Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2022.2 Part 2

Dr. Dwight Owen presents the first update to the ASCO living guideline on stage IV NSCLC with driver alterations. He identifies the latest trials that informed this update, and the updated evidence-based options for second- or later-line therapies for patients with advanced non-small cell lung cancer and an activating HER2 mutation or a KRAS-G12C mutation. Additionally, he provides important context on the reported toxicities associated with these therapeutics. Read the update, “Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2“ 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 Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. 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.' Today, Dr. Dwight Owen from Ohio State University in Columbus, Ohio, is joining us again to discuss the updates for therapy for stage IV non-small cell lung cancer with driver alterations, as the lead author on, 'Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, version 2022.2.' Thank you for being here, Dr. Owen. Dr. Dwight Owen: Thanks for having me. Brittany Harvey: First, I'd like to note the 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 full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Owen, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Dwight Owen: Yeah, thanks for asking that really important question. My institution has received research funding for me to conduct clinical trials from Merck, BMS, Pfizer, and Genentech and Palobiofarma. I have no employment, stocks, stock options, or other disclosures to declare. Brittany Harvey: Thank you for those disclosures. Then getting into the content of this update, this is the first update to the living clinical practice guideline for systemic therapy for patients with stage IV non-small-cell lung cancer with driver alterations. What new studies were reviewed by the panel to prompt an update to this guideline? Dr. Dwight Owen: Thanks for that question. This is a particularly exciting update because as we were preparing for this update, reviewing two manuscripts that we think offer new options for our patients with driver alterations, there were actually updated presentations at a recent meeting that showed us even more data for these targets. So, it's really an ongoing and dynamic place. So, we really focused on two updates; one was for KRAS-G12C alterations, and then one was for HER2 alteration-positive non-small cell lung cancer. So, I'll take them one at a time; for KRAS-G12C, we included an updated recommendation based on the CodeBreak 100 study - this was a multi-center, single group, open-label, phase II study of sotorasib, which is a KRAS-G12C inhibitor, in patients with non-small cell lung cancer positive for KRAS-G12C, who had received prior systemic therapy that could either be with chemotherapy or immune therapy, and the majority of patients had received both. 124 patients were evaluable for response, and the objective response rate was 37%, with the impressive median overall survival of over 12 months, of 12.5 months, specifically. Now, there were some notable toxicities. There's GI toxicities such as diarrhea and nausea, as well as some elevations in LFTs. We also heard recently at ESMO about CodeBreak 200, which was a randomized study of sotorasib compared to docetaxel in previously treated patients with KRAS-G12C non-small cell lung cancer. And that study did meet its primary endpoint of improvement in PFS for sotorasib-treated patients compared to docetaxel, and we are very much looking forward to seeing that final publication. For HER2 alteration-positive non-small cell lung cancer, we really focused our efforts on DESTINY-Lung01. Now, this was a multi-center, multinational, open-label, phase II study evaluating trastuzumab deruxtecan in patients with previously treated HER2-positive non-small cell lung cancer. In this study, 91 patients were evaluable for response, and 50, which was 55%, had a confirmed objective response, and the median survival was presented at 17.8 months. A pretty unique toxicity was observed here. So, drug-related interstitial lung disease or pneumonitis occurred in just over a quarter of patients, and there were two deaths related to this. So, this needs to certainly be monitored for. Also at ESMO, we heard results for DESTINY-Lung02, which was a multi-center, multi cohort, randomized blinded study, which was also a dose optimization study. And this study eventually led to the accelerated approval of the 5.4 milligrams per kilogram dose that seemed to be just as effective as other doses, but perhaps with less toxicity. Again, we're currently awaiting the final publication of DESTINY-Lung02. However, these results are particularly impressive and especially leading to the FDA accelerated approval for a new treatment option for our patients with HER2 alteration positive non-small cell lung cancer. Brittany Harvey: I appreciate you reviewing that data and the new updates for both of these drugs and targets in this population. So then, I'd like to review the recommendations that the panel updated for our listeners. First, what is the new recommendation for patients with advanced non-small cell lung cancer and in activating HER2 mutation? Dr. Dwight Owen: So currently, these patients should continue to receive standard first-line treatment as we do not have head-to-head trials for HER2-directed therapy in the first line. However, for patients who have previously received systemic therapy and have a HER2-activating mutation, trastuzumab deruxtecan certainly should be offered to these patients. Brittany Harvey: Understood. And then the second category of patients that you identified, what does the expert panel recommend for patients with advanced non-small cell lung cancer and a KRAS-G12C mutation? Dr. Dwight Owen: So, similarly, these patients should continue to receive standard first-line treatment, as we do not have head-to-head trials for KRAS-directed therapy in the first line. However, for patients who have previously received systemic therapy and have a KRAS-G12C mutation, sotorasib can be offered as a subsequent therapy. Keep in mind that this is only approved in patients with the KRAS-G12C mutation, and not other KRAS alterations. Brittany Harvey: Thank you for reviewing those two recommendations for second or later-line therapies. What should clinicians know as they implement these updated recommendations? Dr. Dwight Owen: So, I think what we're really excited about is that both of these agents offer new treatment options for patients who historically did not have a personalized targeted treatment option. We are awaiting publication of additional studies to help interpret these data, but for now, clinicians should discuss these treatment options with their patients, and also keep in mind the pattern of toxicities that seem to be unique to each treatment. Brittany Harvey: Great. And then, you've just addressed some of this in your last response, but what does this change mean for patients with stage IV non-small lung cancer with a HER2 or KRAS-G12C mutation? Dr. Dwight Owen: I think the bottom line is that our patients for whom their cancer does not respond, or where it progresses after first-line treatment, will now have additional effective and approved treatment options that are really tailored to the unique characteristics of their tumor and cancer cells. Brittany Harvey: Absolutely. It's great to have new options for patients in this field. So then finally, are there future research developments that the panel is considering for future living guideline updates? Dr. Dwight Owen: So, we're particularly looking forward to the final publication of the studies that were recently presented, including the CodeBreak 200, and DESTINY-Lung02 trials. There are multiple ongoing studies for additional targets, including in the targets that we talked about; so, KRAS-G12C as well as HER2, as well as a number of other targeted options that may benefit subsets of our patients with metastatic non-small cell lung cancer. Brittany Harvey: Great. Well, I appreciate you reviewing all this data and the updated recommendations, and thank you for your time today, Dr. Owen. Dr. Dwight Owen: Thanks for having me. Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/thoracic-cancer-guidelines.  There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer without driver alterations, available there and in the JCO. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes, 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. 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