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Use of Immunotherapy Agents in Melanoma Treatment

Panelists:Keith T. Flaherty, MD, Massachusetts General Hospital; Rene Gonzalez, MD, University of Colorado Melanoma Research Clinics; Jason J. Luke, MD, FACP, University of Chicago Medicine; Jeffrey S. Weber, MD, PhD, NYU Langone Medical Center
Published: Wednesday, Jan 27, 2016


Transcript:

Keith Flaherty, MD:
There’s been so much going on in terms of new information about the long-term benefits of the immune checkpoint antibodies, with ipilimumab being the agent for which we’ve got up to 15-year data now.

PD-1 antibodies have now come to the fore, and even with head-to-head data showing superiority to ipilimumab. So we’re getting this rapid succession of data sets that really disrupt clinical practice. And then, of course, the combination. But let’s hold the combination for a moment. Jeff, if you could just wind back the clock at least a few months before ipilimumab, nivolumab, or PD-1 CTLA4 combination therapy was FDA-approved.

Where are we in terms of thinking through the impact of these therapies, patient selection factors, if any, that you think in terms of driving decision making and choice of therapy?

Jeffrey Weber, MD, PhD: The urban legend is that there’s the proverbial tail in the curve for patients who get immunotherapy, either ipilimumab, nivolumab, pembrolizumab, and probably the PD-L1 antibodies like MEDI4736 or MPDL3280A. But, in fact, it’s a real phenomenon.

Dirk Schadendorf had just published, some months ago in JCO, an article giving some long-term follow-up in expanded access protocol patients who received ipilimumab. If you get beyond three years in remission (partial, complete, or with stable disease), you’re probably going to stay there for a long time.

I’ve been treating ipilimumab patients for 14 years and I occasionally get an e-mail, a letter, or a postcard from a patient I treated 13 or 14 years ago when I was in Los Angeles, and they’re alive and doing well. In fact, the person in whom, I think it was probably 2001, I saw my first case of colitis, is a gentleman living in Dana Point southern California, still doing well. He sent me a postcard some months ago.

I think it is clear you can induce long-term remissions with ipilimumab, because there we have the most experience. I would venture a bet that nivolumab and pembrolizumab, two very similar anti-PD-1 drugs, will show the same exact phenomenon. With pembrolizumab, maybe we have a little less follow-up. With nivolumab, if you look at the long-term data, and I think it was presented by Steve Hodi at ASCO this past year, for nivolumab from the original trial, it appears as if there is a plateau, perhaps in the 30%-40% range.

If you look back at the original AJCC data of, to be honest, ineffective therapy for stage IV disease, that number would be maybe 10% in a good day. With ipilimumab, it goes to 20%. With nivolumab, it goes to 30-40%. Perhaps with the combination, it even goes higher at three to five years. But I think that there’s a real phenomenon of a plateau. It looks like, preliminarily, you see the same thing with pembrolizumab, although I think the follow-up is maybe a little shorter. But I think there’s no question that the tail on the curve exists.

And we’re getting ahead of ourselves, but the other aspect of the urban legend is you don’t see that with targeted therapy. And I think that Georgina Long had some data from the original trial—that you were the first author on that I was the last author on—of dabrafenib/trametinib saying that’s not exactly the case. You can see a bit of tail on the curve in long-term survivals with targeted therapy, but we all agree the best data, the longest term follow-up data, come from ipilimumab, nivolumab, and pembrolizumab. And we’ll soon be hearing, I suspect from Mario Sznol, about some of the longer-term data from the original trial of ipilimumab plus nivolumab, which also looks very promising.

Keith Flaherty, MD: Again, let’s hold that for a moment. Thinking about the PD-1 antibody data, really with nivolumab and pembrolizumab, I think what’s compelling, as an immediate starter, is higher response rates for sure, immediate disease control that seems more impactful than ipilimumab.
                                                                                                                                                                                                                                                                                                                  
Transcript Edited for Clarity
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Transcript:

Keith Flaherty, MD:
There’s been so much going on in terms of new information about the long-term benefits of the immune checkpoint antibodies, with ipilimumab being the agent for which we’ve got up to 15-year data now.

PD-1 antibodies have now come to the fore, and even with head-to-head data showing superiority to ipilimumab. So we’re getting this rapid succession of data sets that really disrupt clinical practice. And then, of course, the combination. But let’s hold the combination for a moment. Jeff, if you could just wind back the clock at least a few months before ipilimumab, nivolumab, or PD-1 CTLA4 combination therapy was FDA-approved.

Where are we in terms of thinking through the impact of these therapies, patient selection factors, if any, that you think in terms of driving decision making and choice of therapy?

Jeffrey Weber, MD, PhD: The urban legend is that there’s the proverbial tail in the curve for patients who get immunotherapy, either ipilimumab, nivolumab, pembrolizumab, and probably the PD-L1 antibodies like MEDI4736 or MPDL3280A. But, in fact, it’s a real phenomenon.

Dirk Schadendorf had just published, some months ago in JCO, an article giving some long-term follow-up in expanded access protocol patients who received ipilimumab. If you get beyond three years in remission (partial, complete, or with stable disease), you’re probably going to stay there for a long time.

I’ve been treating ipilimumab patients for 14 years and I occasionally get an e-mail, a letter, or a postcard from a patient I treated 13 or 14 years ago when I was in Los Angeles, and they’re alive and doing well. In fact, the person in whom, I think it was probably 2001, I saw my first case of colitis, is a gentleman living in Dana Point southern California, still doing well. He sent me a postcard some months ago.

I think it is clear you can induce long-term remissions with ipilimumab, because there we have the most experience. I would venture a bet that nivolumab and pembrolizumab, two very similar anti-PD-1 drugs, will show the same exact phenomenon. With pembrolizumab, maybe we have a little less follow-up. With nivolumab, if you look at the long-term data, and I think it was presented by Steve Hodi at ASCO this past year, for nivolumab from the original trial, it appears as if there is a plateau, perhaps in the 30%-40% range.

If you look back at the original AJCC data of, to be honest, ineffective therapy for stage IV disease, that number would be maybe 10% in a good day. With ipilimumab, it goes to 20%. With nivolumab, it goes to 30-40%. Perhaps with the combination, it even goes higher at three to five years. But I think that there’s a real phenomenon of a plateau. It looks like, preliminarily, you see the same thing with pembrolizumab, although I think the follow-up is maybe a little shorter. But I think there’s no question that the tail on the curve exists.

And we’re getting ahead of ourselves, but the other aspect of the urban legend is you don’t see that with targeted therapy. And I think that Georgina Long had some data from the original trial—that you were the first author on that I was the last author on—of dabrafenib/trametinib saying that’s not exactly the case. You can see a bit of tail on the curve in long-term survivals with targeted therapy, but we all agree the best data, the longest term follow-up data, come from ipilimumab, nivolumab, and pembrolizumab. And we’ll soon be hearing, I suspect from Mario Sznol, about some of the longer-term data from the original trial of ipilimumab plus nivolumab, which also looks very promising.

Keith Flaherty, MD: Again, let’s hold that for a moment. Thinking about the PD-1 antibody data, really with nivolumab and pembrolizumab, I think what’s compelling, as an immediate starter, is higher response rates for sure, immediate disease control that seems more impactful than ipilimumab.
                                                                                                                                                                                                                                                                                                                  
Transcript Edited for Clarity
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