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Immunotherapy Combinations for HNSCC

Panelists:Ezra Cohen, MD, FRCPSC, FASCO, UC San Diego; Joshua M. Bauml, MD, University of Pennsylvania; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center; Barbara A. Burtness, MD, Yale University School of Medicine
Published Online: Thursday, Sep 28, 2017



Transcript: 

Ezra Cohen, MD: Jared, as you alluded to, there are other agents being tested in the first-line. There’s a randomized study with durvalumab looking at it in a similar fashion to what you described, although there isn’t a combination chemotherapy arm. Again, those are data that I think we’re all excited to see.

Jared Weiss, MD: That one has the combination immunotherapy, though. The KESTREL trial has the EXTREME regimen, but it’s 2:1:1 at least, so there’s only a 1-in-4 chance of getting the EXTREME regimen. But it’s EXTREME versus durvalumab alone versus durvalumab/tremelimumab. So, in 1 trial, we’ll get some comparison not only of cytotoxic versus immunotherapy but also of what benefit the second agent has.

Ezra Cohen, MD: Right. This idea is targeting 2 different points in the immune cycle: one is a synapse that’s within the tumor of PD-1/PD-L1 and then another one that predominantly affects the lymph node or presentation of the antigen in CTLA4. And so, Josh, let me turn to you about immunotherapy combinations. Which ones look promising? Which ones look exciting and are being taken forward?

Joshua M. Bauml, MD: I think that the CTLA4 inhibition, either with tremelimumab or ipilimumab, is certainly being evaluated aggressively. The limitation, of course, with CTLA4 blockade, while it has biologic plausibility that is in contrast to the description we’ve given about PD-1/PD-L1 inhibition, is that there’s significant toxicity that’s associated with these drugs. And so while it’s exciting to use them, I’m concerned, in a biomarker-blind environment, about giving all of my patients a combination of PD-1 and CTLA4 inhibition. What we’ve seen in prior studies from other tumors, specifically lung cancer, is a relatively inconsistent story regarding the role of PD-L1 staining amongst patients who receive the combination PD-1 and CTLA4 blockade. I think we end up speaking out of both sides of our mouth. On the one side, we say, “Oh, well, if you give CTLA4, you don’t need PD-L1 expression.” On the other side, you say, “Oh, but look, in PD-L1 strongly-expressing lung cancer patients, ipilimumab plus nivolumab leads to a greater than 90% response rate.” So, we have to pick which one we’re going to go with.

Jared Weiss, MD: We’ll find out from studies.

Joshua M. Bauml, MD: We’ll find out.

Jared Weiss, MD: Crazy thoughts.

Joshua M. Bauml, MD: One of the exciting studies that was presented at ASCO this year, in multiple tumor types, including head and neck cancer, evaluated the combination of pembrolizumab with epacadostat. Epacadostat is an oral IDO inhibitor, and this is another block, another checkpoint, involved in the immune system that seems to have synergistic effect. The nice part about epacadostat is that it’s really well tolerated. In the study that was presented in head and neck cancer, there was a little bit more of increased fatigue than what you’d expect from just PD-1 blockade alone. But outside of that, it was pretty well tolerated. I’m much more likely to get excited about a biomarker-blind application when we are using it with a well-tolerated drug.

Ezra Cohen, MD: Absolutely.

Barbara A. Burtness, MD: Can I just follow up on what you said about biomarkers? There are some patients who are going to do just great with nivolumab or pembrolizumab alone, right?

Joshua M. Bauml, MD: Yes.

Barbara A. Burtness, MD: And so, one of the things is that you’d like to know where you need to add CTLA4. You’d like to know where you don’t need to add it.

Ezra Cohen, MD: I think it gets more and more complex when we begin to invoke a second—and perhaps now in some clinical trials, a third—immunotherapy agent. So, I couldn’t agree with the panel more that as we’re excited about doing the clinical trials, we have to be just as excited about figuring out which patients should go on which therapies. Of course, another doublet that was recently presented was the combination of nivolumab and lirilumab, which is an anti-KIR antibody that also showed an increase in response rate without a significant increase in toxicity. So, I think the idea of using different mechanisms of action that affect the immune system is something that we’re going to see a lot more of going forward.

Transcript Edited for Clarity 

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Transcript: 

Ezra Cohen, MD: Jared, as you alluded to, there are other agents being tested in the first-line. There’s a randomized study with durvalumab looking at it in a similar fashion to what you described, although there isn’t a combination chemotherapy arm. Again, those are data that I think we’re all excited to see.

Jared Weiss, MD: That one has the combination immunotherapy, though. The KESTREL trial has the EXTREME regimen, but it’s 2:1:1 at least, so there’s only a 1-in-4 chance of getting the EXTREME regimen. But it’s EXTREME versus durvalumab alone versus durvalumab/tremelimumab. So, in 1 trial, we’ll get some comparison not only of cytotoxic versus immunotherapy but also of what benefit the second agent has.

Ezra Cohen, MD: Right. This idea is targeting 2 different points in the immune cycle: one is a synapse that’s within the tumor of PD-1/PD-L1 and then another one that predominantly affects the lymph node or presentation of the antigen in CTLA4. And so, Josh, let me turn to you about immunotherapy combinations. Which ones look promising? Which ones look exciting and are being taken forward?

Joshua M. Bauml, MD: I think that the CTLA4 inhibition, either with tremelimumab or ipilimumab, is certainly being evaluated aggressively. The limitation, of course, with CTLA4 blockade, while it has biologic plausibility that is in contrast to the description we’ve given about PD-1/PD-L1 inhibition, is that there’s significant toxicity that’s associated with these drugs. And so while it’s exciting to use them, I’m concerned, in a biomarker-blind environment, about giving all of my patients a combination of PD-1 and CTLA4 inhibition. What we’ve seen in prior studies from other tumors, specifically lung cancer, is a relatively inconsistent story regarding the role of PD-L1 staining amongst patients who receive the combination PD-1 and CTLA4 blockade. I think we end up speaking out of both sides of our mouth. On the one side, we say, “Oh, well, if you give CTLA4, you don’t need PD-L1 expression.” On the other side, you say, “Oh, but look, in PD-L1 strongly-expressing lung cancer patients, ipilimumab plus nivolumab leads to a greater than 90% response rate.” So, we have to pick which one we’re going to go with.

Jared Weiss, MD: We’ll find out from studies.

Joshua M. Bauml, MD: We’ll find out.

Jared Weiss, MD: Crazy thoughts.

Joshua M. Bauml, MD: One of the exciting studies that was presented at ASCO this year, in multiple tumor types, including head and neck cancer, evaluated the combination of pembrolizumab with epacadostat. Epacadostat is an oral IDO inhibitor, and this is another block, another checkpoint, involved in the immune system that seems to have synergistic effect. The nice part about epacadostat is that it’s really well tolerated. In the study that was presented in head and neck cancer, there was a little bit more of increased fatigue than what you’d expect from just PD-1 blockade alone. But outside of that, it was pretty well tolerated. I’m much more likely to get excited about a biomarker-blind application when we are using it with a well-tolerated drug.

Ezra Cohen, MD: Absolutely.

Barbara A. Burtness, MD: Can I just follow up on what you said about biomarkers? There are some patients who are going to do just great with nivolumab or pembrolizumab alone, right?

Joshua M. Bauml, MD: Yes.

Barbara A. Burtness, MD: And so, one of the things is that you’d like to know where you need to add CTLA4. You’d like to know where you don’t need to add it.

Ezra Cohen, MD: I think it gets more and more complex when we begin to invoke a second—and perhaps now in some clinical trials, a third—immunotherapy agent. So, I couldn’t agree with the panel more that as we’re excited about doing the clinical trials, we have to be just as excited about figuring out which patients should go on which therapies. Of course, another doublet that was recently presented was the combination of nivolumab and lirilumab, which is an anti-KIR antibody that also showed an increase in response rate without a significant increase in toxicity. So, I think the idea of using different mechanisms of action that affect the immune system is something that we’re going to see a lot more of going forward.

Transcript Edited for Clarity 
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