Therapy for Stage IV NSCLC Without Drive...

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 I'd like to welcome back Dr. Dwight Owen from Ohio State University in Columbus, Ohio, co-chair on 'Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline Version 2023.1'.  

Thank you for being here, Dr. Owen.

Dr. Dwight Owen: Thanks for having me, Brittany.

Brittany Harvey: Then, before we discuss this update, 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. Owen on this episode, are available online, with a publication of the guideline in the Journal of Clinical Oncology linked in the show notes.  

So then, diving into this update, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is being updated on a regular basis. What was the new evidence identified by the expert panel through routine literature searches to prompt an update to the recommendations?

Dr. Dwight Owen: Yeah. Thanks, Brittany. I think it's really important to point out that these living guidelines are evidence-based. And so, we are constantly reviewing the literature to find new data to support recommendations for treatment options for clinicians to choose for their patients with metastatic non-small cell lung cancer. Clinicians these days, and physicians and oncologists are faced with so much information coming from abstracts to press releases to publications of new clinical trial results that it can be sometimes overwhelming to keep track of all the latest breakthroughs and nuances in the literature for non-small cell lung cancer. 

So for this specific update, the panel and the committee reviewed two papers, including the

EMPOWER Lung-3 Study and the POSEIDON Study. The EMPOWER Lung-3 study was a double-blind, placebo-controlled phase III study investigating cemiplimab plus platinum doublet chemotherapy as the first treatment for patients with either locally advanced stage III or stage IV non-small cell lung cancer without either an EGFR, ALK, or ROS1 alteration. And this is a mode of treatment that we've seen before, which is a PD-1 plus chemotherapy or PD-L1 plus chemotherapy compared to a chemotherapy control. And indeed, we did see an improvement in median overall survival in this study with the addition of cemiplimab to chemotherapy of almost 22 months versus 13 months with the placebo. This was accompanied by a higher rate of grade 3 or higher toxicities. But overall, these data were consistent with what we have seen with other studies of checkpoint inhibitor therapy plus chemotherapy in the first-line setting, which is now the current standard of care. 

The second study we reviewed was the POSEIDON Study, and this was an open-label phase III study of combination checkpoint inhibitors. So this was PD-L1 plus CTLA-4, durvalumab + tremelimumab with chemotherapy versus chemotherapy alone, and these patients were metastatic non-small cell lung cancer without EGFR or ALK alterations. The interesting thing about this study is there was a cohort of patients treated with durvalumab plus chemotherapy alone. But it was really the cohort of patients treated with tremelimumab, durvalumab, and chemotherapy who had a significant improvement in median survival of 14 months versus 11.7 months with chemotherapy alone, with a hazard ratio of 0.77. In this study, the tremelimumab was only given for a total of five cycles, so it was not continued during the maintenance phase with durvalumab, which is a slight difference from other combination checkpoint inhibitor therapies, which are approved based on CheckMate 227 and CheckMate 9LA, which is nivolumab + ipilimumab. 

So, overall, neither of these two studies present a new paradigm of treatment. But they present new treatment options for patients as a first-line treatment for non-small cell lung cancer in the form of either PD1/L1 plus chemotherapy or combined checkpoint inhibitor with a PD-L1 plus CTLA-4 plus chemotherapy, again showing improved survival compared to chemotherapy alone.

Brittany Harvey: I appreciate you reviewing the details of those two trials. So then, based off this new data from the trials that you mentioned, EMPOWER Lung-3 and POSEIDON, what are the updated recommendations from the expert panel?

Dr. Dwight Owen: So we felt it was important to update our prior recommendations for patients, especially with low to intermediate PD-L1 expression from 0% to 49%, that patients may offer cemiplimab plus chemotherapy as an additional treatment option in addition to the recommendations that have already been in place, regardless of histology. And then, based on the POSEIDON data, we felt that this was also a treatment option for those similar patients, especially with PD-L1 negative or up to 49%. 

We do feel that the patients with PD-L1 TPS scores of 50% or higher still seem to benefit the most from checkpoint inhibitor monotherapy and multiple studies that have been done there. And so we did not make any changes to the recommendations for those patients with PD-L1 high non-small cell lung cancer. 

Brittany Harvey: Understood. And then you just mentioned that neither of these therapies represent a paradigm change for treatment options. So what should clinicians know as they consider these new options in addition to previously recommended therapies?

Dr. Dwight Owen: Yes. So I think when clinicians are looking at these studies, things to keep in mind are the size of the study, the cohorts included, the endpoints. The comparison arm, for now, remains chemotherapy alone, which again is no longer the standard of care. So we are sort of looking backwards at a historical standard of care that we no longer really confront other than for patients who have some contraindication to immunotherapy.  

The other thing to keep in mind is, of course, when you add more treatments together, you expect more toxicities. And that is certainly the case when we see the dual combined checkpoint inhibitor therapies plus chemotherapy. Regardless of whether it's nivolumab + ipilimumab and chemotherapy or whether it's durvalumab + tremelimumab plus chemotherapy, we do expect a higher rate of toxicities when we do add the CTLA-4 to the PD1/L1 backbone.  

And so this is a conversation that's really important to have with your patients. We don't have a head-to-head trial, so we are inferring differences in terms of response and benefit using the same comparison of chemotherapy but from different studies and also different populations. So that is probably one of the more important lessons to take from all of these studies is that we know that the toxicity rate does change depending on how you add therapies for these patients. And we also know that there are patients who may not need that additional therapy. So patient selection is key.  

And I think one of the most unmet needs right now is for patients with PD-L1 negative tumors who don't seem to benefit from checkpoint inhibitor monotherapy or even in long term data when checkpoint inhibitor therapy is given just combined with chemotherapy, these patients seem to be the ones who don't benefit as much. And so I think that would be the patient population that really warrants that extra discussion where you may consider a more aggressive treatment depending on a patient's preference in terms of susceptibility, in terms of toxicity.

Brittany Harvey: Absolutely. Considerations of the toxicity profiles of these agents is key for patient quality of life. That leads nicely into my next question, but what do these new recommended therapies mean for patients with stage IV non small cell lung cancer without driver alterations? 

Dr. Dwight Owen: Well, I think, of course, it is beneficial to have more treatment options, but when we have more treatment options, the decision can actually become more challenging because how do you select from any of the treatment options that we have? And in the absence of direct head-to-head trials for now, we really need to look at the toxicity data, look at the outcome data, and see how the patient in front of you fits into the studies that have been done in order to make an inference and to have that informed discussion with the patient about what to expect from a specific treatment.  

And I think the higher rates of immune toxicities that we see when we use combination checkpoint therapy needs to be a discussion with patients, and also the type of chemotherapy backbone and how long that chemotherapy will be continued. Whether it's two cycles like Checkmate 9LA, whether it's four cycles like POSEIDON, whether we have a non-chemotherapy option to offer patients, these are all nuances that right now lead to a really robust conversation with our patients up front. And really trying to guide patients through these discussions because the information can be so overwhelming when it's given at one time. So, really trying to have that meaningful conversation in a way that the patient can help advocate for themselves in the clinical decision-making. 

Brittany Harvey: Definitely, those nuances are important for those individual discussions. So then, finally, you've mentioned that the panel is reviewing literature on an ongoing basis. So, what ongoing developments is this panel monitoring for future updates? 

Dr. Dwight Owen: So, I think all of us are very excited about the announcements that we have been hearing, both in terms of press releases, in terms of abstracts at the upcoming ACR meeting, and of course, ASCO later this year, where we expect to have a wealth of new data for patients with non-small cell lung cancer, both in the metastatic setting but also in the early stage setting. And I think one of the challenges for us in this committee and for practicing oncologists every day is the speed at which this information is coming out and making sure that we have time to really review each study and give each study the time needed to understand how it can impact our treatment selection based on what's already an accepted practice and what maybe is something that we should reconsider. 

And so I think it's very rewarding work to work with the committee members and the panel and ASCO. But it is also something that we take very seriously, just because data can come out so quickly at varying levels of detail. And we really want to make sure that when we make a guideline recommendation, that we are very clear that it is evidence-based and what that evidence is.

Brittany Harvey: Absolutely, we appreciate the panel's evidence-based approach to developing these recommendations. 

So, I want to thank you for your time working on this update and for coming on the podcast to speak with me today, Dr. Owen.

Dr. Dwight Owen: Thanks very much, Brittany. 

Brittany Harvey: And thank you to all of our listeners for tuning into ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/living-guidelines.  There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer with driver alterations available there and in the JCO. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. 

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