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Combination Strategies in Melanoma

Panelists:Keith T. Flaherty, MD Massachusetts General Hospital;Georgina Long, BSc, MBBS, FRACP, Melanoma Institute of Australia;Jason J. Luke, MD, FACP, University of Chicago;Jeffrey S. Weber, MD, NYU Langone Medical Center;Jonathan S. Zager, MD, Moffitt Cancer Center
Published: Thursday, Sep 22, 2016



Transcript:

Keith T. Flaherty, MD:
Jason, one of the missing pieces of this puzzle, as PD-1 has moved so firmly to frontline monotherapy or combination therapy, is, what’s the role of ipilimumab as a second-line therapy for those patients who receive frontline PD-1 antibody?

Jason J. Luke, MD: Well, unfortunately, I think it’s a little bit undefined. For a BRAF wild-type patient, it’s the de facto second-line therapy, but it has really not been well explored what the true efficacy there is. One of the things we just didn’t mention about CTLA/PD-1 combination is what the actual efficacy is. So, the efficacy actually is quite impressive. Your response rate does increase 40% in monotherapy to 55% in combination therapy. But, the question then is, out further, are people doing better? And we can talk about that here in just a second. But, in considering the overall picture of toxicity and where to go with this, that’s why I presented going throughout the series, because then you can say, “Here are the trade-offs of each one of these combinations.”

Keith T. Flaherty, MD: Just to build on your point, progression-free survival, which was the primary endpoint of the randomized phase III trial, with ipilimumab/nivolumab versus either of the single agents was clearly superior, slam dunk. Ipilimumab is the protocol control arm, no question, but also appeared to be superior with significance over PD-1 monotherapy. I guess it goes back into this issue about patient selection for this discussion. In other words, for response rate and PFS, one has to think about low disease burden middle of the road, and high disease burden. What’s the value proposition of making the scans look prettier or holding disease, not having to transition from drug number 1 to drug number 2? If overall survival was clearly better than PD-1 monotherapy followed by CTLA4 as the default second-line therapy, that settles that. But, how do you talk to patients about—again, across this kind of disease burden spectrum—whether you’re favoring or recommending combination therapy over monotherapy?

Jason J. Luke, MD: Well, again, I can put it in the context of toxicity profile. My personal opinion, which everyone has their own, is that the risk-benefit of monotherapy outweighs the risk-benefit of combination therapy in most patients. And, I think that where the most lies from every individual person is going to be different. I think one of the main things we need to know is what’s the benefit? In the initially refractory PD-1 patients, what’s the benefit to combination therapy in the second line relative to monotherapy? And there are a couple of trials that are about to get started to look at that, but that’s really the big question, because we expect that those patients probably have slightly less than a 10% response. And they’re going to do worse, because a lot of the best players were already selected out. They would have responded to PD-1. This is where we just don’t have the answer, unfortunately.

Georgina Long, BSc, MBBS: And, the other thing is, we are actually changing the paradigm about how we think about metastatic cancer. We want a cure and we want a cure up front. We’re not going to go from one treatment to the other, and eventually the patient will die at the end of 8 years. That’s not what we’re aiming for here. And, I think in melanoma, particularly, we’ve had this opportunity, where it’s been a desert for so long, to really think about how can we cure up front, which is the attractive thing about ipilimumab/nivolumab where you draw this line. For most patients, maybe the risk-benefit is for anti-PD-1. But, if the paradigm is to cure up front and quickly, yes, there’s toxicity, but what if they only get two or three doses and they’re done? What quality of life is that in 6 months’ time when they’ve recovered? Now, these are phase II data, but from the CheckMate-069, the 2-year survival in the ipilimumab/nivolumab all-comers, BRAF wild-type and mutant, was up above 60%. It was 63%. This is pretty incredible stuff.

Jeffrey S. Weber, MD: The interesting thing, though, is related to what we just discussed: the control arm was ipilimumab, where 2-year survival would be 30 some odd percent perhaps.

Georgina Long, BSc, MBBS: Oh, actually, in 2010 when we had nothing, the 2-year survival was 22% pure ipilimumab.

Jeffrey S. Weber, MD: Yes. But, today, you figure it was somewhere between 20% and 30%. But, it was actually 55%, because many of them, not all of them, crossed over to get either pembrolizumab or nivolumab on expanded access, other trials, or eventually a standard therapy. The interesting question is, will those curves come together at years 3 and 4? I’m not so sure. That’s essentially a non-forced sequential therapy, because I’m sure there was a fair gap. And, actually, 40% of the patients never got a PD-1 antibody anyway. So, you wonder what would have happened had all those patients gotten the PD-1 antibody. Would those curves have come together? It’s an interesting question. We’ll learn more when we look at the 3- and 4-year data next year.

Keith T. Flaherty, MD: I think Georgina is raising this point about raising the bar further, and I think that is a big motivator of these combination targeted therapy, immunotherapy trials. We don’t really have the type of data that informs practice yet. So, I’m just looking back and forth to see if there’s anyone who thinks there’s a case to be made for BRAF/MEK plus PD-1 in routine practice outside of a trial.

Jeffrey S. Weber, MD: That’s an expensive routine practice, and people are getting away with it.

Jason J. Luke, MD: I want to just make a comment. We have a little bit of data from a couple of phase I trials that have reported out initial experiences. And, again, in the context of not having robust data, that data doesn’t actually look that interesting to me. The response rate looks very similar to targeted therapy. The question is going to be, is it a long-term benefit that’s there somehow, but it also looks a little toxic? And so, I’m not sure why that would be something. There are caveats to this. We talk about brain metastasis patients that are just very difficult. I can understand how it’s very difficult to withdraw the BRAF inhibitor, but I think in a standard clinical approach, it should not be considered standard of care to just overlap everything at this point.

Georgina Long, BSc, MBBS: Having said that, it is all about durability. The whole idea of combining targeted therapy with anti-PD-1 is not about improving that response rate, because, as we said before, 95% of patients have tumor reduction. It’s all about durability. And the data we have from the dabrafenib/trametinib/pembrolizumab trials are on only 15 patients, not long enough follow-up yet to really make that assessment. But, there were some good CRs, and there haven’t been a lot of progressors yet in those 15 patients. But, it is a matter of, “Watch this space.” And at this point, I agree with you. You’ve got to be in clinical trials.

Transcript Edited for Clarity

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Transcript:

Keith T. Flaherty, MD:
Jason, one of the missing pieces of this puzzle, as PD-1 has moved so firmly to frontline monotherapy or combination therapy, is, what’s the role of ipilimumab as a second-line therapy for those patients who receive frontline PD-1 antibody?

Jason J. Luke, MD: Well, unfortunately, I think it’s a little bit undefined. For a BRAF wild-type patient, it’s the de facto second-line therapy, but it has really not been well explored what the true efficacy there is. One of the things we just didn’t mention about CTLA/PD-1 combination is what the actual efficacy is. So, the efficacy actually is quite impressive. Your response rate does increase 40% in monotherapy to 55% in combination therapy. But, the question then is, out further, are people doing better? And we can talk about that here in just a second. But, in considering the overall picture of toxicity and where to go with this, that’s why I presented going throughout the series, because then you can say, “Here are the trade-offs of each one of these combinations.”

Keith T. Flaherty, MD: Just to build on your point, progression-free survival, which was the primary endpoint of the randomized phase III trial, with ipilimumab/nivolumab versus either of the single agents was clearly superior, slam dunk. Ipilimumab is the protocol control arm, no question, but also appeared to be superior with significance over PD-1 monotherapy. I guess it goes back into this issue about patient selection for this discussion. In other words, for response rate and PFS, one has to think about low disease burden middle of the road, and high disease burden. What’s the value proposition of making the scans look prettier or holding disease, not having to transition from drug number 1 to drug number 2? If overall survival was clearly better than PD-1 monotherapy followed by CTLA4 as the default second-line therapy, that settles that. But, how do you talk to patients about—again, across this kind of disease burden spectrum—whether you’re favoring or recommending combination therapy over monotherapy?

Jason J. Luke, MD: Well, again, I can put it in the context of toxicity profile. My personal opinion, which everyone has their own, is that the risk-benefit of monotherapy outweighs the risk-benefit of combination therapy in most patients. And, I think that where the most lies from every individual person is going to be different. I think one of the main things we need to know is what’s the benefit? In the initially refractory PD-1 patients, what’s the benefit to combination therapy in the second line relative to monotherapy? And there are a couple of trials that are about to get started to look at that, but that’s really the big question, because we expect that those patients probably have slightly less than a 10% response. And they’re going to do worse, because a lot of the best players were already selected out. They would have responded to PD-1. This is where we just don’t have the answer, unfortunately.

Georgina Long, BSc, MBBS: And, the other thing is, we are actually changing the paradigm about how we think about metastatic cancer. We want a cure and we want a cure up front. We’re not going to go from one treatment to the other, and eventually the patient will die at the end of 8 years. That’s not what we’re aiming for here. And, I think in melanoma, particularly, we’ve had this opportunity, where it’s been a desert for so long, to really think about how can we cure up front, which is the attractive thing about ipilimumab/nivolumab where you draw this line. For most patients, maybe the risk-benefit is for anti-PD-1. But, if the paradigm is to cure up front and quickly, yes, there’s toxicity, but what if they only get two or three doses and they’re done? What quality of life is that in 6 months’ time when they’ve recovered? Now, these are phase II data, but from the CheckMate-069, the 2-year survival in the ipilimumab/nivolumab all-comers, BRAF wild-type and mutant, was up above 60%. It was 63%. This is pretty incredible stuff.

Jeffrey S. Weber, MD: The interesting thing, though, is related to what we just discussed: the control arm was ipilimumab, where 2-year survival would be 30 some odd percent perhaps.

Georgina Long, BSc, MBBS: Oh, actually, in 2010 when we had nothing, the 2-year survival was 22% pure ipilimumab.

Jeffrey S. Weber, MD: Yes. But, today, you figure it was somewhere between 20% and 30%. But, it was actually 55%, because many of them, not all of them, crossed over to get either pembrolizumab or nivolumab on expanded access, other trials, or eventually a standard therapy. The interesting question is, will those curves come together at years 3 and 4? I’m not so sure. That’s essentially a non-forced sequential therapy, because I’m sure there was a fair gap. And, actually, 40% of the patients never got a PD-1 antibody anyway. So, you wonder what would have happened had all those patients gotten the PD-1 antibody. Would those curves have come together? It’s an interesting question. We’ll learn more when we look at the 3- and 4-year data next year.

Keith T. Flaherty, MD: I think Georgina is raising this point about raising the bar further, and I think that is a big motivator of these combination targeted therapy, immunotherapy trials. We don’t really have the type of data that informs practice yet. So, I’m just looking back and forth to see if there’s anyone who thinks there’s a case to be made for BRAF/MEK plus PD-1 in routine practice outside of a trial.

Jeffrey S. Weber, MD: That’s an expensive routine practice, and people are getting away with it.

Jason J. Luke, MD: I want to just make a comment. We have a little bit of data from a couple of phase I trials that have reported out initial experiences. And, again, in the context of not having robust data, that data doesn’t actually look that interesting to me. The response rate looks very similar to targeted therapy. The question is going to be, is it a long-term benefit that’s there somehow, but it also looks a little toxic? And so, I’m not sure why that would be something. There are caveats to this. We talk about brain metastasis patients that are just very difficult. I can understand how it’s very difficult to withdraw the BRAF inhibitor, but I think in a standard clinical approach, it should not be considered standard of care to just overlap everything at this point.

Georgina Long, BSc, MBBS: Having said that, it is all about durability. The whole idea of combining targeted therapy with anti-PD-1 is not about improving that response rate, because, as we said before, 95% of patients have tumor reduction. It’s all about durability. And the data we have from the dabrafenib/trametinib/pembrolizumab trials are on only 15 patients, not long enough follow-up yet to really make that assessment. But, there were some good CRs, and there haven’t been a lot of progressors yet in those 15 patients. But, it is a matter of, “Watch this space.” And at this point, I agree with you. You’ve got to be in clinical trials.

Transcript Edited for Clarity
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