presentation from ASCO with the Neotorch trial presented by Dr. Shun Lu of China. This was a Chinese trial only that presented results just for patients with stage 3 disease thus far. This included patients with stage 2 or stage 3, but what we saw is stage 3 results and that looked at chemo with toripalimab for 3 cycles versus placebo and then a year of checkpoint inhibitor or placebo. This also shows a benefit with the addition of immunotherapy, but not clear if that's better than what we can already achieve with neoadjuvant alone with the Checkmate-816 approach.   And then what we have now is a presentation and simultaneous publication by Dr. Heather Wakelee of KEYNOTE-671. And this is really almost the exact same trial design as AEGEAN. It's 4 cycles of platinum doublet chemotherapy and it is for patients with stage 2 to 3a disease. And this gave 4 cycles of chemotherapy with placebo or pembrolizumab. And then after surgery, patients would go on in the investigation arm to a year of pembrolizumab or to the additional year with placebo. And this shows a significant improvement in event-free survival with a hazard ratio of 0.58. It's most prominent in patients with high PD-L1, where the hazard ratio is 0.42. But there's still a benefit in patients with PD-L1 less than 1%, where it's 0.77. And there was a trend toward better overall survival here, hazard ratio of 0.73. It does not reach statistical significance at this early point. It's still preliminary but certainly looks encouraging. And there are also significant improvements in major pathologic response, where less than 10%, about a threefold difference from 30.2% with immunotherapy compared to 11% with placebo. And a very impressive improvement in pCR rate, which is 18.1% with the chemo and pembro compared to 4% with chemotherapy alone. Not surprisingly, when we look at event-free survival, it's best in the patients who achieve a pathologic complete response, but pembrolizumab improved outcomes in event-free survival even for those who didn't achieve a pCR.   The real question I would say is does the addition of a year of checkpoint inhibitor therapy postoperatively add to what we already achieve with those first three cycles with chemo-neo or 4 cycles with maybe one of these other options? And these trials can't answer that question because they just include them as a package deal. There's no way to tease apart right now the component of what incremental benefits you get from that. And it certainly adds a year of time coming in for every 3-week infusions. Even if you space that out, it's still a year of coming in and getting infusions, potential cumulative immune-related toxicities, and a lot of cost versus potentially being done. And I think that really is the big question at this point of do you want to recommend something when we don't really have a precedent for much benefit beyond the first 4 cycles? Perhaps. Certainly, we give maintenance pemetrexed and other immunotherapies and there can be benefit there. So, I wouldn't say you necessarily cap that. But if there is resistant disease after the first 4 cycles you've already given 3 cycles, how much benefit is there? How likely is it that you're going to eradicate the last cancer cells with more?   That said, I think many patients, and oncologists myself perhaps included, are going to be inclined to err on the side of possibly over-treating, but at least trying to give everything that is part of a widely studied, FDA-approved approach once these options become available. I just think it's going to end up as a careful discussion with each patient about whether they'd prefer to just say they're done or do that extra year and really feel that even if it comes back, they've done everything that made sense to try.  Dr. Vamsi Velcheti: Very good points, Jack. So let's move on to another abstract, which is the LBA9000. This is the KEYNOTE-789 trial. In my opinion, this is the most important negative phase 3 trial in lung cancer in a while. This is a trial looking at pemetrexed platinum with or without pembrolizumab in patients who have EGFR mutation-positive metastatic non-small cell lung cancer. So, what are your key takeaways, Jack?  Dr. Jack West: Well, I would say essentially we've been waiting to figure out what is the best treatment approach for patients with acquired resistance after osimertinib. And most of the patients had received osimertinib for their EGFR mutation-positive non-small cell. This is essentially KEYNOTE-189 being run in the EGFR mutation-positive patients after they've exhausted at least the major benefit of EGFR TKI therapy.   What we saw was a hazard ratio for progression-free survival of 0.8. It didn't quite make it across the threshold for efficacy, a significant difference. And so it missed that efficacy boundary. And overall survival, the hazard ratio is 0.84, also missing the efficacy boundary. When you look at the actual curves, they show modest separation, nothing eye-popping, certainly compared to some of the other trials we're talking about. But I wouldn't say they show no benefit. And I think that's, to me, why there's really still a role for a nuanced thought process and maybe some discussion about how negative this is. This is not, in my mind, stone-cold negative with no patients benefiting from immunotherapy. This is a trial that really suggests that there's a subset of patients who are benefiting from immunotherapy.   And we've also seen going back to subset analysis of the IMpower150 trial and also the ORIENT-31 trial with sintilimab and a bevacizumab biosimilar, another anti-VEGF inhibitor. These trials both really indicated a benefit in this population after EGFR TKI therapy of immunotherapy combined with VEGF. I think there could still be a value in there. I don't want to be a Pollyanna or too open-minded, but I think that there was at least a suggestion that this could still be a fruitful avenue. I think that this is still something we should do additional studies on that could bear fruit. I wouldn't close the door and categorically say this is just never going to translate to any benefit for any of these patients.   Dr. Vamsi Velcheti: The key thing, though, is, like in EGFR mutant patients I think in the previous studies as well, the response rates with single-agent PD-1 have been very minimal. And I think one of the things that's actually very important to highlight is in the operative setting, the early-stage setting, unfortunately, some of the trials with immunotherapy have included patients with an EGFR mutation. And now we have a treatment option for those patients within the adjuvant setting, especially osimertinib. We just heard from the ADAURA trial, which has a clear significant overall survival benefit. So I think it's really important to test for EGFR mutation in all stages. And if somebody with the early stage has an EGFR mutation, adjuvant immunotherapy, or perioperative immunotherapy may not be the best option for those patients.  Dr. Jack West: Right. I agree with that, although it is interesting that the KEYNOTE-671 trial did have some small population of patients with an EGFR mutation, and in that subset analysis, they seem to benefit from the pembrolizumab. I would not say that we should divert from ADAURA, but I'm just not as sure that our previous statement and mindset that immunotherapy just categorically doesn't work for patients with driver mutations is that simple.   First of all, there is some heterogeneity about which driver mutation, and the ALK-positive patients seem to really get no benefit. But I think there's still some questions about immunotherapy for EGFR. Certainly, patients with KRAS or BRAF V600E seem to benefit like the broader range of patients. And I would also say maybe it's different whether you're giving immunotherapy combined with chemotherapy versus as monotherapy. So that's why I'm just not that sure we really can characterize this that well yet.   The one additional point I would make about KEYNOTE-789 and the potential role of immunotherapy is that some experts in thoracic oncology and general oncologists alike may prefer to introduce chemotherapy at a time of progression, but keep the osimertinib going, maybe particularly for patients with brain metastases, whether current or a history of them, where we really feel that the osimertinib adds a critical component to CNS control. We don't want to ever give osimertinib or probably other EGFR TKIs concurrently with immunotherapy. So that's just a factor that we'd really want to consider when we're prioritizing where to fit in immunotherapy, if at all.  Dr. Vamsi Velcheti: Thank you, Jack. And let's move on to the next abstract, Abstract 9002. This is a pivotal study of results from the sunvozertinib, which is an EGFR exon 20 insertion site mutation drug. There's some very promising data. Jack, how do you feel this study is going to influence practice?  Dr. Jack West: Well, this is not an agent we have access to broadly yet, but I was quite impressed by it overall. I didn't mention it. We talked about it in the pre-ASCO discussion, and it was really one that I would mark as potentially practice-changing when we can get it. DZD 9008 or sunvozertinib is a potent inhibitor of exon 20 insertion mutations, and this was 97 patients, and the majority had had a couple of lines of prior therapy. They had to have gotten chemo, and the response rate was 60%, and it was really comparable efficacy with the different mutation subtypes.   I think that the main thing that I would want to clarify a little better in my own patient population is how well the drug is really tolerated. We talked about that there was not really much grade 3 toxicity and that's true, but diarrhea rates were 67%, even though it was grade 3 and just about 8%. But grade 2 diarrhea or grade 2 rash in patients who are on this therapy, we hope for a long time, I think is something we shouldn't minimize. And I think that particularly our mindset about toxicity needs to be different when we're talking about giving a treatment for 2 or 4 cycles and then being done with it versus something we hope we're going to be giving longitudinally. And we really don't want to minimize the potential impact on the quality of life of patients who are experiencing grade 2 rash, diarrhea, or paronychia for months and months, maybe more than a year at a time.   But that said, this is twice the response rate if not more than that of what we have already had for patients with this molecular aberration with an exon 20 insertion. So I think it's compelling and I think that it's going to be really valuable to offer to our patients. I just would like to clarify better how well patients who are actually on it are feeling when you incorporate the potentially chronic toxicity issues.  Dr. Vamsi Velcheti: Thank you, Jack. And let's move on to the last abstract. This the LUNAR study, LBA9005. This is a positive phase 3 study that looked at tumor-treating fields or TTF therapy with standard of care treatments in metastatic non-small-cell lung cancer following platinum failure. This has been talked about a lot at ASCO, and Jack I'm eager to hear your key takeaways about this study.  Dr. Jack West: Well, we knew from a press release several months ago, I think back in February, that there was a significant improvement in overall survival with the addition of tumor-treated fields. Again, this concept that electric fields can lead to antimitotic effect and potentially downstream induction of immunogenic cell death and enhanced immune response, that's at least the concept. And it's of course established, has utility in patients with glioblastoma, although kind of, I would say underutilized because it can be cumbersome. And I think that's one of the things we need to factor in is that this is not the easiest approach to pursue.   But we don't have that many therapies that improve overall survival significantly in previously treated patients with non-small cell lung cancer. So, I think there's good reason to focus on this and ask how beneficial it is. It was notable, it was pretty much an even split of patients enrolled on the trial, 276 patients total, but about half had gotten chemo but not gotten immunotherapy before. And then the other half, I would say the clear majority, had gotten immunotherapy as well as chemo and got docetaxel-based treatment.     And the overall survival benefit was significant for the intent to treat total population with a hazard ratio of 0.74 and a difference in 3-year survival of 18% favoring the addition of tumor-treating fields on the chest versus 7% in the patients who didn't. It really seemed to separate between the patients who had not had an immune checkpoint inhibitor and got tumor-treating fields with the checkpoint inhibitor where the hazard ratio is 0.63 and those who got tumor-treating fields with docetaxel where the hazard ratio was 0.81. So it really wasn't significant in this population.  Toxicity, no real surprises compared to what we already knew about tumor-treating fields. Mostly dermatitis, but I would say that one of the kind of unmeasured issues is that this is a device that people have to wear on their chest carrying a battery pack with them all day long. It's essentially all the waking day, and so I think that's at least cumbersome. I wouldn't call it prohibitive, but it's a challenge. And I think we need to really ask whether the juice is worth the squeeze, whether the benefit is that compelling. And I question that when we're talking about an agent that doesn't significantly move the needle against docetaxel alone.   Again, this is a population where in the U.S. we have ramucirumab to add to docetaxel. Not everyone does that. It's not uniform, but that has a statistically significant, though modest survival benefit associated with that. We don't do better than that with tumor treating fields. And so, I think that this is an option that merits discussion and some patients may opt for it, but I suspect that most of my patients would not find the absolute difference to be that compelling for the challenges it incurs. I don't know what your perspective is here.  Dr. Vamsi Velcheti: I completely agree, Jack. And I think the study design and just the fact that the standard of care has changed over the last 5, actually 6 years since the study has been open. And I'm not really so sure I could really make much sense of the data in terms of the standard of care combination with TTF providing more benefit. And I think there are more questions than answers here and I'm not so sure which populations would benefit the most. And I think, I hate to say this, but this is a nice proof of concept. I hate to say this because it's a phase 3 study and it's a positive phase 3 study, but it's clinical relevance with the current standard of care, I think, I'm not really sure how much of an impact this would really have.    Well, Jack, I've really enjoyed speaking with you about these key advances in lung cancer that were featured at the 2023 ASCO Annual Meeting. Our listeners will find links to all the studies discussed today in the transcript of this episode. Thank you so much, Jack, for joining us today.  Dr. Jack West: Always a pleasure. Thanks so much.  Dr. Vamsi Velcheti: And just like that, we've reached the end of another enriching episode. But remember, like all good things, this too must come to an end, but only until we meet again. We really would like your feedback on the podcast. If you enjoyed the podcast, please rate, review and subscribe wherever you get your podcasts.  Disclaimer:    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:   Dr. Vamsidhar Velcheti   @VamsiVelcheti   Dr. H. Jack West   @JackWestMD   Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:    Dr. Vamsidhar Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline     Dr. Jack West:   Honoraria: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati, Regneron, Amgen, Abbvie   Consulting or Advisory Role: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati Therapeutics, Regneron, Amgen, Abbvie, Summit Therapeutics   Speakers' Bureau: Takeda, Merck, AstraZeneca        

- Bệnh viện Ung bướu Đà Nẵng vừa điều trị hiệu quả ca bệnh ung thư phổi giai đoạn cuối với thuốc nhắm trúng đích EGFR-TKI thế hệ 3. Hơn 36 tháng điều trị, tình trạng sức khỏe bệnh nhân được kiểm soát tốt, chưa có biểu hiện kháng thuốc. Chủ đề : EGFR-TKI, ung thư phổi --- Support this podcast: https://podcasters.spotify.com/pod/show/vov1tintuc/support

In this special episode of Lung Cancer Considered, hosts Dr. Stephen Liu and Dr. Narjust Florez discuss the seminal IPASS trial with its principal investigator, Dr. Tony Mok. IPASS was a randomized phase III trial that compared the EGFR TKI gefitinib to carboplatin plus paclitaxel and showed, for the first time, that in a selected population, targeted therapy was superior to chemotherapy. The initial results were published in the New England Journal of Medicine in 2009 and helped usher in the era of precision oncology. Dr. Tony Mok is the Li Shu Fan Medical Foundation endowed Professor and Chairman of the Department of Clinical Oncology at the Chinese University of Hong Kong. He cofounded the Lung Cancer Research Group, Chinese Thoracic Oncology Research Group and Asia Thoracic Oncology Research Group.

Missed the key developments from recent conferences? Join our panel of experts and stay up to date. Credit available for this activity expires: 11/02/2023 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/983346?src=mkm_podcast_addon_983346

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.17.512459v1?rss=1 Authors: Shi, B. Abstract: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control of non-small cell lung cancer (NSCLC). The rapidly acquired TKIs resistance accounts for a major hurdle in successful treatment. However, the mechanisms controlling EGFR-TKIs resistance remain largely unknown. RNA structures have widespread and crucial roles in various biological processes; but, their role in regulating cancer drug resistance remains unclear. Here, the PARIS method is used to establish the higher-order RNA structure maps of EGFR-TKI resistant- and sensitive-cells of NSCLC. According to our results, RNA structural regions are enriched in UTRs and correlate with translation efficiency. Moreover, YRDC facilitates resistance to EGFR-TKIs in NSCLC cells, and RNA structure formation in YRDC 3'UTR suppress ELAVL1 binding leading to EGFR-TKIs sensitivity by impairing YRDC translation. A potential cancer therapy strategy is provided by using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism in which the RNA structure switch modulates EGFR-TKIs resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

We discuss a phase I study (CALM) of an allogeneic anti-CD19 CART-T product, using aprepitant (?) for pruritis from EGFR TKIs, and the widely discussed NordICC study on colonoscopy screening. CALM: https://doi.org/10.1016/S2352-3026(22)00245-9 Aprepitant vs. desloratidine: https://doi.org/10.1002/cncr.34474 NordICC: https://www.nejm.org/doi/full/10.1056/NEJMoa2208375 NordICC editorial: https://www.nejm.org/doi/full/10.1056/NEJMe2211595

In this episode, experts explore new data related to EGFR TKI resistance, specifically resistance to osimertinib. Listen to our experts evaluating the real-world data on most common resistance mechanisms to osimertinib and emerging strategies to overcome resistance. 

Are you aware of the rapid progress for patients with epidermal growth factor receptor (EGFR) exon 20 insertion-mutated non-small cell lung cancer (NSCLC) and strategies for tackling osimertinib resistance? Credit available for this activity expires: [07/11/23] Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/976634?src=mkm_podcast_addon_976634

George Chen Biography George Chen, MD MBA, is an oncologist by training with a successful track record in the world of global pharmaceutical companies. Prior to founding D3 Bio, Dr. Chen held senior global positions in research, drug development and management at leading institutions, such as the National Institutes of Health, and multinational pharmaceutical companies, such as Eli Lilly, GlaxoSmithKline, Johnson & Johnson, BeiGene, and Astra Zeneca. At these organizations he led development and regulatory registrations of blockbuster drugs into the U.S. and Chinese markets, directing more than 70 IND approvals and more than 30 NDAs. His medical degree is from the Shanghai Medical College of Fudan University and his MBA is from the Wharton School of Business at the University of Pennsylvania. D3 Bio D3 Bio, Inc is an “in China, for global” biotech company aiming to become a world-class biotherapeutic company to develop and register the First/best-in-class medicines for cancer and autoimmune disease patients in large unmet medical needs through a continuously progressing cycle of using the insight of Development to guide Discovery and back to Development process. The company has launched 6 pre-clinical portfolio projects with first and best in class potential and recently received IND clearance from the FDA to initiate Phase 1 trial for D3S-001. D3 Bio is backed by a syndicate of world-class investors whose support underscores their belief in the promise of the Company. Major investors include Boyu Capital, Matrix Partners China, Sequoia Capital China, Temasek, and WuXi AppTec's Corporate Venture Fund. In this episode of Behind Biotech, we spoke with George about: Training as an oncologist in China in the 80s and his motivation to come to the US to learn about immunotherapy His experience of building the foundation of BeiGene as the company's first Chief Medical Officer The success story of and lessons learned from developing Tagrisso, an EGFR-TKI for NSCLC, at Astrazeneca China D3 Bio's plans after launching with a $200M Series A-the second largest Series A in 2020 of any biotech company

Do you know that primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) occurs in approximately 20% to 30% of patients with EGFR-mutated non-small cell lung cancer (NSCLC), and acquired resistance is inevitable? Credit available for this activity expires: 5/23/2023 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/974097?src=mkm_podcast_addon_974097

In this podcast episode, Conor Ernst Steuer, MD, a medical oncologist; Frank Schneider, MD, a pathologist; and Elise Hitron, MSN, FNP-C, a phase I clinical trials nurse practitioner, engage in a multidisciplinary discussion of the latest management strategies for EGFR-mutated NSCLC. Topics include:Testing for targetable biomarkersTalking with patients about biomarker testingFrontline therapy for EGFR-positive NSCLCResistance to front-line osimertinibTreatment of EGFR TKI–resistant disease, including the emerging antibody–drug conjugate patritumab deruxtecanHER3 protein testingPathology considerationsNursing considerationsInterdisciplinary communicationPresenters:Conor Ernst Steuer, MDAssistant ProfessorDepartment of Medical OncologyWinship Cancer InstituteEmory UniversityAtlanta, GeorgiaFrank Schneider, MDAssociate Professor of PathologyDepartment of Pathology and Laboratory MedicineDirector, Cancer Tissue and Pathology Shared ResourceWinship Cancer InstituteEmory UniversityAtlanta, GeorgiaElise Hitron, MSN, FNP-CAdjunct InstructorSchool of NursingPhase I Clinical Trials Nurse PractitionerWinship Cancer InstituteEmory UniversityAtlanta, GeorgiaSupported by an educational grant from Daiichi Sankyo, Inc.Link to full program, including a series of short interactive virtual presentations with downloadable slidesets on EGFR-mutated advanced NSCLC, including the evolving role of HER3 in the setting of EGFR TKI resistance:https://bit.ly/3G32Jkm

Host: Mark Socinski, MD Guest: Edward B. Garon, MD, MS In the treatment of EGFR-mutated advanced non-small cell lung cancer (NSCLC), when is an EGFR TKI not enough? Answer: When you don't have all of the information. Digging deeper into the specific EGFR mutations has led to advances in the dual blockade of VEGF and EGFR in the frontline setting. Join Drs. Mark Socinski and Edward Garon as they discuss the evolving role of EGFR and VEGF blockade based on clinical trial data. Find out how you can have an immediate impact on your patients by making targeted treatment decisions based on specific oncogenic driver mutations in NSCLC. Be sure to keep up with our experts because making the right choice is more critical than ever.

CME credits: 0.25 Valid until: 30-11-2022 Claim your CME credit at https://reachmd.com/programs/cme/keeping-pace-in-lung-cancer-all-about-antiangiogenics-and-tkis-current-roles-and-future-directions-in-egfr-mutant-nsclc/13019/ In the treatment of EGFR-mutated advanced non-small cell lung cancer (NSCLC), when is an EGFR TKI not enough? Answer: When you don't have all of the information. Digging deeper into the specific EGFR mutations has led to advances in the dual blockade of VEGF and EGFR in the frontline setting. Join Drs. Mark Socinski and Edward Garon as they discuss the evolving role of EGFR and VEGF blockade based on clinical trial data. Find out how you can have an immediate impact on your patients by making targeted treatment decisions based on specific oncogenic driver mutations in NSCLC. Be sure to keep up with our experts because making the right choice is more critical than ever.

CME credits: 0.25 Valid until: 30-11-2022 Claim your CME credit at https://reachmd.com/programs/cme/keeping-pace-in-lung-cancer-all-about-antiangiogenics-and-tkis-current-roles-and-future-directions-in-egfr-mutant-nsclc/13019/ In the treatment of EGFR-mutated advanced non-small cell lung cancer (NSCLC), when is an EGFR TKI not enough? Answer: When you don't have all of the information. Digging deeper into the specific EGFR mutations has led to advances in the dual blockade of VEGF and EGFR in the frontline setting. Join Drs. Mark Socinski and Edward Garon as they discuss the evolving role of EGFR and VEGF blockade based on clinical trial data. Find out how you can have an immediate impact on your patients by making targeted treatment decisions based on specific oncogenic driver mutations in NSCLC. Be sure to keep up with our experts because making the right choice is more critical than ever.

CME credits: 0.25 Valid until: 16-06-2022 Claim your CME credit at https://reachmd.com/programs/cme/meeting-future-global-challenges-case-based-presentations-management-nsclc/12600/ For the 3% to 4% of patients with non-small cell lung cancer (NSCLC) who harbor a MET exon 14 skipping mutation, the prognosis is grave. MET gene dysregulation may also play a role in the emergence of resistance to EGFR TKI therapy in patients with EGFR-mutated NSCLC, further complicating treatment. Join our case discussion as Dr. Paul Paik and Dr. Josh Sabari highlight the importance of identifying MET gene aberrations in patients with NSCLC.

CME credits: 0.25 Valid until: 16-06-2022 Claim your CME credit at https://reachmd.com/programs/cme/meeting-future-global-challenges-case-based-presentations-management-nsclc/12600/ For the 3% to 4% of patients with non-small cell lung cancer (NSCLC) who harbor a MET exon 14 skipping mutation, the prognosis is grave. MET gene dysregulation may also play a role in the emergence of resistance to EGFR TKI therapy in patients with EGFR-mutated NSCLC, further complicating treatment. Join our case discussion as Dr. Paul Paik and Dr. Josh Sabari highlight the importance of identifying MET gene aberrations in patients with NSCLC.

Host: Paul Paik, MD Guest: Joshua K. Sabari, MD For the 3% to 4% of patients with non-small cell lung cancer (NSCLC) who harbor a MET exon 14 skipping mutation, the prognosis is grave. MET gene dysregulation may also play a role in the emergence of resistance to EGFR TKI therapy in patients with EGFR-mutated NSCLC, further complicating treatment. Join our case discussion as Dr. Paul Paik and Dr. Josh Sabari highlight the importance of identifying MET gene aberrations in patients with NSCLC.

In this episode, Helena A. Yu, MD, and Maria E. Arcila, MD, provide medical oncology and pathology perspectives, respectively, on new data from ESMO 2020 informing precision medicine in NSCLC, with topics including:Updated efficacy data from the phase III ADAURA study of adjuvant osimertinib for resected EGFR-mutated NSCLC with a focus on CNS disease recurrenceBiomarker testing in early-stage lung cancer New data for sotorasib, a small molecule inhibitor of KRAS G12C, in heavily pretreated NSCLCInterim results from the phase I portion of the CHRYSALIS trial evaluating amivantamab, a bispecific antibody that targets EGFR and MET, in combination with lazertinib, a third-generation EGFR TKI, for the treatment of EGFR-mutated NSCLCPhase I data on the HER3-directed antibody–drug conjugate patritumab deruxtecan for NSCLC with progression on an EGFR TKIPresenters:Helena A. Yu, MDAssistant AttendingDepartment of MedicineMemorial Sloan Kettering Cancer CenterNew York, New YorkMaria E. Arcila, MDPathologistDirector, Diagnostic Molecular Pathology LaboratoryMemorial Sloan Kettering Cancer CenterNew York, New YorkContent supported by an educational grant from Lilly.Link to full program, including an associated Podcast Pearls PDF, downloadable slidesets, and on-demand Webcasts:http://bit.ly/3a3e1Xs

Faculty panel moderated by Dr. Daniel Tan discusses the latest data on adjuvant use of EGFR TKIs in early-stage NSCLC. Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/940688?src=mkm_podcast_addon_940688

Host: Jennifer Caudle, DO Guest: Tracey Evans, MD Join Dr. Tracey Evans as she discusses the efficacy data for TAGRISSO® (osimertinib) and the potential impact for metastatic EGFRm NSCLC patients. In 2018, first-line TAGRISSO became a standard of care for metastatic EGFRm NSCLC with an unprecedented 18.9 months median PFS vs 10.2 months for erlotinib/gefitinib (HR=0.46 [95% CI: 0.37, 0.57]; P

Host: Jennifer Caudle, DO Guest: Tracey Evans, MD Join Dr. Tracey Evans as she discusses the efficacy data for TAGRISSO® (osimertinib) and the potential impact for metastatic EGFRm NSCLC patients. In 2018, first-line TAGRISSO became a standard of care for metastatic EGFRm NSCLC with an unprecedented 18.9 months median PFS vs 10.2 months for erlotinib/gefitinib (HR=0.46 [95% CI: 0.37, 0.57]; P

Biomarker Assessment and Targeted Treatment of Nonsquamous Non-Small Cell Lung Cancer — A roundtable discussion with clinical investigators Drs Justin F Gainor, Matthew Gubens, Geoffrey R Oxnard and Heather Wakelee and general medical oncologists Drs Isaac Levy and Estelamari Rodriguez regarding biomarker analysis and related treatment decision-making for patients with non-small cell lung cancer. Biomarker testing and therapeutic decision-making for patients with non-small cell lung cancer (NSCLC) (00:00) Case: A woman in her late 80s, a never smoker, is diagnosed with metastatic adenocarcinoma of the lung with an EGFR exon 21 L858R mutation (01:56) Therapeutic approach for patients with NSCLC and EGFR tumor mutations (04:14) Results of the Phase III FLAURA trial evaluating osimertinib versus gefitinib or erlotinib for untreated advanced NSCLC with EGFR tumor mutations (06:08) Pneumonitis and cardiotoxicity associated with osimertinib in patients with NSCLC (09:56) Second-line therapy for patients after disease progression on osimertinib (13:25) Efficacy and tolerability of immune checkpoint inhibitors in patients with NSCLC harboring an actionable genomic alteration (17:08) Resistance mutations in patients who experience disease progression on osimertinib (18:58) Genomic profiling for patients with metastatic nonsquamous NSCLC; optimal testing platforms (24:38) Evaluation of biomarkers in patients with squamous cell carcinoma of the lung (28:54) Targeting KRAS G12C and MET exon 14 splice mutations  (31:39) Case: A woman in her mid-50s who presents with cough, dyspnea and respiratory distress is diagnosed with metastatic adenocarcinoma of the lung with an EGFR exon 21 L858R mutation (36:15) Considerations for switching to an EGFR tyrosine kinase inhibitor (TKI) in a symptomatic patient initially started on chemotherapy prior to the identification of an EGFR tumor mutation (38:18) Role of liquid biopsy in monitoring patients who are receiving EGFR TKI therapy (40:56) Activity of immune checkpoint inhibitors in patients with NSCLC and targetable genomic alterations (44:35) Results of the IMpower150 and IMpower130 trials of atezolizumab with bevacizumab/chemotherapy and atezolizumab with chemotherapy, respectively, as first-line treatment for metastatic nonsquamous NSCLC (47:32) Immune checkpoint inhibitors for patients with advanced lung cancer with oncogenic driver alterations: Results from the IMMUNOTARGET registry (50:37) Toxicities associated with the use of targeted therapy after immunotherapy in patients with NSCLC; risk of pneumonitis with durvalumab and osimertinib (53:33) Increased hepatotoxicity associated with sequential immune checkpoint inhibitor and crizotinib therapy for patients with NSCLC (56:20) Therapeutic approach for patients with locally advanced NSCLC with EGFR tumor mutations who experience disease relapse after treatment with durvalumab (59:10) Cardiac toxicity associated with immune checkpoint inhibitors (1:03:56) Monitoring for and management of the cardiac side effects of immune checkpoint inhibitors (1:06:52) Case: A man in his late 70s with adenocarcinoma of the lung and brain metastases is found through next-generation sequencing to have an EGFR exon 21 L858R mutation, HER2 amplification and high PD-L1 expression (1:09:58) Use of liquid biopsy to detect genomic alterations in patients with NSCLC (1:11:22) FGFR alterations in patients with NSCLC (1:14:42) Targeting HER2 alterations in patients with lung cancer (1:16:27) Efficacy of EGFR TKIs in patients with lung cancer and CNS metastases; sequencing stereotactic radiosurgery and EGFR TKIs (1:18:22) Diagnosis and management of radiation necrosis in patients with lung cancer (1:22:26) Preservation of neurocognitive function during whole-brain radiation therapy with hippocampal sparing for patients with NSCLC and brain metastases (1:25:33) Case: A woman in her early 80s with adenocarcinoma of the lung with an EGFR exon 21 L858R mutation and metastases to the brain receives osimertinib as first-line therapy (1:27:11) Activity of EGFR TKIs in patients with brain metastases; CNS penetration and dosing of osimertinib (1:30:59) Results of the BLOOM study evaluating osimertinib for patients with leptomeningeal metastases from NSCLC with EGFR tumor mutations (1:34:34) Targeting EGFR exon 20 insertions with TAK-788 and poziotinib (1:36:12) Results of the Phase III ALEX study evaluating alectinib and the Phase III ALTA-1L study investigating brigatinib for patients with advanced NSCLC and ALK rearrangements (1:39:36) Sequencing ALK inhibitors for patients with NSCLC with ALK rearrangements (1:42:08) Tolerability of brigatinib, alectinib, ceritinib and lorlatinib in patients with NSCLC with ALK rearrangements (1:45:41) Emerging data with targeted therapies for patients with NSCLC in the (neo)adjuvant setting (1:50:16) Ongoing (neo)adjuvant trials of targeted therapies for patients with locally advanced NSCLC (1:52:38) Perspective on emerging data from studies evaluating adjuvant targeted therapy for advanced NSCLC (1:55:56) Risks associated with neoadjuvant therapy for patients with advanced NSCLC (1:59:02) Case: A woman in her late 50s with metastatic NSCLC with a RET rearrangement receives carboplatin/pemetrexed/bevacizumab followed by selpercatinib upon disease progression (2:01:04) Activity of the selective RET inhibitors selpercatinib and pralsetinib; detection of RET alterations in patients with NSCLC (2:05:48) Duration of response, CNS penetration and tolerability profile of RET inhibitors (2:08:56) Efficacy of pemetrexed-based chemotherapy regimens for patients with NSCLC with RET fusions (2:12:33) Case: A woman in her mid-50s with metastatic NSCLC with a BRAF V600E tumor mutation attains a good response to dabrafenib/trametinib after experiencing disease progression on multiple lines of therapy (2:15:05) Activity and tolerability of BRAF and MEK inhibitors in patients with NSCLC with BRAF tumor mutations (2:17:26) Duration of therapy with BRAF and MEK inhibitors (2:19:47) Biology, detection and management of NSCLC with MET exon 14 mutations (2:22:35) Significance of HER2 mutations in patients with lung cancer (2:26:43) Targeting NTRK gene fusions with larotrectinib and entrectinib (2:29:44) Therapeutic options for patients with NSCLC and ROS1 translocations (2:35:52) CME information and select publications

CME credits: 0.25 Valid until: 29-04-2021 Claim your CME credit at https://reachmd.com/programs/cme/acquired-resistance-to-targeted-therapy-of-nsclc-a-global-perspective/11313/ EGFR tyrosine kinase inhibitors, or EGFR-TKIs, have resulted in dramatic improvements for patients with EGFR-mutant advanced non-small cell lung cancer. However, acquired resistance continues to limit their long-term benefit. While often due to an acquired T790M mutation, dysregulation of the MET pathway in non-small cell lung cancer is emerging as an important participant in acquired EGFR-TKI resistance. Join us as we discuss the dysregulation of the MET pathway in non-small cell lung cancer, as well as the therapeutic potential of MET pathway inhibitors.

CME credits: 0.25 Valid until: 29-04-2021 Claim your CME credit at https://reachmd.com/programs/cme/acquired-resistance-to-targeted-therapy-of-nsclc-a-global-perspective/11313/ EGFR tyrosine kinase inhibitors, or EGFR-TKIs, have resulted in dramatic improvements for patients with EGFR-mutant advanced non-small cell lung cancer. However, acquired resistance continues to limit their long-term benefit. While often due to an acquired T790M mutation, dysregulation of the MET pathway in non-small cell lung cancer is emerging as an important participant in acquired EGFR-TKI resistance. Join us as we discuss the dysregulation of the MET pathway in non-small cell lung cancer, as well as the therapeutic potential of MET pathway inhibitors.

In this second episode of our new podcast series, Dr Tom Lynch, who began his position as director of the Fred Hutchinson Cancer Research Center as Seattle became the first epicenter of the COVID-19 pandemic in the United States, comments on the current status of oncology research and data soon to be presented from a Phase III trial evaluating the EGFR TKI osimertinib as adjuvant therapy for patients with non-small cell lung cancer and EGFR tumor mutations. Additional resources: * Lynch TJ et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129-39. Abstract (https://pubmed.ncbi.nlm.nih.gov/15118073/) * AstraZeneca. [Osimertinib] Phase III ADAURA trial will be unblinded early after overwhelming efficacy in the adjuvant treatment of patients with EGFR-mutated lung cancer [press release (https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/tagrisso-phase-iii-adaura-trial-will-be-unblinded-early-after-overwhelming-efficacy-in-the-adjuvant-treatment-of-patients-with-egfr-mutated-lung-cancer.html)]. April 10, 2020. * National Comprehensive Cancer Network. Short-term recommendations for non-small cell lung cancer management during the COVID-19 pandemic. COVID-19 NCCN guidelines (https://www.nccn.org/covid-19/pdf/COVID_NSCLC.pdf).

This podcast describes the results of the BLOOM study, evaluating the efficacy of osimertinib in EGFR-mutated lung cancer with leptomeningeal disease after failure of prior EGFR TKI therapy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Osimertinib In Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study” by Yang et al. My name is Jürgen Wolf and I am the medical director of the Center for Integrated Oncology at the University Hospital of Cologne in Germany. I am a medical oncologist with expertise in personalized lung cancer care.   About 10% of patients with advanced EGFR-mutated lung cancer suffer from leptomeningeal disease. While this disease manifestation in non-small-cell lung cancer is generally associated with a particularly poor prognosis, with survival times of only a few months, the question arises whether treatment with specific tyrosine kinase inhibitors might enable a better disease control. Most studies evaluating the efficacy of 1st and 2nd generation EGFR-TKIs in leptomeningeal disease were retrospective and difficult to interpret, given the heterogeneity of the disease as well as of the preceding treatment procedures. Small prospective studies with patient numbers below 20 tested standard dose erlotinib or afatinib as well as high-dose pulsatile EGFR TKI treatment and reported disappointing results with survival times of around 4 months only.   The 3rd generation EGFR TKI osimertinib initially was approved for T790M positive failure of 1st and 2nd generation EGFR TKIs and is now commonly regarded as 1st line standard treatment for EGFR-mutated lung cancer based on a superior progression-free survival, overall survival and toxicity profile. In studies with primates and healthy volunteers, osimertinib has been shown to exert a higher blood-brain barrier permeability and a higher brain exposure compared with other TKIs. In the AURA clinical development program for osimertinib, 22 patients with T790M-positive relapse after EGFR TKI treatment and leptomeningeal disease were retrospectively identified, and an impressive median overall survival of 18.8 months was reported. A small prospective Japanese trial evaluated osimertinib in 13 patients with T790M-positive leptomeningeal disease which, however, could be confirmed only in 5 patients. Responses were seen in some patients, and the median progression free survival for all patients was reported with 7.2 months.   The BLOOM study part B, which is discussed in this podcast, is a multicenter phase I study evaluating osimertinib in EGFR-mutated lung cancer patients with leptomeningeal metastases and failure of previous EGFR TKI treatment. Study objectives were the assessment of clinical parameters like response, overall survival neurological status, and safety but also pharmacokinetics in blood and cerebrospinal fluid. Main inclusion criteria included confirmed diagnosis of EGFR Exon 19 deletion or L858R mutation and confirmation of leptomeningeal disease by positive cytology of cerebrospinal fluid and at least one leptomeningeal site assessable by MRI. There were two sequential cohorts, one unselected for the T790M mutation and with stable non-CNS disease at enrollment, and one for T790M positive patients without the requirement for stable non-CNS disease. Osimertinib dose was 160 mg once daily, which is twice the approved dose. Besides investigator-based response assessment, according to RECIST, leptomeningeal disease was also assessed by a neuroradiological blinded central review according to the RANO-LM working group criteria, which integrates clinical examination, cerebrospinal fluid cytology and neuraxis MRI.   41 patients from South Korea and Taiwan were included, 20 in the unselected and 21 in the T790M-positive cohort. About 70% of the patients had co-existing brain mets and about 50% prior radiotherapy. For 4 patients, no response data from the independent review were available.   The confirmed overall response rate for leptomeningeal disease was impressive at 62% as assessed by blinded independent review and nearly identical between both cohorts.  By comparison, the overall response rate was only 27% by investigator assessment, which, in turn, revealed a higher stable disease rate. Prior brain radiotherapy had no influence on efficacy. Median duration of response was comparable between blinded independent review and investigator, with 15.2 and 18.9 months, respectively. In about one third of the evaluable patients confirmed CSF clearance could be observed. PK analysis indicated that plasma concentration of osimertinib and its active metabolites reached steady state by day 15; the ratio for osimertinib exposure in cerebrospinal fluid vs. plasma was around 16%.   Surprisingly, only half of the patients had an abnormal neurological baseline assessment, most of them with mild symptoms. Symptom stabilization occurred in 54% during treatment; only 5% showed regression of neurological functions.   Overall, median progression-free survival, as assessed by the investigators, was 8.6 months and median overall survival 11 months. Progression-free survival and overall survival differed markedly between both cohorts. For instance, overall survival was 16.6 months in the unselected and 8.1 months in the selected group. Possibly, the requirement for stable non-CNS disease in the unselected group was partly responsible for the better survival outcome in this subset . However, this has to be interpreted cautiously in view of small patient numbers and large confidence intervals.   Osimertinib 160mg was well tolerated in the majority of patients with the known osimertinib side-effect profile. However, 24% of the patients suffered from adverse events grade 3 or more—possibly related to osimertinib, according to the investigators’ assessment. Dose reduction had to be performed in 12% and discontinuation of treatment in 22% of the patients due to adverse events. 17% of the patients had fatal events that did not appear to be causally related to osimertinib.   What can we learn from this study? This is the largest prospective study so far in this setting and osimertinib clearly shows clinical efficacy. The study methodology was sound, with response assessment by blinded independent review and based on RECIST criteria as well as on the RANO criteria established in particular for leptomeningeal disease. The overall response rate of leptomeningeal disease of around 60% and the duration of response of around 15 months is clinically relevant in particular, as it is correlated with improvement or at least neurological stabilization in most patients. Although the toxicity of the treatment is substantially higher than reported in osimertinib trials so far, it is manageable, and the risk/benefit ratio appears to be favorable.   What are the limitations of the study? Patient numbers are small, and the patients are heterogeneous with respect to several important factors such as pretreatment whole-brain radiotherapy, occurrence of simultaneous CNS metastases and neurological symptoms. Thus, absolute values for efficacy have to be interpreted cautiously, and comparison with already published trials remains difficult. Also, unfortunately in view of the toxicity, the question remains open whether the 160mg dose, which is not approved, is actually necessary. Finally, since osimertinib increasingly becomes the first-line treatment standard in EGFR-mutated lung cancer, the number of patients with failure of 1st- or 2nd-generation EGFR TKI treatment will decrease.   Despite these limitations, the trial provides the most convincing data so far in this special patient population and, in my opinion, defines  an important new option to consider for patients with EGFR-mutated lung cancer and leptomeningeal disease after failure of previous EGFR TKI treatment.   This concludes this JCO Podcast. Thank you for listening.

Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. The phase III trial Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA) showed a significant increase in progression free survival. In the now available finale survival analysis also the overall survival showed a statistical significant increase. Expert: Suresh S. Ramalingam, Winship Cancer Institute of Emory University, Atlanta, GA

This JCO Podcast provides observations and commentary on the JCO article “Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment for Stage IIIA-N2 EGFR-Mutant NSCLC (EMERGING-CTONG 1103): A Randomized Phase II Study” by Zhong et al. My name is Tony Mok, and I am a Professor of Clinical Oncology at the Chinese University of Hong Kong in the Prince of Wales Hospital in Hong Kong. My oncologic specialty is Medical Oncology.   With the advent of molecular targeted therapy, patients harboring driver oncogenes may now survive longer and better than before, and EGFR mutation is the prime example of such achievement. However, evidence for “cure” of patients with metastatic EGFR mutation positive lung cancer remains scanty. In contrast, It may be more reasonable to first attempt cure of patients with earlier stage disease using molecular targeted therapy. CTONG 1103, published in this issue of Journal of Clinical Oncology, is the first randomized study comparing neoadjuvant erlotinib with chemotherapy for patients with stage IIIA EGFR mutation positive lung cancer.   CTONG 1103, the report that accompanies this podcast, is not an easy study to conduct. Between December 2011 and December 2017, investigators from 17 centers across China managed to screen 386 patients with stage IIIA non-small cell lung cancer (NSCLC) and identified only 72 (which is about 19%) eligible EGFR mutation positive patients. They were randomized to receive either erlotinib 150mg daily for 42 days or two cycles of chemotherapy using gemcitabine and cisplatin as neo-adjuvant therapy. After neoadjuvant therapy, 73% of the erlotinib arm, and 63% of the chemotherapy arm, received curative surgery, including two patients in erlotinib arm who received pneumonectomy. The primary endpoint of this study is tumor response rate, which is 54.1% for erlotinib and 34.3% for chemotherapy. However, the odds ratio of 2.26 for tumor response rate was not statistically significant. Two other important and impactful endpoints include major pathological response and progression free survival (PFS). Major pathological response is defined as less than 10% residual viable tumor cell and it occurred only in 10.7% of patients who received erlotinib and none with the chemotherapy. But on the other hand, PFS was significantly better with erlotinib arm, reporting median of 21.5 month comparing with 11.4 months with chemotherapy arm.   In reference to the primary endpoint of tumor response rate, we should conclude that CTONG 1103 is a negative study. Zhong et al has reasonably estimated the sample size based on a presumptive response rate of 70% in the erlotinib arm and 36% in the chemotherapy arm.  The reported response rate at 54.1% with erlotinib in this study has significantly fallen short of the expected rate of 70%, which was actually the widely accepted response rate in patients with stage IV disease. The authors selected to offer 42 days of neo-adjuvant erlotinib in order to match the two cycles of neo-adjuvant chemotherapy. While there is no biologic reason to explain the low response rate in earlier stage disease, the shorter duration of treatment may contribute to the relatively lower response rate. The other important outcome is the major pathological response of 10.7% with neo-adjuvant erlotinib, which is supposed to be a surrogate for overall survival. Hellman et al were among the first groups to suggest the predictive power of major pathological response for neo-adjuvant chemotherapy for patients with early stage lung cancer. The lower than expected major pathological response may be considered a surrogate indicator for overall survival but it is more important to wait for the mature survival outcomes.   A negative study can still be impactful. This study has established the feasibility of neo-adjuvant EGFR TKI for patients with potentially resectable EGFR mutation positive lung cancer. The first single arm phase II study on pre-operative gefitinib published in 2009 in the Journal of Clinical Oncology enrolled 36 patients but only 6 harbored the activating EGFR mutations. Tumor response was observed in 4 patients and all were positive for the mutations. Another single arm study published in 2018 in the journal The Oncologist enrolled 19 patients with EGFR mutation positive stage IIIA NSCLC and treated with neoadjuvant erlotinib for 56 days. Tumor response rate was 42.1% and resection rate was 68.4%. Only 5 of the 14 patients (35.7%) with surgical resection had documented pathologic downstaging from N2 to N0/N1 disease. The median PFS and OS was 11.2 and 51.6 months respectively. CTONG 1103 is the first and only randomized comparative study that confirmed the feasibility and efficacy of neo-adjuvant EGFR TKI. Tumor response rate is higher than chemotherapy by 20% although not statistically significant, but toxicity profile is better, which is an established fact from multiple phase III studies on advanced stage disease. The resection rates were similar between the two arms but it was unclear how many of the enrolled patients had unresectable disease prior to neo-adjuvant therapy. Key objectives of neo-adjuvant therapy are to down-stage tumor/nodal disease and to improve resectability. This randomized study may potentially document if erlotinib is more capable of converting unresectable stage IIIA disease to being resectable, however, this data is not currently available.   The authors of the current study have also reported improvement in progression free survival, but we cannot conclude that the improvement is solely due to the neo-adjuvant therapy. As per study protocol, patients from neo-adjuvant EGFR TKI arm did receive 12 months of erlotinib as adjuvant therapy while the chemotherapy arm received only 2 more cycles of similar treatment. Considering the duration of therapy, the adjuvant erlotinib may in fact  contribute more to prolongation of progression free survival than the neo-adjuvant therapy. In 2017 in the journal Lancet Oncology, the same group of investigators have reported a randomized phase III study comparing adjuvant gefitinib with chemotherapy and the median disease free survival was 28.7 months and 18.0 months, respectively. All patients enrolled in this study had resectable lung cancer with over 60% of patients having N2 disease, and the authors had concluded on the potential survival advantage of adjuvant EGFR TKI. Thus, the improvement in progression free survival should be explained by both neo-adjuvant and adjuvant erlotinib.   In summary, CTONG 1103 is a negative study but it has significant impact on management of stage IIIA EGFR mutation positive lung cancer. With high screening failure rate at 80%, it took the authors 6 years to enroll 72 patients. This study will remain the only randomized study on this patient group for a long time as similar  large scale phase III trials of this strategy will be unlikely. Clinicians are obligated to share and explain CTONG 1103 to patient with stage IIIA EGFR mutation positive lung cancer. For patients with resectable disease at presentation, the benefit of neo-adjuvant EGFR TKI may be debatable. But for patients with un-resectable stage IIIA disease, neo-adjuvant EGFR TKI may potentially downstage the disease status and facilitate resection.     This concludes this JCO podcast. Thank you for listening.

Go online to PeerView.com/GPR860 to view the entire programme with slides. In this activity, an expert in oncology discusses the evolving evidence on molecular testing and treatment of EGFR mutation-positive NSCLC, including new data from real-world studies, and provides practical guidance for nuanced, individualized decision-making related to selection and sequencing of EGFR-targeted therapies throughout the continuum of advanced NSCLC. Upon completion of this activity, participants will be able to: Review the current understanding of the biology of EGFR mutation-based heterogeneity in NSCLC and the clinical roles of EGFR TKIs in the newly diagnosed setting, Assess mechanisms of acquired resistance to EGFR TKIs and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation-positive NSCLC, Discuss real-world evidence on the efficacy and safety of EGFR TKIs and its impact on long-term treatment planning for patients with advanced NSCLC exhibiting EGFR mutations, Employ effective strategies to prevent, mitigate, and manage adverse effects of EGFR TKI therapy to optimize patient outcomes.

Dr. Jack West reviews the results of the ARCHER-1050 trial that showed superior efficacy with dacomitinib vs. gefitinib in EGFR mutation-positive NSCLC. Is it too little, too late for dacomitinib, or can it find a place in a crowded first line setting?

Dr. Jack West summarizes the likely practice-changing results of the FLAURA trial of osimertinib vs. standard of care EGFR TKI therapy (gefitinib or erlotinib) as first line treatment for patients with EGFR mutation-positive NSCLC.

Dr. Greg Riely, medical oncologist from MSKCC, discusses the controversial question of whether patients should continue on an oral EGFR tyrosine kinase inhibitor after progression.

Dr. Greg Riely, medical oncologist from MSKCC, discusses the controversial question of whether patients should continue on an oral EGFR tyrosine kinase inhibitor after progression.

Dr. Greg Riely, medical oncologist from MSKCC, discusses the controversial question of whether patients should continue on an oral EGFR tyrosine kinase inhibitor after progression.

Dr. Jack West, medical oncologist, reviews evidence in favor of adding Avastin (bevacizumab) to the EGFR inhibitor Tarceva (erlotinib) for patients with lung cancer that harbors an activating EGFR mutation.

Dr. Jack West, medical oncologist, reviews evidence in favor of adding Avastin (bevacizumab) to the EGFR inhibitor Tarceva (erlotinib) for patients with lung cancer that harbors an activating EGFR mutation.

Dr. Jack West, medical oncologist, reviews evidence in favor of adding Avastin (bevacizumab) to the EGFR inhibitor Tarceva (erlotinib) for patients with lung cancer that harbors an activating EGFR mutation.

Case-based discussion with multiple lung cancer experts on optimal treatment of a patient with advanced lung adenocarcinoma, EGFR mutation, & now acquired resistance to EGFR TKI after very good prior response.

Case-based discussion with multiple lung cancer experts on optimal treatment of a patient with advanced lung adenocarcinoma, EGFR mutation, & now acquired resistance to EGFR TKI after very good prior response.

Dr. Lecia Sequist of Massachusetts General Hospital answers questions about acquired resistance to EGFR tyrosine kinase inhibitors and repeat biopsies of tumors over the course of treatment for advanced NSCLC.

Dr. Lecia Sequist of Massachusetts General Hospital answers questions about acquired resistance to EGFR tyrosine kinase inhibitors and repeat biopsies of tumors over the course of treatment for advanced NSCLC.