Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline (Part 2)

An interview with Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, MI, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline." Dr. Jaiyesimi and Dr. Robinson review the latest recommendation updates for therapeutic options for patients with stage IV NSCLC with ALK rearrangement or RET rearrangement. They also discuss new agents on the horizon. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.   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 today I'm interviewing Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, Michigan, and Dr. Andrew Robinson from Kingston General Hospital at Queen's University in Ontario, Canada, authors on 'Therapy for Stage IV Non-small Cell Lung Cancer with Driver Alterations: ASCO Guideline Update'. Thank you for being here, Dr. Jaiyesimi and Dr. Robinson. Dr. Ishmael Jaiyesimi: Thank you. Dr. Andrew Robinson: It’s a pleasure to be here. Brittany Harvey: Great! First, 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 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. Jaiyesimi, do you have any relevant disclosures that are directly related to this guideline? Dr. Ishmael Jaiyesimi: None. Brittany Harvey: Thank you. And, Dr. Robinson, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Andrew Robinson: Yes, I have received funding less than $5,000 from AstraZeneca, Merck, and BMS over the past two years. Brittany Harvey: I appreciate those disclosures. So, then Dr. Jaiyesimi, let's talk about the purpose of this guideline. So, what is the purpose of this guideline update, and what clinical scenarios does this guideline address? Dr. Ishmael Jaiyesimi: The purpose of therapy for stage IV non-small cell lung cancer with driver alterations, is to rapidly update the ASCO and Ontario Health guideline on the systemic treatment of patients with stage IV non-small cell lung cancer, last published in February of 2021. The update is a result of potentially practice-changing evidence published since the last publication in February 2021. The update is based on two clinical trials from 2020 to 2021. The clinical scenario this guideline covers are stage IV non-small cell lung cancer with driver alteration with an ALK gene rearrangement and RET gene rearrangements. Brittany Harvey: Great. So, then let's review those two clinical scenarios that you just mentioned. So, there are a few new recommendations regarding ALK rearrangement. So, what are the recommended first-line options for patients with stage 4 non-small cell lung cancer in an ALK rearrangement? Dr. Ishmael Jaiyesimi: In the previous guideline alectinib or brigatinib were recommended as first-line therapy with a strong recommendation and level of evidence in patients with ALK gene rearrangement, and a performance status of zero to two. In the current update, lorlatinib was cited as the first-line ALK inhibitor that may be offered as an alternative first-line therapy. If alectinib, brigatinib, or lorlatinib are not available, ceritinib or crizotinib should be offered. This is based on the CROWN study that showed alectinib was superior to crizotinib in the first-line setting. Unfortunately, we don't have head-to-head comparative data with alectinib or brigatinib, so we cannot conclude that any one treatment is more effective than the other, and decisions should be made on experience, toxicity, and on. Brittany Harvey: Okay, thank you for describing how a clinician should select between those treatments as well. So, then the second clinical scenario that Dr. Jaiyesimi just mentioned, Dr. Robinson, what is recommended for both first-line and second-line treatment for patients with stage IV non-small cell lung cancer and a RET rearrangement. Dr. Andrew Robinson: Thank you. So, for patients with a RET rearrangement and a good performance status of zero to two and previously untreated non-small cell lung cancer, clinicians may offer selpercatinib or pralsetinib as first-line therapy. Selpercatinib was recommended in the 2020 guidelines and pralsetinib has been added to that. As with other driver mutation recommendations for scenarios where randomized studies against standard non-driver mutation treatments have not been done or completed, these recommendations are with a lower level of evidence and somewhat weaker recommendations, an alternative approach of first-line standard non-driver mutation treatment may also be offered. As a guideline group, we listed this approach of non-driver treatment behind the targeted therapies, because there's a belief that the targeted approach may be superior upfront. But we should also continue to, of course, encourage participation in ongoing trials comparing selpercatinib or pralsetinib to standard first-line non-driver mutation treatment to determine whether our assumptions are correct. For patients with a RET rearrangement who've had previous RET targeted therapy, clinicians may offer treatment as per the non-driver mutation guidelines. And for patients with a RET rearrangement who have had previous chemotherapy, chemoimmunotherapy, clinicians may offer selpercatinib or pralsetinib for them. Brittany Harvey: Okay. And then you've just mentioned some ongoing trials as well. So, that leads to my next question of what ongoing trials and new agents is the panel monitoring for the next guideline iteration? Dr. Andrew Robinson: It's really an exciting time with new agents on trials and I think we can divide it into more driver mutations, more lines of therapy, and more certainty with what we're doing. In terms of driver mutations, there are several phase II and III trials with agents such as sotorasib and adagrasib in KRAS-G12C mutated non-small cell lung cancer, trastuzumab deruxtecan in the DESTINY trials in HER-2 mutated lung cancer, mobicertinib and amivantamab in EGFR, exon 20 insertion lung cancer or HER-2 exon 20 insertion lung cancer, etc. So, looking at more driver mutations is all of those agents plus a number of others that will be coming out over the next couple of years at ASCO. We're also interested in more lines of therapy. So, for patients who progress after standard first-line, say osimertinib with EGFR or after progression on ALK therapies such as lorlatinib. So, we're looking forward to studies such as the CHRYSALIS studies of amivantamab and lazertinib in EGFR mutation-positive patients who have progressed after osimertinib, and other studies that are looking at the increasing treatment options for second-line treatment and third-line treatment. And then we're looking at interest to phase three studies that are comparing targeted agents to docetaxel in the second-line setting such as the sotorasib studies in KRAS-G12C patients and capmatinib and MET exon 14 patients, particularly as many of these patients may do well with non-driver mutated guided first-line treatment. There are phase three trials comparing RET inhibitors to standard first-line chemoimmunotherapy which will also be keenly awaited to see if our, and when I say our, I mean, the ASCO guideline panel and also the thoracic oncology community writ large, our assumption that targeted therapy will be superior to first-line therapy is actually borne out with clinical trial evidence. So, there's plenty of evidence that we're excited to keep our eye on and update as soon as possible, which is more driver mutations, more lines of therapy for patients who have established driver mutations, and more certainty, hopefully, regarding the timing of these various interventions. Brittany Harvey: Definitely, there's a lot going on in this space. So, we'll look forward to the results from these ongoing trials and the panel's review of that evidence, and eventually updated recommendations. So, then Dr. Jaiyesimi, in your view, why is this guideline update important and how will it impact practice? Dr. Ishmael Jaiyesimi: This guideline is important because it emphasizes rapid development in the research and treatment in advanced non-small cell lung cancer and that non-small cell lung cancer are heterogeneous. Clinicians need to identify biomarkers of the molecular pathways, including targetable driver mutations, example: epidermal growth factor receptors, the BRAF, the MET, the KRAS, and etcetera, and fusion rearrangement, example: anaplastic lymphoma kinase, c-ROS oncogene 1, RET, and on that drive malignancy in patients with non-small cell lung cancer, especially in those patients with adenocarcinoma histology and a little or never smoking history regardless of histology. Because of the availability of effective targeted agent for many of these cancers, at minimum, determination of epidermal growth factor receptor mutation status and anaplastic lymphoma kinase rearrangement status before initiating therapy because rapid and sensitive tests are available. An initiation of immunotherapy could increase the toxicity of tyrosine kinase inhibitors later in the patient’s course. All this, in my opinion, will impact clinical practice. Furthermore, an opportunity for patients with driver mutation to enrolled in ongoing clinical trials targeting the driver mutations. Brittany Harvey: Yes. You've just mentioned that this is not a one size fits all approach for patients. And so, in your view, Dr. Jaiyesimi, how do these guideline recommendations affect patients living with stage IV non-small cell lung cancer with driver alterations? Dr. Ishmael Jaeysimi: I believe along with my associates the improvement in the treatment of stage IV non-small cell lung cancer brings hope to the patient with driver alteration for a possibility to use targeted therapy and no chemotherapy or immunotherapy upfront to some patients and this may enhance their lives, increase longevity with some tolerable side effects, and better quality of life, and a truly wide range of opportunities for patients to participate in clinical trials. Brittany Harvey: Great! Yes, it seems like the data has come fast, and a lot of new results of recent trials have driven these updated recommendations and we're also looking forward to many of the results from upcoming clinical trials that you both mentioned. So, I want to thank you so much for your work on these guideline updates, and thank you for taking the time to speak with me today, Dr. Jaiyesimi and Dr. Robinson. Dr. Ishmael Jaiyesimi: Thank you, Brittany. Dr. Andrew Robsinson: It was a pleasure to be here and I hope that this was educational. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline go to www.asco.org/thoracic-cancer-guidelines. There's a companion guideline update on therapy for stage IV non-small cell lung cancer without driver alterations available there and on 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. 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.