Dr. Natash Leighl and Dr. Jyoti Patel are back on the podcast to discuss the update to the living guideline on stage IV NSCLC with driver alterations. This guideline includes recommendations for first-, second-, and subsequent-line therapy for patients with driver alterations including: EGFR, ALK, ROS1, BRAFV600E, MET exon skipping mutation, RET rearrangement, NTRK rearrangement, HER2, and KRAS G12C. They highlight the key changes to the recommendations, addition of recent trials, the importance of biomarker testing, and the impact of this guideline for clinicians and patients living with advanced NSCLC. 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 2023.3" 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.23.02744. 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 am interviewing Dr. Jyoti Patel and Dr. Natasha Leighl, co-chairs on "Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3." Thank you for being here, Dr. Patel and Dr. Leighl. And before we discuss this guideline, I would 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 and Dr. Leighl, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So, to start us off on this living clinical practice guideline, Dr. Leighl, this guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being routinely updated. What new data was reviewed in this full update to the living guideline? Dr. Natasha Leighl: Thanks so much, Brittany. So, we looked through the literature for publications between February and the end of October 2023, and also any novel agents that were approved, in particular by the United States FDA, to really incorporate this update in the current guidelines. In particular, we had updates in EGFR-driven tumors, BRAF and RET-driven tumors. And we also worked very hard to make this more digestible. In particular, it was turning into a bit of a laundry list of all of the things that we had ever recommended. So we really wanted to shorten things, pare them down, and really make them helpful and very, very current for the treatment of people with lung cancer in 2023 and 2024. Brittany Harvey: Excellent. Thank you for providing that overview of the evidence reviewed and the key updates that we will address in this guideline. So then I would like to talk about some of those key updated recommendations from the expert panel. You mentioned both EGFR, BRAF, and RET. So starting with patients with stage IV non-small cell lung cancer with EGFR alterations, Dr. Leighl, what are the key changes to those recommendations? Dr. Natasha Leighl: So, as I said, we really started to get quite a long list of things we recommended, including drugs that, to be honest, we no longer think are what we should lead with first-line. So we updated the recommendation to recommend first-line osimertinib in patients with sensitizing mutations. We were also able to capture in this update for patients with EGFR exon 20 insertion mutant lung cancer, the data from the randomized PAPILLON trial, recommending amivantamab plus chemotherapy for progression-free survival benefit. Not yet an overall survival benefit, but we will see how these data mature. The other thing that we did was we moved all of the- I don't want to call them "legacy agents" because, in many countries, these are still very important. But older agents such as gefitinib, approaches such as gefitinib plus chemotherapy, and drugs like dacomitinib and other agents where we truly believe as an international panel that we would prefer a third-generation kinase inhibitor like osimertinib. We moved all of those to our discussion, just to recognize that, around the world, not everybody may have access. And we also specified that things are different in different countries. So, for example, in China, there are other third-generation kinase inhibitors with randomized data to support their use. And those are approved and used in China. And also, for example, in Korea, there are other agents that are used. So, we have really tried to be both inclusive and yet keep things simple at the same time. And hopefully, we have succeeded. One of the challenges was that, with all of the updates that we made, we did not have all of the publications out yet at the end of October to make recommendations about moving beyond osimertinib in the first-line setting. So, please stay tuned for the next guideline update, where we're going to tackle whether we should give osimertinib alone or combination therapy. Brittany Harvey: Excellent. Thank you for providing those updates and clarifications for those patients with non-small cell lung cancer and an EGFR alteration. And we will look forward to the guideline panel's review of that evidence and future updates as well. So then, Dr. Leighl, you had previously mentioned that additional recommendations were updated, such as those for patients with BRAF alterations and RET alterations. So, Dr. Patel, what are the other key updated recommendations from the expert panel? Dr. Jyoti Patel: Thanks so much, Brittany. So certainly, I think we have seen many of these trials mature over time, which has been fantastic. I think one remarkable achievement was the reporting of a phase III selpercatinib trial. This was a trial in the front-line setting, in which patients who were RET-positive were randomized to selpercatinib versus carboplatin-based chemotherapy. And the selpercatinib significantly outperformed platinum-based chemotherapy, and I think really demonstrated a significant improvement in progression-free survival. So, based on that phase III trial, the recommendation for selpercatinib was elevated. Many of these agents that are used in clinical practice are approved initially on smaller phase I or phase II trials. And so, seeing the maturity of these phase III trials gives clinicians and patients greater certainty that these agents are really effective. And so, the evidence was increased for that, and that's now a preferred agent over another TKI, pralsetinib, in which there is only phase II data. So, certainly, those kinds of real things that we can explain to patients are important in these guidelines. Another thing that we were able to update was another doublet for BRAF V600E non-small cell lung cancer. So, the combination of the two TKIs, encorafenib and binimetinib, was also included in the guidelines. One thing that we tried to help was really identifying the best therapy post-progression on these first-generation TKIs. And again, there is a paucity of data, but often we went back to carboplatin-based doublets, and there is some data regarding whether or not patients with driver alterations should get immunotherapy in the second-line setting. And so, certainly, I think we have a number of randomized studies for patients with classical EGFR mutations, and our recommendation is generally avoidance of immunotherapy for these patients and treating many of these patients with carboplatin and pemetrexed when appropriate. I do not think we have the data for a lot of other subsets of patients. So, again, stay tuned as these data evolve. Brittany Harvey: Thank you for reviewing those updated recommendations and the supporting evidence. I think it's helpful for our listeners to understand the level of evidence behind these recommendations as well. So then, Dr. Leighl, what should clinicians know as they implement these new and updated recommendations? Dr. Natasha Leighl: It's really important, first of all, to make sure that you have the information that you need to get your patients to these great new treatments as part of the shared decision-making process. So your patients need biomarker testing. You need to get that as quickly as you can. As Dr. Patel has highlighted, you really want to get that before they start their first-line therapy, if at all possible. We also really tried to bring out in this guideline that when things are delayed, I mean, this is the real world that we live in, just to be very cautious of immunotherapy with chemotherapy for that first cycle. That obviously, again, is a discussion with your patient, but this concept that the approach of a cycle of chemotherapy while you wait for the next-generation sequencing testing. And then if the patient does not have a driver alteration, adding any other therapy as appropriate is okay. It's something that people do. We believe it's important as we talk about the balance between benefits and harms. And so I think that's in there for clinicians, and I hope that they and patients can really benefit from that to avoid toxicity and also to really improve the ability to get molecular testing results first line. Also, I think it's really important that when people read the wording of the guidelines, that this really follows GRADE, which is a type of system that we use to develop our recommen
