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CheckMate-227: Testing Ipilimumab/Nivolumab 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: Let’s move on. Another trial was presented in one form at AACR back in mid-April and then there were further facets of this very complex trial, CheckMate-227, presented by Dr. Hoss Borghaei at ASCO very recently. And it’s really a challenging trial, with a lot of questions being asked. Jared, can you just outline some of the key points of what at least we’ve seen so far and what it might mean?

Jared Weiss, MD: So, this was a very simple trial that gave us an absolute answer. This was a complex design. Patients were divided by their PD-L1 status in terms of how they were randomized. So, those with a negative PD-L1 status were randomized to ipilimumab/nivolumab, nivolumab/chemotherapy, or chemotherapy alone. Where those with a positive PD-L1 marker, any level of positivity, were randomized to ipilimumab/nivolumab, nivolumab alone, or chemotherapy plus nivolumab. And, actually, I think that from a human perspective, that was reasonable to design this.

The other novel thing about this trial was the use of biomarkers. In addition to PD-L1, this trial looked at and prespecified, in its statistical plan, analysis by tumor mutational burden. So, we’ve heard something about tumor mutational burden. It is just what it sounds like. You do next-generation sequencing and its number of mutations per megabase. And we’ve seen in prior data sets, in melanoma, in lung, in head and neck, I think basically every time we’ve looked, that this is a predictive biomarker. And I think it makes common sense. The more mutations you have, the more potential immunogenic neoantigens you’re going to have, potentially with a greater efficacy of these agents. And we’ve seen that before. So, what we saw at AACR and in the New England Journal of Medicine publication that followed…

Jack West, MD: This was by Matt Hellmann.

Jared Weiss, MD: Was that for patients with a high tumor mutation burden? We have to be careful how we define that because it changes every 20 minutes. But in this study, for a tumor mutation burden of at least 10, we saw the efficacy of ipilimumab/nivolumab compared to the other arms, both in PD-L1–low patients and in PD-L1–high patients and both in squamous and in nonsquamous histology.

Jack West, MD: So, the specific breakdown of what they focused on was nivolumab/ipilimumab versus chemotherapy doublet, although they did include a bit on nivolumab as well, which kind of fell between the other 2 arms. And this was in terms of progression-free survival. There was a trend toward better overall survival, I believe, if not…

Gregory J. Riely, MD, PhD: Yes, early data, I think, on overall survival.

Jack West, MD: Fair enough. And then Dr. Borghaei presented some additional data at ASCO, really just focusing on the low PD-L or the PD-L1 negatives, which showed that the nivolumab/chemotherapy arm did better than chemotherapy alone but that this was also in progression-free survival, and that was limited only to the patients with high tumor mutation burden. You lost that difference in the…

Jared Weiss, MD: Right, so this may be worth summarizing by the statuses. So, he showed us 2 key curves in that. He showed us a lot of curves, but the 2 key ones were in the tumor. All of the patients had PD-L1 negativity in what he showed us. For those with high tumor mutation burden, the top curve was ipilimumab/nivolumab followed by nivolumab/chemotherapy followed by chemotherapy, with not huge numbers of patients at risk actually; small patient numbers. But even smaller yet were the curves that he showed us for the double-negative marker, so the patients negative for PD-L1 and for tumor mutation burden. I think it was 40 or 50ish patients at the beginning of the curve, so essentially, 3 phase II studies in terms of size.

But what was interesting is those were absolutely overlapping curves. For the patients who were double-biomarker negative, there seemed to be no benefit of integrating immunotherapy in any context. And given that while these agents may have lesser toxicity than cytotoxics—and I would say in my practice, I’m far less afraid of hurting people, at least with single-agent immunotherapy compared to cytotoxics—they’re not a free ride. If you’re that person with one of the rare severe side effects, it can be awful. And so, if that hypothesis generated by these small numbers ends up being true, those are people that we could spare these risks.

Jack West, MD: One of the other provocative findings, though—still limiting numbers of patients kind of early—is the long duration of the responses seen, especially with the nivolumab/ipilimumab combination where it ends up with pretty small numbers. I think one of the challenges in interpreting the CheckMate-227 is you started out with over 1700 patients and you’re ending up with all of these subsets that end up being a few dozen patients overall. But it looks like in patients who were responding well to nivolumab/ipilimumab, they were having very long duration, which is, of course, a goal that we really want.

Jared Weiss, MD: Extremely important. This is what our patients come in asking for. And so, I don’t think it’s inappropriate, all of the attention that has been paid to the tail of the curve. Our patients don’t use those words, “tail of the curve.” But in more human language, that’s what every patient comes in asking for. They’re not asking us for an average expectation of an extra month. They’ll take it, of course. But what they come in asking for is some chance at being alive 2 years down the road, 3 years down the road. So, from a human perspective, that’s extremely provocative. I strongly agree with your commentary, though, on paying attention to the number of patients. When you get to that tail, it’s extremely small numbers that you’re talking about even being evaluated.

Jack West, MD: And we also will hope to see what this translates to in terms of overall survival with more time. Because PFS alone is limited when we’re talking about a campaign over what we hope is going to be several lines of therapy.

Transcript Edited for Clarity 
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Transcript: 

Jack West, MD: Let’s move on. Another trial was presented in one form at AACR back in mid-April and then there were further facets of this very complex trial, CheckMate-227, presented by Dr. Hoss Borghaei at ASCO very recently. And it’s really a challenging trial, with a lot of questions being asked. Jared, can you just outline some of the key points of what at least we’ve seen so far and what it might mean?

Jared Weiss, MD: So, this was a very simple trial that gave us an absolute answer. This was a complex design. Patients were divided by their PD-L1 status in terms of how they were randomized. So, those with a negative PD-L1 status were randomized to ipilimumab/nivolumab, nivolumab/chemotherapy, or chemotherapy alone. Where those with a positive PD-L1 marker, any level of positivity, were randomized to ipilimumab/nivolumab, nivolumab alone, or chemotherapy plus nivolumab. And, actually, I think that from a human perspective, that was reasonable to design this.

The other novel thing about this trial was the use of biomarkers. In addition to PD-L1, this trial looked at and prespecified, in its statistical plan, analysis by tumor mutational burden. So, we’ve heard something about tumor mutational burden. It is just what it sounds like. You do next-generation sequencing and its number of mutations per megabase. And we’ve seen in prior data sets, in melanoma, in lung, in head and neck, I think basically every time we’ve looked, that this is a predictive biomarker. And I think it makes common sense. The more mutations you have, the more potential immunogenic neoantigens you’re going to have, potentially with a greater efficacy of these agents. And we’ve seen that before. So, what we saw at AACR and in the New England Journal of Medicine publication that followed…

Jack West, MD: This was by Matt Hellmann.

Jared Weiss, MD: Was that for patients with a high tumor mutation burden? We have to be careful how we define that because it changes every 20 minutes. But in this study, for a tumor mutation burden of at least 10, we saw the efficacy of ipilimumab/nivolumab compared to the other arms, both in PD-L1–low patients and in PD-L1–high patients and both in squamous and in nonsquamous histology.

Jack West, MD: So, the specific breakdown of what they focused on was nivolumab/ipilimumab versus chemotherapy doublet, although they did include a bit on nivolumab as well, which kind of fell between the other 2 arms. And this was in terms of progression-free survival. There was a trend toward better overall survival, I believe, if not…

Gregory J. Riely, MD, PhD: Yes, early data, I think, on overall survival.

Jack West, MD: Fair enough. And then Dr. Borghaei presented some additional data at ASCO, really just focusing on the low PD-L or the PD-L1 negatives, which showed that the nivolumab/chemotherapy arm did better than chemotherapy alone but that this was also in progression-free survival, and that was limited only to the patients with high tumor mutation burden. You lost that difference in the…

Jared Weiss, MD: Right, so this may be worth summarizing by the statuses. So, he showed us 2 key curves in that. He showed us a lot of curves, but the 2 key ones were in the tumor. All of the patients had PD-L1 negativity in what he showed us. For those with high tumor mutation burden, the top curve was ipilimumab/nivolumab followed by nivolumab/chemotherapy followed by chemotherapy, with not huge numbers of patients at risk actually; small patient numbers. But even smaller yet were the curves that he showed us for the double-negative marker, so the patients negative for PD-L1 and for tumor mutation burden. I think it was 40 or 50ish patients at the beginning of the curve, so essentially, 3 phase II studies in terms of size.

But what was interesting is those were absolutely overlapping curves. For the patients who were double-biomarker negative, there seemed to be no benefit of integrating immunotherapy in any context. And given that while these agents may have lesser toxicity than cytotoxics—and I would say in my practice, I’m far less afraid of hurting people, at least with single-agent immunotherapy compared to cytotoxics—they’re not a free ride. If you’re that person with one of the rare severe side effects, it can be awful. And so, if that hypothesis generated by these small numbers ends up being true, those are people that we could spare these risks.

Jack West, MD: One of the other provocative findings, though—still limiting numbers of patients kind of early—is the long duration of the responses seen, especially with the nivolumab/ipilimumab combination where it ends up with pretty small numbers. I think one of the challenges in interpreting the CheckMate-227 is you started out with over 1700 patients and you’re ending up with all of these subsets that end up being a few dozen patients overall. But it looks like in patients who were responding well to nivolumab/ipilimumab, they were having very long duration, which is, of course, a goal that we really want.

Jared Weiss, MD: Extremely important. This is what our patients come in asking for. And so, I don’t think it’s inappropriate, all of the attention that has been paid to the tail of the curve. Our patients don’t use those words, “tail of the curve.” But in more human language, that’s what every patient comes in asking for. They’re not asking us for an average expectation of an extra month. They’ll take it, of course. But what they come in asking for is some chance at being alive 2 years down the road, 3 years down the road. So, from a human perspective, that’s extremely provocative. I strongly agree with your commentary, though, on paying attention to the number of patients. When you get to that tail, it’s extremely small numbers that you’re talking about even being evaluated.

Jack West, MD: And we also will hope to see what this translates to in terms of overall survival with more time. Because PFS alone is limited when we’re talking about a campaign over what we hope is going to be several lines of therapy.

Transcript Edited for Clarity 
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