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KEYNOTE Trial Data: Pembrolizumab's Role in NSCLC

Panelists: Jack West, MD, Swedish Cancer Institute; Gregory J. Riely, MD, PhD, Memorial Sloan Kettering Cancer Center; Jared Weiss, MD, UNC School of Medicine; Charu Aggarwal, MD, MPH, University of Pennsylvania Hospital
Published: Monday, Jul 23, 2018



Transcript: 

Jack West, MD: Welcome to this OncLive® News Network® presentation, broadcasting live from MJH Studios. Today’s discussion will be focused on “Practice Changes for Metastatic Non–Small Cell Lung Cancer,” specifically the implications of recent data and FDA approvals as far as their application to the clinical management of patients.

I am your host, Dr. Jack West, medical oncologist and medical director of the Thoracic Oncology Program at the Swedish Cancer Institute in Seattle, Washington. Today, I am joined by 3 of my colleagues, who are also experts in lung cancer clinical research: Dr. Charu Aggarwal, assistant professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania; Dr. Greg Riely, medical oncologist from Memorial Sloan Kettering Cancer Center and vice chair of clinical research for the Department of Medicine, in New York, New York; and Dr. Jared Weiss, section chief of Thoracic and Head & Neck Oncology and associate professor at the UNC School of Medicine in Chapel Hill, North Carolina. During the next 60 minutes, we are going to navigate through some of the questions surrounding how we treat patients with metastatic non–small cell lung cancer today. We’ll consider how the most recent clinical trial data will shape the path forward for the busy medical oncologist in community practice. In the last few minutes of the broadcast, we’ll answer some of the questions that were previously submitted by our viewing audience. During the broadcast, we invite you to submit questions to our panel by using the entry field located below this video.

We’ll start with the broad area of the many new trials and flood of new data that came in about treating patients without a driver mutation who have advanced non–small cell lung cancer, either squamous or nonsquamous. And I think at the top of that list, at least as we would have expected going into the season of big meetings, was the KEYNOTE-042 trial. Just to recap that, that was a plenary session presentation, by Dr. Gilberto Lopes, that we knew beforehand was positive for a survival benefit. And this was a trial for patients with advanced non–small cell, squamous or nonsquamous, who had PD-L1 tumor expression of 1% or greater. So that’s about two-thirds of our patients. And it was a direct comparison of pembrolizumab monotherapy to doublet chemotherapy that was histology appropriate. And, of course, we have already had a similar trial, KEYNOTE-024, that came out in late 2016 as highly positive in the subset of patients that was narrower, with a PD-L1 level of 50% or greater. And this was broader to now include the 1% to 49% population.

And we did see that, yes, it was positive for an improvement in overall survival in this broader population. But actually, the results, I would say, were very interesting in that we actually saw that the big benefits were in the patients who we already knew benefit from pembrolizumab monotherapy. The big dramatic benefit with pembrolizumab monotherapy was in the 50% or higher subset, and it diluted progressively as you added the patients with a 20% cutoff or a 1% cutoff. And when you look just at the group of patients with 1% to 49%, there was really no difference. In fact, the hazard ratio was 0.92. And so, you could perhaps argue that you did as well in efficacy and had a better tolerability with pembrolizumab. That comes as no surprise, as we know what to expect for the chemotherapy doublet, we know what pembrolizumab monotherapy does. But I think it was still significant that in the trial design for this, patients who were assigned to the first-line chemotherapy were not permitted to cross over as part of the trial to get pembrolizumab monotherapy second line.

And, in fact, in this global trial, only about 20% of the patients ended up getting immunotherapy subsequently if they started with chemotherapy. And so, I think that is a real detriment and speaks to the difference between how it was performed and how it would be performed in my practice. I think in the United States, we have much better access and an expectation that if you didn’t get it first line and you were ever a candidate for immunotherapy, you’d get it second line. My interpretation is that while it may be permitted to do this in the 1% to 49% population, it’s not the most attractive option for that group. But I think that the big issues are that there are some more compelling options, namely chemotherapy and immunotherapy. We’ll talk about the nonsquamous population and KEYNOTE-189, and we also got some more information in the squamous population as well. So, let’s start with KEYNOTE-189. Greg, can you please just summarize the key points of this? This was not actually from ASCO but still very timely, only coming out a couple of months ago.

Gregory J. Riely, MD, PhD: Right. So, KEYNOTE-189 was presented first at the AACR meeting, but it’s already published in the New England Journal of Medicine. And this was really a key trial looking at the question of, can we combine chemotherapy and immunotherapy? The control arm here was platinum/pemetrexed, so patients were allowed to receive either carboplatin or cisplatin. And then the experimental arm was combining platinum/pemetrexed and immunotherapy, specifically pembrolizumab. And when we look at the outcomes of KEYNOTE-189—regardless of PD-L1 status, regardless of performance status—patients did better if they got pembrolizumab plus chemotherapy rather than chemotherapy alone. I think regardless of how you approach initial therapy with regard to PD-L1 status, if you look at PD-L1 status or don’t, this applies to all from PD-L1 0%, 1%, or 50%. And so, I think this was probably the most practice-changing trial we’ve seen in lung cancer over the past year or two.

Jack West, MD: So, it’s interesting that this—I agree with you—is practice changing. But it’s actually a regimen that was already FDA approved based on the KEYNOTE-021g phase II trial: 123 patients, good results, but not universally adopted because of the size of it and the lack of a clear overall survival benefit. And so, you would say that even though we had this available for us as a carboplatin/pemetrexed/pembrolizumab combination, this phase III presentation really changed the landscape.

Gregory J. Riely, MD, PhD: Yes. I think the original data that the FDA approval was based on were really provocative, showed a progression-free survival benefit. Now, I’m still adamant that a progression-free survival endpoint is a good one in the first-line setting. But when the question is whether sequential therapy would do as well, it’s really important to look at that overall survival endpoint. And the fact that KEYNOTE-189 showed a survival endpoint was really a big plus. And I think the other power in this study was that it was so much bigger. And so, we’re able to look at PD-L1 status and see more clear signals. In the original study, some of those PD-L1 numbers looked a little funny in that it seemed like some people with sort of midlevel PD-L1 didn’t do as well as people who had no PD-L1. It was all very confusing. But when we see the KEYNOTE-189 data, we see very clear progression-free survival, overall survival signals that really are across PD-L1 status and are very robust. I think it’s impressive stuff.

Transcript Edited for Clarity 
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Transcript: 

Jack West, MD: Welcome to this OncLive® News Network® presentation, broadcasting live from MJH Studios. Today’s discussion will be focused on “Practice Changes for Metastatic Non–Small Cell Lung Cancer,” specifically the implications of recent data and FDA approvals as far as their application to the clinical management of patients.

I am your host, Dr. Jack West, medical oncologist and medical director of the Thoracic Oncology Program at the Swedish Cancer Institute in Seattle, Washington. Today, I am joined by 3 of my colleagues, who are also experts in lung cancer clinical research: Dr. Charu Aggarwal, assistant professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania; Dr. Greg Riely, medical oncologist from Memorial Sloan Kettering Cancer Center and vice chair of clinical research for the Department of Medicine, in New York, New York; and Dr. Jared Weiss, section chief of Thoracic and Head & Neck Oncology and associate professor at the UNC School of Medicine in Chapel Hill, North Carolina. During the next 60 minutes, we are going to navigate through some of the questions surrounding how we treat patients with metastatic non–small cell lung cancer today. We’ll consider how the most recent clinical trial data will shape the path forward for the busy medical oncologist in community practice. In the last few minutes of the broadcast, we’ll answer some of the questions that were previously submitted by our viewing audience. During the broadcast, we invite you to submit questions to our panel by using the entry field located below this video.

We’ll start with the broad area of the many new trials and flood of new data that came in about treating patients without a driver mutation who have advanced non–small cell lung cancer, either squamous or nonsquamous. And I think at the top of that list, at least as we would have expected going into the season of big meetings, was the KEYNOTE-042 trial. Just to recap that, that was a plenary session presentation, by Dr. Gilberto Lopes, that we knew beforehand was positive for a survival benefit. And this was a trial for patients with advanced non–small cell, squamous or nonsquamous, who had PD-L1 tumor expression of 1% or greater. So that’s about two-thirds of our patients. And it was a direct comparison of pembrolizumab monotherapy to doublet chemotherapy that was histology appropriate. And, of course, we have already had a similar trial, KEYNOTE-024, that came out in late 2016 as highly positive in the subset of patients that was narrower, with a PD-L1 level of 50% or greater. And this was broader to now include the 1% to 49% population.

And we did see that, yes, it was positive for an improvement in overall survival in this broader population. But actually, the results, I would say, were very interesting in that we actually saw that the big benefits were in the patients who we already knew benefit from pembrolizumab monotherapy. The big dramatic benefit with pembrolizumab monotherapy was in the 50% or higher subset, and it diluted progressively as you added the patients with a 20% cutoff or a 1% cutoff. And when you look just at the group of patients with 1% to 49%, there was really no difference. In fact, the hazard ratio was 0.92. And so, you could perhaps argue that you did as well in efficacy and had a better tolerability with pembrolizumab. That comes as no surprise, as we know what to expect for the chemotherapy doublet, we know what pembrolizumab monotherapy does. But I think it was still significant that in the trial design for this, patients who were assigned to the first-line chemotherapy were not permitted to cross over as part of the trial to get pembrolizumab monotherapy second line.

And, in fact, in this global trial, only about 20% of the patients ended up getting immunotherapy subsequently if they started with chemotherapy. And so, I think that is a real detriment and speaks to the difference between how it was performed and how it would be performed in my practice. I think in the United States, we have much better access and an expectation that if you didn’t get it first line and you were ever a candidate for immunotherapy, you’d get it second line. My interpretation is that while it may be permitted to do this in the 1% to 49% population, it’s not the most attractive option for that group. But I think that the big issues are that there are some more compelling options, namely chemotherapy and immunotherapy. We’ll talk about the nonsquamous population and KEYNOTE-189, and we also got some more information in the squamous population as well. So, let’s start with KEYNOTE-189. Greg, can you please just summarize the key points of this? This was not actually from ASCO but still very timely, only coming out a couple of months ago.

Gregory J. Riely, MD, PhD: Right. So, KEYNOTE-189 was presented first at the AACR meeting, but it’s already published in the New England Journal of Medicine. And this was really a key trial looking at the question of, can we combine chemotherapy and immunotherapy? The control arm here was platinum/pemetrexed, so patients were allowed to receive either carboplatin or cisplatin. And then the experimental arm was combining platinum/pemetrexed and immunotherapy, specifically pembrolizumab. And when we look at the outcomes of KEYNOTE-189—regardless of PD-L1 status, regardless of performance status—patients did better if they got pembrolizumab plus chemotherapy rather than chemotherapy alone. I think regardless of how you approach initial therapy with regard to PD-L1 status, if you look at PD-L1 status or don’t, this applies to all from PD-L1 0%, 1%, or 50%. And so, I think this was probably the most practice-changing trial we’ve seen in lung cancer over the past year or two.

Jack West, MD: So, it’s interesting that this—I agree with you—is practice changing. But it’s actually a regimen that was already FDA approved based on the KEYNOTE-021g phase II trial: 123 patients, good results, but not universally adopted because of the size of it and the lack of a clear overall survival benefit. And so, you would say that even though we had this available for us as a carboplatin/pemetrexed/pembrolizumab combination, this phase III presentation really changed the landscape.

Gregory J. Riely, MD, PhD: Yes. I think the original data that the FDA approval was based on were really provocative, showed a progression-free survival benefit. Now, I’m still adamant that a progression-free survival endpoint is a good one in the first-line setting. But when the question is whether sequential therapy would do as well, it’s really important to look at that overall survival endpoint. And the fact that KEYNOTE-189 showed a survival endpoint was really a big plus. And I think the other power in this study was that it was so much bigger. And so, we’re able to look at PD-L1 status and see more clear signals. In the original study, some of those PD-L1 numbers looked a little funny in that it seemed like some people with sort of midlevel PD-L1 didn’t do as well as people who had no PD-L1. It was all very confusing. But when we see the KEYNOTE-189 data, we see very clear progression-free survival, overall survival signals that really are across PD-L1 status and are very robust. I think it’s impressive stuff.

Transcript Edited for Clarity 
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