Dr. Dwight Owen is back on the ASCO Guidelines podcast, discussing the latest updates to the ASCO living guidelines for stage IV NSCLC. In Part 2, Dr. Owen presents the update for stage IV NSCLC with driver alterations. He reviews new evidence from KRYSTAL-1, and reviews a new recommended option for patients with stage IV NSCLC with a KRAS G12C mutation, adagrasib. Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.1” and view all recommendations at www.asco.org/living-guidelines. Listen to Part 1 for recommendations for patients with stage IV NSCLC without driver alterations. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00281  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 in our last episode, we addressed the living guideline updates for therapy for stage IV non-small-cell lung cancer without driver alterations. Dr. Dwight Owen from Ohio State University in Columbus, Ohio, has joined us again to discuss the updates for therapy for stage IV non-small-cell lung cancer with driver alterations, as a co-chair on ‘Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.1’.  Thank you for joining us again, Dr. Owen. Dr. Dwight Owen: Thanks for having me, Brittany. Brittany Harvey: Then, before we discuss this update, I'd just 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. Owen, who's joined us on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology linked in the show notes.   So then, jumping into the content here, this living clinical practice guideline for systemic therapy for stage IV non-small-cell lung cancer with driver alterations is being routinely updated. What new studies were reviewed by the panel to prompt an update to the recommendations?  Dr. Dwight Owen: Yeah. Thank you, Brittany. For this update, the panel and committee felt that it was important to review the KRYSTAL-1 trial. This was a phase I/II open-label study of adagrasib in patients with KRAS G12C mutation-positive solid tumors, which included multiple expansion cohorts, including a cohort of patients with non-small cell lung cancer. Importantly, the data that was presented in this recent publication included only patients treated at the phase II dose of 600 milligrams twice daily. The study included 160 patients with a primary endpoint of a response rate, which was evaluated in 112 of those patients. The confirmed response rate was 43%, including one complete response, with the remaining being partial responses. The median progression-free survival was six and a half months, and the median overall survival for this pretreated patient population was approaching one year.  One thing of note is we saw similar toxicities as we have seen with other KRAS G12C inhibitors, which included predominantly GI side effects such as diarrhea, nausea, vomiting, but also hepatic side effects including transaminitis, some renal dysfunction as well. Dose interruption was common in over 60% of patients, and dose reduction was required in over half of patients. Overall, given the efficacy seen in this cohort, again, even though it was a phase I/II trial, it was a substantial number of pat