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Dual Checkpoint Inhibitor Therapy for NSCLC

Panelists: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Hossein Borghaei, DO, MS, Fox Chase Cancer Center; Roy S. Herbst, MD, PhD, Yale Cancer Center; Suresh S. Ramalingam, MD, Emory University School of Medicine; Naiyer A. Rizvi, MD, Columbia University Medical Center; Thomas E. Stinchcombe, MD, Duke Cancer Institute
Published: Wednesday, Feb 28, 2018



Transcript: 

Benjamin P. Levy, MD: Let’s move on for the sake of time to the last part of this segment, which is looking at the role of dual checkpoint blockade, both in treatment-naïve non–small cell lung cancer and the treatment-refractory in small-cell lung cancer. Naiyer, you’ve been a part of some of these efforts. Can you talk to us about combination approaches for non–small cell and small-cell, starting with MYSTIC?

Naiyer A. Rizvi, MD: I think we have certainly proof of concept for immunotherapy combinations in melanoma where ipilimumab and nivolumab have been improved. We started working with ipilimumab and nivolumab in lung cancer a number of years ago and found the combination was much more toxic in our lung population than in the melanoma database. And so, in general, we’ve been using much lower doses of CTLA4 in our clinical trials in lung cancer. Nevertheless, the ipilimumab/nivolumab combination seemed to be very promising, having a high rate of response rate, including complete response rate, in a number of patients. And that combination has moved forward in phase III trials in CheckMate-227, which is likely going to read out over the next few months or so, comparing combination immunotherapy with chemotherapy combinations and other standard of care. It’s a complicated regimen.

There’s also the MYSTIC trial, which is combining durvalumab and tremelimumab in first-line therapy versus chemotherapy. And that actually completed enrollment, and certainly, the first coprimary endpoint of PFS, it did not hit in terms of PFS in the first set of analysis. So, that trial is ongoing. But I think that immunotherapy combinations are definitely another strategy that could be effective in lung cancer.

Benjamin P. Levy, MD: And CheckMate-012 is another study looking at ipilimumab and nivolumab up front. We seem to see responses that are there, that are durable, and that may be contingent on PD-L1 expression. Is this what the potential future holds, using these combination approaches without chemotherapy?

Naiyer A. Rizvi, MD: I think that in the next year, we’re going to be doing dual analysis for lung cancer. We’re going to be doing PD-L1 expression or we’re going to be doing tumor mutation burden because lung cancer is many diseases. It’s not as clean as melanoma, for example. And I think that the paradigm that I envision is going to be that if you’re TMBI-high, you’re PD-L1–high, you should get immunotherapy, whether it’s single-agent or doublet. If you’re TMBI-high and you’re PD-L1–negative, then you should get CTLA4/PD-1 combinations or chemotherapy/PD-1 combinations. If you’re TMBI-low and you’re PD-L1–low, there probably isn’t a big role for immunotherapy for you. So, that’s kind of how I interpret the landscape right now.

Benjamin P. Levy, MD: Let’s talk small-cell for a second. We had some data published in Lancet Oncology. It has been updated in World Lung looking at combination CTLA4/PD-1 in recurrent small cell. I believe this is listed on the NCCN as an option. I don’t know whether it’s necessarily FDA approved. People on the panel use of these drugs in recurrent small-cell, given how little we have in this setting.

Suresh S. Ramalingam, MD: If you look at the study that looked at the combination of ipilimumab/nivolumab in second-line treatment of small-cell lung cancer, the response rate was promising, about 25%. This was a group where we don’t have really good effects or options. Topotecan is approved in terms of relapsed, but the responses of even topotecan are not long-lived; they’re transient responses. So, that’s where the combination of ipilimumab/nivolumab seems promising. But if they get nivolumab alone, the response rate was less than 10%. So, if you’re going to immunotherapy in that setting, it may be the combination approach. And a randomized phase III trial in that space is ongoing, and we should find out either this year or next year about those. The NCCN has included this regimen in their recommendations as an option in the second line. Prior, early development of the fact that there’s nothing else to do for these patients.

Benjamin P. Levy, MD: Sadly.

Suresh S. Ramalingam, MD: So, I think it’s reasonable to consider. I have definitely given it to some patients in my practice, and I have seen some good responses in patients. I feel optimistic, and I hope that this will fill in the much-needed space or in treatment regimens for small-cell lung cancers.

Roy S. Herbst, MD, PhD: Right. Remember, small-cell lung cancers are a very smoking-related disease, so a very high mutation burden, so it makes sense that it would work here.

Hossein Borghaei, DO, MS: Right, and definitely I offer it in the combination. You have to be cognizant of the potential toxicities if you stick to the publication and use the dosages that were in the publication. But I agree that I’ve seen some wonderful responses, but at the same time, I’ve seen pretty severe side effects. So, you do have to balance it. It’s for a patient who really has a good performance status and who can handle potential toxicity if it happens. But I’m definitely offering it, and I can tell you I have colleagues at Fox Chase who absolutely don’t like to use the combination because of the toxicity profile, and they’re not convinced that the phase II is enough despite the NCCN label. So, everybody interprets data a little bit differently, but I think it’s a reasonable option.

Benjamin P. Levy, MD: Yes, the immune-related adverse events are a little more pronounced with the combination approach.

Hossein Borghaei, DO, MS: Absolutely.

Benjamin P. Levy, MD: And I was encouraged by the World Lung update of this looking at TMB. And I’ve started to send off TMB on these patients because that’s really where you get a response rate up to 40% with combination approach with a TMB-high. That is compelling and clinically meaningful.

Naiyer A. Rizvi, MD: Yes, and I think that, again, TMB provides some sort of threshold that is required for immunotherapy to be effective. And the interesting thing about it, as you know about small-cell lung cancer, is that they’re almost all PD-L1–negative, 80%-plus have no PD-L1 expression at all. So, it’s not a good biomarker for that disease, but if you look at TMB, and if you just look at the upper third of patients, those patients who got ipilimumab and nivolumab together had a 1-year survival, like 70%, which is like just crazy. But if you got single-agent PD-L1, they really didn’t do very well. So, I think that identifying the subset based on TMB is a reasonable thing to do and then give them combination I-O.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: Let’s move on for the sake of time to the last part of this segment, which is looking at the role of dual checkpoint blockade, both in treatment-naïve non–small cell lung cancer and the treatment-refractory in small-cell lung cancer. Naiyer, you’ve been a part of some of these efforts. Can you talk to us about combination approaches for non–small cell and small-cell, starting with MYSTIC?

Naiyer A. Rizvi, MD: I think we have certainly proof of concept for immunotherapy combinations in melanoma where ipilimumab and nivolumab have been improved. We started working with ipilimumab and nivolumab in lung cancer a number of years ago and found the combination was much more toxic in our lung population than in the melanoma database. And so, in general, we’ve been using much lower doses of CTLA4 in our clinical trials in lung cancer. Nevertheless, the ipilimumab/nivolumab combination seemed to be very promising, having a high rate of response rate, including complete response rate, in a number of patients. And that combination has moved forward in phase III trials in CheckMate-227, which is likely going to read out over the next few months or so, comparing combination immunotherapy with chemotherapy combinations and other standard of care. It’s a complicated regimen.

There’s also the MYSTIC trial, which is combining durvalumab and tremelimumab in first-line therapy versus chemotherapy. And that actually completed enrollment, and certainly, the first coprimary endpoint of PFS, it did not hit in terms of PFS in the first set of analysis. So, that trial is ongoing. But I think that immunotherapy combinations are definitely another strategy that could be effective in lung cancer.

Benjamin P. Levy, MD: And CheckMate-012 is another study looking at ipilimumab and nivolumab up front. We seem to see responses that are there, that are durable, and that may be contingent on PD-L1 expression. Is this what the potential future holds, using these combination approaches without chemotherapy?

Naiyer A. Rizvi, MD: I think that in the next year, we’re going to be doing dual analysis for lung cancer. We’re going to be doing PD-L1 expression or we’re going to be doing tumor mutation burden because lung cancer is many diseases. It’s not as clean as melanoma, for example. And I think that the paradigm that I envision is going to be that if you’re TMBI-high, you’re PD-L1–high, you should get immunotherapy, whether it’s single-agent or doublet. If you’re TMBI-high and you’re PD-L1–negative, then you should get CTLA4/PD-1 combinations or chemotherapy/PD-1 combinations. If you’re TMBI-low and you’re PD-L1–low, there probably isn’t a big role for immunotherapy for you. So, that’s kind of how I interpret the landscape right now.

Benjamin P. Levy, MD: Let’s talk small-cell for a second. We had some data published in Lancet Oncology. It has been updated in World Lung looking at combination CTLA4/PD-1 in recurrent small cell. I believe this is listed on the NCCN as an option. I don’t know whether it’s necessarily FDA approved. People on the panel use of these drugs in recurrent small-cell, given how little we have in this setting.

Suresh S. Ramalingam, MD: If you look at the study that looked at the combination of ipilimumab/nivolumab in second-line treatment of small-cell lung cancer, the response rate was promising, about 25%. This was a group where we don’t have really good effects or options. Topotecan is approved in terms of relapsed, but the responses of even topotecan are not long-lived; they’re transient responses. So, that’s where the combination of ipilimumab/nivolumab seems promising. But if they get nivolumab alone, the response rate was less than 10%. So, if you’re going to immunotherapy in that setting, it may be the combination approach. And a randomized phase III trial in that space is ongoing, and we should find out either this year or next year about those. The NCCN has included this regimen in their recommendations as an option in the second line. Prior, early development of the fact that there’s nothing else to do for these patients.

Benjamin P. Levy, MD: Sadly.

Suresh S. Ramalingam, MD: So, I think it’s reasonable to consider. I have definitely given it to some patients in my practice, and I have seen some good responses in patients. I feel optimistic, and I hope that this will fill in the much-needed space or in treatment regimens for small-cell lung cancers.

Roy S. Herbst, MD, PhD: Right. Remember, small-cell lung cancers are a very smoking-related disease, so a very high mutation burden, so it makes sense that it would work here.

Hossein Borghaei, DO, MS: Right, and definitely I offer it in the combination. You have to be cognizant of the potential toxicities if you stick to the publication and use the dosages that were in the publication. But I agree that I’ve seen some wonderful responses, but at the same time, I’ve seen pretty severe side effects. So, you do have to balance it. It’s for a patient who really has a good performance status and who can handle potential toxicity if it happens. But I’m definitely offering it, and I can tell you I have colleagues at Fox Chase who absolutely don’t like to use the combination because of the toxicity profile, and they’re not convinced that the phase II is enough despite the NCCN label. So, everybody interprets data a little bit differently, but I think it’s a reasonable option.

Benjamin P. Levy, MD: Yes, the immune-related adverse events are a little more pronounced with the combination approach.

Hossein Borghaei, DO, MS: Absolutely.

Benjamin P. Levy, MD: And I was encouraged by the World Lung update of this looking at TMB. And I’ve started to send off TMB on these patients because that’s really where you get a response rate up to 40% with combination approach with a TMB-high. That is compelling and clinically meaningful.

Naiyer A. Rizvi, MD: Yes, and I think that, again, TMB provides some sort of threshold that is required for immunotherapy to be effective. And the interesting thing about it, as you know about small-cell lung cancer, is that they’re almost all PD-L1–negative, 80%-plus have no PD-L1 expression at all. So, it’s not a good biomarker for that disease, but if you look at TMB, and if you just look at the upper third of patients, those patients who got ipilimumab and nivolumab together had a 1-year survival, like 70%, which is like just crazy. But if you got single-agent PD-L1, they really didn’t do very well. So, I think that identifying the subset based on TMB is a reasonable thing to do and then give them combination I-O.

Transcript Edited for Clarity 
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