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Emerging Immunotherapy Combinations for Melanoma

Panelists: Jeffrey Weber, MD, PhD, NYU Langone Medical Center; Reinhard Dummer, MD, University of Zurich Hospital;Axel Hauschild, MD, University of Kiel;Caroline Robert, MD, PhD, Gustave Roussy; Dirk Schadendorf, MD, University Hospital Essen
Published Online: Wednesday, Jan 18, 2017



Transcript:

Jeffrey Weber, MD, PhD:
It was pembrolizumab/T-VEC that gave me the biggest surprise, and I have a lecture to talk about new developments in immunotherapy, but I was quite impressed by the data from T-VEC/pembrolizumab.

Axel Hauschild, MD: I’m the discussant here at ESMO for this particular poster. Indeed, it’s very impressive to have a 58% response rate, no additional toxicity. I think it’s charming. And also, they have data on a randomized study with ipilimumab; it’s ipilimumab plus/minus T-VEC, which is interesting because the response rate is far better. And, therefore, because ipilimumab is more toxic, I believe pembrolizumab is the better combination or partner, and this is already in phase III, the MASTERKEY-265 study. It’s the first study I know where we have an intralesional agent, which is a vaccine combined with a checkpoint inhibitor. There might be other clinical trials coming up soon.

Jeffrey Weber, MD, PhD: But I think everybody wants to be able to get an influx of T cells into the cold tumors that might have lots of mutations. So, you’ve got targets, but you don’t have the effectors. It would appear that giving T-VEC is just another way of warming up the tumor.

Reinhard Dummer, MD: I like the T-VEC; it gives really very good danger signals. And as a virus, it is a natural optimized danger signal. So, I think T-VEC is a fantastic approach. The question is, is it enough to inject a few lesions? Is it enough to inject all lesions in a certain environment, so, typically, they’re all cutaneous? And is this cutaneous immune stimulation enough to have a systemic impact? Well, we are encouraged by responses outside of injected lesions; also, with tumor metastases. But we have to see that the response rates of these lesions are quite low.

Axel Hauschild, MD: But honestly, Jeff, you were saying you were impressed by the waterfall plots of dabrafenib, trametinib, and pembrolizumab. I was impressed that this was tolerable, because all the previous clinical trials for ipilimumab have been used as a combinational partner for BRAF plus MEK or BRAF alone—vemurafenib plus ipilimumab. It was stopped because it was for futility and for certain toxicities. And I think this is really a good sign that we can go ahead with a triple combination, if we need a triple, or one of the other ones—combination versus sequencing. That’s another question that is important.

Jeffrey Weber, MD, PhD: Poor ipilimumab always gets a bad rap for toxicity. It’s too bad. Dirk?

Dirk Schadendorf, MD: Yes, but I think that’s probably the property of ipilimumab causing some inflammation, and this inflammation was causing side effects and toxicity. And for that, I’m not surprised that we are seeing, in combination with T-VEC, some beautiful responses. The question, in my view is—we are all impressed with the response rates of PD-1 antibodies—whether the combination of pembrolizumab and T-VEC is as efficacious as the combination with ipilimumab, because you do not have this inflammatory component of ipilimumab. I think ipilimumab, in my view, is a facilitator—and actually, that’s also what we see in the combination with nivolumab, for example—or as a low-dose treatment in combination with pembrolizumab. So, I’m still not convinced whether a low dose or a less-frequent ipilimumab combination with a PD-1 antibody is as clinically effective as the full dose.

Jeffrey Weber, MD, PhD: Yes. Aren’t there data to suggest that Dirk’s right? Those are lung cancer data, right? I think that was presented maybe at this past ASCO. This was a trial in lung cancer—I forget the number—but it was a trial where ipilimumab was given at 1 week and nivolumab every 3 weeks, and then they extended to 6 weeks and 12 weeks.

Dirk Schadendorf, MD: It was 6 weeks, and now it’s to 12 weeks.

Jeffrey Weber, MD, PhD: Small numbers, but the same results. So, I think we all like the idea of low-dose ipilimumab and higher-dose nivolumab; they’re better tolerated. But if T-VEC/pembrolizumab looks as good as ipilimumab/nivolumab, I guess I would have to assume, because of the lower toxicity, everyone’s going to like the idea of pembrolizumab/T-VEC.

Caroline Robert, MD, PhD: But how much of the response is due to the reduction of the injected site? That is important because we know we inject T-VEC, it reduces size. So, if, among the targets, it increases the resistance rate, what does it mean?

Jeffrey Weber, MD, PhD: I think you raise a good question. And then there’s also the issue of pembrolizumab/epacadostat or nivolumab/epacadostat that’s been looked at, too.

Axel Hauschild, MD: But for T-VEC, there are waterfall plots available for injected versus noninjected lesions.

Caroline Robert, MD, PhD: But if you look at noninjected, do you also have, by patient, a 58% response rate?

Jeffrey Weber, MD, PhD: It’s not 58%.

Axel Hauschild, MD: It’s not the same, it’s lower, but they’re still good data.

Caroline Robert, MD, PhD: You think better than the anti–PD-1?

Axel Hauschild, MD: That’s a good question, but how can you distinguish if you’re giving it immediately in combination?

Jeffrey Weber, MD, PhD: The answer is, it looks the same. But if you add the injected lesions together, it looks awfully promising. And to me, this would justify a phase III study.

Dirk Schadendorf, MD: I had the privilege to discuss the T-VEC data last year at ESMO, so I think it will be a tough call for T-VEC, actually, to improve overall survival at the end after 2 or 3 years, to have this visible incremental increase in overall survival. And this is actually only possible if, indeed, this concept we are discussing, inflammation leading to a systemic increase in T-cell activity, is also translating to overall survival, which is also a “dogma,” a legend you need to discuss during one of the next discussion rounds, which has not been proven formerly.

Jeffrey Weber, MD, PhD: Yes. Well, remember, ipilimumab/nivolumab: 2-year survival in the CheckMate-069 study; it’s 62% in the sequential trial (CheckMate-064) that Steve Hodi and I did. It was 62% at 2 years. You’re going to have to match that with T-VEC/pembrolizumab or epacadostat/pembrolizumab to make people buy in to the idea that you can get away with less toxicity, but still have benefit.

Transcript Edited for Clarity

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Transcript:

Jeffrey Weber, MD, PhD:
It was pembrolizumab/T-VEC that gave me the biggest surprise, and I have a lecture to talk about new developments in immunotherapy, but I was quite impressed by the data from T-VEC/pembrolizumab.

Axel Hauschild, MD: I’m the discussant here at ESMO for this particular poster. Indeed, it’s very impressive to have a 58% response rate, no additional toxicity. I think it’s charming. And also, they have data on a randomized study with ipilimumab; it’s ipilimumab plus/minus T-VEC, which is interesting because the response rate is far better. And, therefore, because ipilimumab is more toxic, I believe pembrolizumab is the better combination or partner, and this is already in phase III, the MASTERKEY-265 study. It’s the first study I know where we have an intralesional agent, which is a vaccine combined with a checkpoint inhibitor. There might be other clinical trials coming up soon.

Jeffrey Weber, MD, PhD: But I think everybody wants to be able to get an influx of T cells into the cold tumors that might have lots of mutations. So, you’ve got targets, but you don’t have the effectors. It would appear that giving T-VEC is just another way of warming up the tumor.

Reinhard Dummer, MD: I like the T-VEC; it gives really very good danger signals. And as a virus, it is a natural optimized danger signal. So, I think T-VEC is a fantastic approach. The question is, is it enough to inject a few lesions? Is it enough to inject all lesions in a certain environment, so, typically, they’re all cutaneous? And is this cutaneous immune stimulation enough to have a systemic impact? Well, we are encouraged by responses outside of injected lesions; also, with tumor metastases. But we have to see that the response rates of these lesions are quite low.

Axel Hauschild, MD: But honestly, Jeff, you were saying you were impressed by the waterfall plots of dabrafenib, trametinib, and pembrolizumab. I was impressed that this was tolerable, because all the previous clinical trials for ipilimumab have been used as a combinational partner for BRAF plus MEK or BRAF alone—vemurafenib plus ipilimumab. It was stopped because it was for futility and for certain toxicities. And I think this is really a good sign that we can go ahead with a triple combination, if we need a triple, or one of the other ones—combination versus sequencing. That’s another question that is important.

Jeffrey Weber, MD, PhD: Poor ipilimumab always gets a bad rap for toxicity. It’s too bad. Dirk?

Dirk Schadendorf, MD: Yes, but I think that’s probably the property of ipilimumab causing some inflammation, and this inflammation was causing side effects and toxicity. And for that, I’m not surprised that we are seeing, in combination with T-VEC, some beautiful responses. The question, in my view is—we are all impressed with the response rates of PD-1 antibodies—whether the combination of pembrolizumab and T-VEC is as efficacious as the combination with ipilimumab, because you do not have this inflammatory component of ipilimumab. I think ipilimumab, in my view, is a facilitator—and actually, that’s also what we see in the combination with nivolumab, for example—or as a low-dose treatment in combination with pembrolizumab. So, I’m still not convinced whether a low dose or a less-frequent ipilimumab combination with a PD-1 antibody is as clinically effective as the full dose.

Jeffrey Weber, MD, PhD: Yes. Aren’t there data to suggest that Dirk’s right? Those are lung cancer data, right? I think that was presented maybe at this past ASCO. This was a trial in lung cancer—I forget the number—but it was a trial where ipilimumab was given at 1 week and nivolumab every 3 weeks, and then they extended to 6 weeks and 12 weeks.

Dirk Schadendorf, MD: It was 6 weeks, and now it’s to 12 weeks.

Jeffrey Weber, MD, PhD: Small numbers, but the same results. So, I think we all like the idea of low-dose ipilimumab and higher-dose nivolumab; they’re better tolerated. But if T-VEC/pembrolizumab looks as good as ipilimumab/nivolumab, I guess I would have to assume, because of the lower toxicity, everyone’s going to like the idea of pembrolizumab/T-VEC.

Caroline Robert, MD, PhD: But how much of the response is due to the reduction of the injected site? That is important because we know we inject T-VEC, it reduces size. So, if, among the targets, it increases the resistance rate, what does it mean?

Jeffrey Weber, MD, PhD: I think you raise a good question. And then there’s also the issue of pembrolizumab/epacadostat or nivolumab/epacadostat that’s been looked at, too.

Axel Hauschild, MD: But for T-VEC, there are waterfall plots available for injected versus noninjected lesions.

Caroline Robert, MD, PhD: But if you look at noninjected, do you also have, by patient, a 58% response rate?

Jeffrey Weber, MD, PhD: It’s not 58%.

Axel Hauschild, MD: It’s not the same, it’s lower, but they’re still good data.

Caroline Robert, MD, PhD: You think better than the anti–PD-1?

Axel Hauschild, MD: That’s a good question, but how can you distinguish if you’re giving it immediately in combination?

Jeffrey Weber, MD, PhD: The answer is, it looks the same. But if you add the injected lesions together, it looks awfully promising. And to me, this would justify a phase III study.

Dirk Schadendorf, MD: I had the privilege to discuss the T-VEC data last year at ESMO, so I think it will be a tough call for T-VEC, actually, to improve overall survival at the end after 2 or 3 years, to have this visible incremental increase in overall survival. And this is actually only possible if, indeed, this concept we are discussing, inflammation leading to a systemic increase in T-cell activity, is also translating to overall survival, which is also a “dogma,” a legend you need to discuss during one of the next discussion rounds, which has not been proven formerly.

Jeffrey Weber, MD, PhD: Yes. Well, remember, ipilimumab/nivolumab: 2-year survival in the CheckMate-069 study; it’s 62% in the sequential trial (CheckMate-064) that Steve Hodi and I did. It was 62% at 2 years. You’re going to have to match that with T-VEC/pembrolizumab or epacadostat/pembrolizumab to make people buy in to the idea that you can get away with less toxicity, but still have benefit.

Transcript Edited for Clarity
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