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Immunotherapy in Advanced 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: Tuesday, Aug 09, 2016



Transcript:

Jeffrey S. Weber, MD:
Interestingly, if you look closely at the fine print on the article—I think it was in Lancet Oncology—it lists not a survival curve, since we only have relapse-free survival, but it lists number of deaths over time. And at every point in time, there are fewer deaths on the ipilimumab arm, by a fair margin, than on the placebo arm. It leads you to believe—at ESMO in October, we will hear about the survival data—that it’s going to be favorable. Now, how favorable it’s going to be, I don’t know. With that hazard ratio, will it go below the magic 0.75? I don’t know.

But it interests me that you say that most Australian oncologists would not be using ipilimumab. I feel more comfortable using adjuvant ipilimumab, certainly more comfortable than using adjuvant interferon. Each one has its own type of toxicities.

Georgina Long, BSc, MBBS, FRACP: So, I think that’s the key. Because adjuvant interferon is not actually well taken up in many countries around the world, given the very low-risk/benefit ratio.

Jeffrey S. Weber, MD: Well, I don’t think it’s taken up in any country around the world, not even the United States.

Georgina Long, BSc, MBBS, FRACP: Just in terms of your comparison. But it’ll be interesting. And the only other thing to say about the overall survival is that we now have a lot of treatments, and when that study was accrued, we didn’t. So, the data you’re quoting—which we probably shouldn’t discuss because it’s only just death, it’s not hazard ratios, it’s not proper analysis—it’s in a time where we probably didn’t have much to treat patients with when they recurred.

Jeffrey S. Weber, MD: You can discuss it. You have to be careful how you interpret it.

Georgina Long, BSc, MBBS, FRACP: Exactly. I would not be using that.

Keith T. Flaherty, MD: Let’s go to a tiebreaker. So, Jason, in the United States, we do have patients walk into our office—stage 3A up through 3C, maybe at those ends of the spectrum even. How do you present them? How do you minimize the toxicity and then this anguished choice about efficacy?

Jason J. Luke, MD, FACP: This is the toughest issue right now in melanoma medical oncology: what to do with stage 3 patients. And this consult takes an hour every single time. I actually fall much closer to Georgina than to Jeff. I think that despite whether or not there will be a benefit, the toxicity tradeoff is hard. And so in my practice, I would say I would almost never treat a patient who’s stage 3A, probably never 3B. A stage 3C starts to get pretty close to metastatic disease anyway; then you start thinking, maybe so. This is another analysis that I don’t know if we should really do, but if you look at the relapsed-free survival benefit in the adjuvant trial, with a 25% improvement in hazard for relapse, now we’re developing this longer-term series of patients treated out. Some of them are going 5 years, 8 years, so on and so on. And that’s a debatable analysis, because it’s not really powered, it’s not prospective, but it’s looking at 20%, 25% of patients.

So, now we’ve got 25% over here, and those are a little bit like apples and oranges—but they’re fruit. And so, that also makes me worried about doing something to the patient in the adjuvant setting if there’s a bad toxicity that puts them at risk, and they cannot be a candidate for subsequent therapies that we know are high-efficacious. Again, in my practice, I tend to really not give much adjuvant ipilimumab. There are ongoing trials still investigating agents in this space, so I would really prioritize the idea that patients should participate in those.

Jeffrey S. Weber, MD: But could we explore that? What would occur that would make an ipilimumab-adjuvant patient not a candidate for subsequent immunotherapy?

Jason J. Luke, MD, FACP: Well, it’s a risk/benefit ratio at all times, right? But if you had a high-grade colitis in the adjuvant setting, it’s…, what are the options you have? But you would be ineligible for a clinical trial thereafter probably.

Jeffrey S. Weber, MD: If it resolves and some…

Jason J. Luke, MD, FACP: But most trials would say no.

Jeffrey S. Weber, MD: If it resolves and some period of time would occur, you would then be in a position to give them subsequent therapy. You could even give them subsequent ipilimumab up the road, or pembrolizumab, or nivolumab. And actually, that was something discussed at the poster discussion at ASCO this year. That series from Australia by…

Georgina Long, BSc, MBBS, FRACP: That was actually international by the way. It was actually international across the whole of United States, Europe, and Australia, but driven by Australia, of course.

Jeffrey S. Weber, MD: A guy collected cases of patients who had had significant immune-related adverse events to checkpoint inhibitors, and he showed that there are at least 50, 60 patients for whom you could successfully retreat them without reproducing the same side effects. I’ve done that in a smaller series that was buried in a larger study that was just published. So, I think that the myth that once you get a severe immune-related adverse event from one checkpoint inhibitor, you can’t use another, that’s probably not true.

Keith T. Flaherty, MD: Let’s leave the safety part aside for a moment and circle back to efficacy. I think Jason was touching on this. So, let’s play it forward a little bit. Let’s say that we have data in 1 to 2 years that really supports the idea that ipilimumab/nivolumab combination is a superior approach with overall survival, leave aside progression-free response rate benefits.

Georgina Long, BSc, MBBS, FRACP: In stage 4, you’re talking about?

Keith T. Flaherty, MD: Yes, that’s what I’m saying, right? So, then, if you have that regimen with survival data behind it, how do you feel about giving adjuvant ipilimumab, recognizing that based on the emerging evidence that a fair fraction of those patients are still going to relapse? You expose them to CTLA-4, 10 mg/kg—I’m making up a number here—and they relapse 2 years later. Do you have confidence that ipilimumab/nivolumab—so, you’re going to reuse the CTLA-4 component—is still a regimen that’s going to pack all of its punch in a patient who’s been previously exposed to ipilimumab in the adjuvant setting?

Jeffrey S. Weber, MD: I think if enough time has gone by, probably. I would also say that that will be a moot point within a year because we’ll have the relapse-free survival data from the randomized phase III ipilimumab versus nivolumab trial. And if nivolumab is the winner, everyone’s going to be using single-agent nivolumab as an adjuvant therapy with a very modest toxicity profile, and no one will be using ipilimumab anymore.

Georgina Long, BSc, MBBS, FRACP: So, you’re referring to the trial of stage 3B, 3C, and 4 resected, randomized ipilimumab or nivolumab?

Jeffrey S. Weber, MD: Correct.

Georgina Long, BSc, MBBS, FRACP: Okay.

Jeffrey S. Weber, MD: I think that has a decent chance of being a positive trial, and if it is, adjuvant ipilimumab will have gone through a year or two of use and then faded—maybe not in Australia, but at least in the United States. And then we’ll think about, could you drop the dose of ipilimumab, keep the nivolumab, and use combination therapy as an adjuvant?

Keith T. Flaherty, MD: Alright, now you’re getting way out into the future.

Jason J. Luke, MD, FACP: Just, again, I’d like to bring it back to emphasize how complicated this decision is for patients and physicians. And I would strongly emphasize that there are trials ongoing that we just really don’t know the answer here, and it’s really important that people continue to participate.

Georgina Long, BSc, MBBS, FRACP: May I make one comment on the trials that are ongoing? Because it will answer that question that we’re struggling with. For example, the EORTC trial of stage 3 resected cancer: patients are randomized to placebo or pembrolizumab. And patients who relapse on the placebo are allowed to cross over to pembrolizumab. So, it will be very interesting. And it’s powered for survival, as well as relapsed-free survival as primary endpoints. It will be very interesting to see whether you still see an overall survival benefit after you’ve crossed over. Because if you don’t, then it tells you just wait until people have stage 4, and don’t give 50% of the people the drug up front. Wait until they have stage 4, because you’re going to have the same effect.

Keith T. Flaherty, MD: Good point.

Transcript Edited for Clarity

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Transcript:

Jeffrey S. Weber, MD:
Interestingly, if you look closely at the fine print on the article—I think it was in Lancet Oncology—it lists not a survival curve, since we only have relapse-free survival, but it lists number of deaths over time. And at every point in time, there are fewer deaths on the ipilimumab arm, by a fair margin, than on the placebo arm. It leads you to believe—at ESMO in October, we will hear about the survival data—that it’s going to be favorable. Now, how favorable it’s going to be, I don’t know. With that hazard ratio, will it go below the magic 0.75? I don’t know.

But it interests me that you say that most Australian oncologists would not be using ipilimumab. I feel more comfortable using adjuvant ipilimumab, certainly more comfortable than using adjuvant interferon. Each one has its own type of toxicities.

Georgina Long, BSc, MBBS, FRACP: So, I think that’s the key. Because adjuvant interferon is not actually well taken up in many countries around the world, given the very low-risk/benefit ratio.

Jeffrey S. Weber, MD: Well, I don’t think it’s taken up in any country around the world, not even the United States.

Georgina Long, BSc, MBBS, FRACP: Just in terms of your comparison. But it’ll be interesting. And the only other thing to say about the overall survival is that we now have a lot of treatments, and when that study was accrued, we didn’t. So, the data you’re quoting—which we probably shouldn’t discuss because it’s only just death, it’s not hazard ratios, it’s not proper analysis—it’s in a time where we probably didn’t have much to treat patients with when they recurred.

Jeffrey S. Weber, MD: You can discuss it. You have to be careful how you interpret it.

Georgina Long, BSc, MBBS, FRACP: Exactly. I would not be using that.

Keith T. Flaherty, MD: Let’s go to a tiebreaker. So, Jason, in the United States, we do have patients walk into our office—stage 3A up through 3C, maybe at those ends of the spectrum even. How do you present them? How do you minimize the toxicity and then this anguished choice about efficacy?

Jason J. Luke, MD, FACP: This is the toughest issue right now in melanoma medical oncology: what to do with stage 3 patients. And this consult takes an hour every single time. I actually fall much closer to Georgina than to Jeff. I think that despite whether or not there will be a benefit, the toxicity tradeoff is hard. And so in my practice, I would say I would almost never treat a patient who’s stage 3A, probably never 3B. A stage 3C starts to get pretty close to metastatic disease anyway; then you start thinking, maybe so. This is another analysis that I don’t know if we should really do, but if you look at the relapsed-free survival benefit in the adjuvant trial, with a 25% improvement in hazard for relapse, now we’re developing this longer-term series of patients treated out. Some of them are going 5 years, 8 years, so on and so on. And that’s a debatable analysis, because it’s not really powered, it’s not prospective, but it’s looking at 20%, 25% of patients.

So, now we’ve got 25% over here, and those are a little bit like apples and oranges—but they’re fruit. And so, that also makes me worried about doing something to the patient in the adjuvant setting if there’s a bad toxicity that puts them at risk, and they cannot be a candidate for subsequent therapies that we know are high-efficacious. Again, in my practice, I tend to really not give much adjuvant ipilimumab. There are ongoing trials still investigating agents in this space, so I would really prioritize the idea that patients should participate in those.

Jeffrey S. Weber, MD: But could we explore that? What would occur that would make an ipilimumab-adjuvant patient not a candidate for subsequent immunotherapy?

Jason J. Luke, MD, FACP: Well, it’s a risk/benefit ratio at all times, right? But if you had a high-grade colitis in the adjuvant setting, it’s…, what are the options you have? But you would be ineligible for a clinical trial thereafter probably.

Jeffrey S. Weber, MD: If it resolves and some…

Jason J. Luke, MD, FACP: But most trials would say no.

Jeffrey S. Weber, MD: If it resolves and some period of time would occur, you would then be in a position to give them subsequent therapy. You could even give them subsequent ipilimumab up the road, or pembrolizumab, or nivolumab. And actually, that was something discussed at the poster discussion at ASCO this year. That series from Australia by…

Georgina Long, BSc, MBBS, FRACP: That was actually international by the way. It was actually international across the whole of United States, Europe, and Australia, but driven by Australia, of course.

Jeffrey S. Weber, MD: A guy collected cases of patients who had had significant immune-related adverse events to checkpoint inhibitors, and he showed that there are at least 50, 60 patients for whom you could successfully retreat them without reproducing the same side effects. I’ve done that in a smaller series that was buried in a larger study that was just published. So, I think that the myth that once you get a severe immune-related adverse event from one checkpoint inhibitor, you can’t use another, that’s probably not true.

Keith T. Flaherty, MD: Let’s leave the safety part aside for a moment and circle back to efficacy. I think Jason was touching on this. So, let’s play it forward a little bit. Let’s say that we have data in 1 to 2 years that really supports the idea that ipilimumab/nivolumab combination is a superior approach with overall survival, leave aside progression-free response rate benefits.

Georgina Long, BSc, MBBS, FRACP: In stage 4, you’re talking about?

Keith T. Flaherty, MD: Yes, that’s what I’m saying, right? So, then, if you have that regimen with survival data behind it, how do you feel about giving adjuvant ipilimumab, recognizing that based on the emerging evidence that a fair fraction of those patients are still going to relapse? You expose them to CTLA-4, 10 mg/kg—I’m making up a number here—and they relapse 2 years later. Do you have confidence that ipilimumab/nivolumab—so, you’re going to reuse the CTLA-4 component—is still a regimen that’s going to pack all of its punch in a patient who’s been previously exposed to ipilimumab in the adjuvant setting?

Jeffrey S. Weber, MD: I think if enough time has gone by, probably. I would also say that that will be a moot point within a year because we’ll have the relapse-free survival data from the randomized phase III ipilimumab versus nivolumab trial. And if nivolumab is the winner, everyone’s going to be using single-agent nivolumab as an adjuvant therapy with a very modest toxicity profile, and no one will be using ipilimumab anymore.

Georgina Long, BSc, MBBS, FRACP: So, you’re referring to the trial of stage 3B, 3C, and 4 resected, randomized ipilimumab or nivolumab?

Jeffrey S. Weber, MD: Correct.

Georgina Long, BSc, MBBS, FRACP: Okay.

Jeffrey S. Weber, MD: I think that has a decent chance of being a positive trial, and if it is, adjuvant ipilimumab will have gone through a year or two of use and then faded—maybe not in Australia, but at least in the United States. And then we’ll think about, could you drop the dose of ipilimumab, keep the nivolumab, and use combination therapy as an adjuvant?

Keith T. Flaherty, MD: Alright, now you’re getting way out into the future.

Jason J. Luke, MD, FACP: Just, again, I’d like to bring it back to emphasize how complicated this decision is for patients and physicians. And I would strongly emphasize that there are trials ongoing that we just really don’t know the answer here, and it’s really important that people continue to participate.

Georgina Long, BSc, MBBS, FRACP: May I make one comment on the trials that are ongoing? Because it will answer that question that we’re struggling with. For example, the EORTC trial of stage 3 resected cancer: patients are randomized to placebo or pembrolizumab. And patients who relapse on the placebo are allowed to cross over to pembrolizumab. So, it will be very interesting. And it’s powered for survival, as well as relapsed-free survival as primary endpoints. It will be very interesting to see whether you still see an overall survival benefit after you’ve crossed over. Because if you don’t, then it tells you just wait until people have stage 4, and don’t give 50% of the people the drug up front. Wait until they have stage 4, because you’re going to have the same effect.

Keith T. Flaherty, MD: Good point.

Transcript Edited for Clarity
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