Dr. Jyoti Patel discusses the latest update to the stage IV NSCLC with driver alterations living guideline, specifically for patients with EGFR or ROS1 alterations. She shares the latest recommendations based on recently published evidence, such as the FLAURA2, MARIPOSA-2, and TRIDENT-1 trials. Dr. Patel talks about how to choose between these new options and the impact for patients living with stage IV NSCLC, as well as novel drugs the panel is monitoring for future guideline updates.

Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1" at www.asco.org/living-guidelines.

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 in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00762

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. Jyoti Patel from Northwestern University, co-chair on, "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1."

Thank you for being here today, Dr. Patel.

Dr. Jyoti Patel: Thanks so much.

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. Patel, who has 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 then to dive into the content of why we're here today, Dr. Patel, this living clinical practice guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being updated on a regular basis. So what prompted the update to the recommendations in this latest update?

Dr. Jyoti Patel: This recent update, I think, absolutely reflects how quickly the science is changing. The landscape of treatment options for patients with advanced non-small cell lung cancer is evolving so rapidly, and guidelines from even six months ago don't address some of the newest approvals and newest data and the newest clinical scenarios that we're presented with when we see patients. I think it's harder because before there was usually a single answer, and now there are a number of scenarios, and we hope that the guideline addresses this.

Brittany Harvey: Absolutely. The panel's had a lot of data to review as you keep this guideline up to date.

So then this latest update addresses updates to both EGFR and ROS1 alterations. So starting with EGFR, what are the updated recommendations for patients with stage four non-small cell lung cancer and an EGFR exon 19 deletion or exon 21 L858R substitution?

Dr. Jyoti Patel: So for patients with classical driver mutations in EGFR, our recommendation remains that patients should be offered osimertinib. We now also have data to support intensification of therapy with osimertinib and chemotherapy. The FLAURA2 trial was a global randomized study in which patients with classical mutations were assigned to receive either osimertinib or osimertinib with doublet chemotherapy. The trial showed that progression free survival was longer with osimertinib plus chemotherapy with a hazard ratio that was pretty profound, 0.62. In patients who had CNS metastasis as well as patients with L858R mutations, this benefit remained and was perhaps even greater. Now the study remains immature in terms of OS. What we can say is that chemotherapy adds toxicity, so the inconvenience of 13 weekly infusions, expected toxicities from chemotherapy of myelosuppression and fatigue. I think this- we'll continue to watch as the study matures to really see the OS benefit, but certainly intensification in the frontline setting is an option for patients.

The other major update was for second and subsequent line therapy for these patients with EGFR mutations. Another important trial, a study called MARIPOSA-2, was published in the interim, and this was for patients who had received osimertinib in the frontline setting. Patients were randomized to one of three arms. The two arms that are most relevant for us to discuss are chemotherapy with amivantamab or chemotherapy alone. Chemotherapy with amivantamab was associated with an improvement in progression free survival with a hazard ratio of 0.48 as well as improvements in response rate with almost a doubling of response rate to the mid 60%. There was certainly an increase in AEs associated with amivantamab, primarily rash and lower extremity edema and importantly infusion reaction. Based on this data, though in the superior PFS and response rate, we've said that patients after osimertinib should be offered chemotherapy plus amivantamab. Patients may opt for chemotherapy alone because of the toxicity profile, but this recent update is reflective of that data.

Brittany Harvey: Excellent. Thank you for reviewing those updated recommendations and the supporting evidence behind those recommendations. I think that's important to the nuance and the toxicity associated with these new recommendations as well.

So then, following those recommendations, what are the updated recommendations for patients with stage four non-small cell lung cancer and a ROS1 rearrangement?

Dr. Jyoti Patel: ROS1 fusions have been noted in a small but important subset of patients. We now reflect multiple new options for patients. Traditionally, crizotinib was the primary drug that was recommended, but we now have two very active drugs, repotrectinib, and entrectinib, that have both been FDA approved. Repotrectinib was approved based on a study called the TRIDENT-1 trial. In this study, patients who were treatment naive, who had not received a prior TKI, had a response rate of 79% and a long duration of response over 34 months. For patients who had received prior TKIs, so primarily crizotinib, the response rate was lower at 38%. But again, very clinically meaningful. Repotrectinib has known CNS activity, so it would be the favored drug over crizotinib, which doesn't have CNS penetration. The decision between entrectinib and repotrectinib is one, I think, based on toxicity. Repotrectinib can cause things like dizziness and hypotension. Entrectinib can cause weight gain, and also has CNS effects.

Brittany Harvey: Appreciate you reviewing those recommendations as well.

So then you've already talked a little bit about this in terms of deciding between some of the options. But in your view, what should clinicians know as they implement these new recommendations, and how do these new recommendations fit into the previous recommendations?

Dr. Jyoti Patel: So there's an onslaught of new data, and certainly many of us want to remain at the front of our fields and prescribe the newest drug, our most effective drug, to all of our patients. But for the person living with cancer and in the practice of medicine, I think it's much more nuanced than that. For example, for a patient with an EGFR mutation exon deletion 19, the expectation is that osimertinib will have a deep and durable response. Certainly a patient will eventually have progression. I think the decision about intensification of therapy and chemotherapy on the onset really has to do with how much the patient is willing to deal with the inconvenience of ongoing chemotherapy, the uncertainty about what comes next after progression on chemotherapy. It may be, though, that a patient may very much fear progressive disease, and so that inconvenience is lessened because anxiety around feeling like they're doing everything for their cancer is diminished by intensification of therapy. Others who may have a large volume of disease or profoundly symptomatic, or who have L858R or brain metastasis it may make sense to give chemotherapy again, we're improving the time until progression significantly by combination therapy.

Brittany Harvey: Definitely those nuances are important as we think about which options that patients should receive, along with shared decision making as well.

So then what do these new options mean for patients with EGFR or ROS1 alterations?

Dr. Jyoti Patel: It's fantastic for patients that there are multiple options. It's also really hard for patients that there are multiple options, because then again, we have to really clarify aims of therapy, identify what's really important in patient experience and the lived importance of treatment delivery and the burden of treatment delivery. Now more than ever, oncologists have to know what's new and exciting. But patients have to be willing to ask and participate in the shared decision making - understanding their cancer and understanding that their options are absolutely important. As patients start making their decisions, we have the data just in terms of trial outcomes. I think we're now trying to understand the burden of treatment for patients. And so that piece of communicating financial toxicity, long term cumulative lower grade toxicity is going to be more important than ever.

Brittany Harvey: Absolutely. It's great to have these new options, and those elements of communication are key to ensuring that patients meet their goals of care.

So then finally, as this is a living guideline, what ongoing research is the panel monitoring for future updates to these recommendations for patients with stage four non-small cell lung cancer with driver alterations?

Dr. Jyoti Patel: It's certainly been an exciting time, and that's primarily because we've been able to build on years of foundational science and we have new drugs. Patients have been willing to volunteer to go on clinical trials and to think about what treatment options may be best. Now, the work really comes on seeing the longer term outcomes from these trials. So looking at these trials for overall survival, we want to also better identify which patients will benefit the most from these treatments and so that might be additional biomarker analysis. So it may be that we can identify patients that may need intensification of therapy based on tumor factors as well as patient factors as well in those patients in whom we can de-escalate treatment. I think there are a number of new compounds that are in the pipeline. So fourth generation EGFR TKIs are certainly interesting. They may be able to overcome resistance for a subset of patients who progress on osimertinib. We also think about novel drugs such as antibody drug conjugates and how they'll fit into our paradigm with osimertinib or after carboplatin-based doublets.

Brittany Harvey: Definitely. We'll look forward to both longer term readouts from the current trials and new trials in this field to look at additional options for patients.

So I want to thank you so much for your time today, Dr. Patel, and thank you for all of your work to keep this living guideline up to date.

Dr. Jyoti Patel: Great. Thanks so much, Brittany. It really is an exciting time for people who treat lung cancer and for patients who have lung cancer. We certainly have a long way to go, but certainly the rapid uptake of these guidelines reflect the progress that's being made.

Brittany Harvey: Absolutely. And just a final 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, 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.

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