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Future Advances 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: Monday, Mar 14, 2016


Transcript:

Keith Flaherty, MD:
It’s interesting. I think we’re all of the mindset now, that with the progress over the past five years, we’re aiming for complete responses and long-lasting durable responses. We’ve totally adjusted our expectations such that a promising new regimen, a PD-1-based combination, a BRAF/MEK plus another agent triplet, needs to produce a ≥20% complete response rate, or we’re not going to follow that up. It’s a fascinating shift, and I think folks in the community who have begun to see these therapies emerge are getting that sense also that we’re really starting to shift our expectations for patients.

Well, this has been a great discussion. We’ve reviewed and discussed a lot of the information that’s emerged just within the past year, in terms of new treatment strategies, as well as future directions. To close, I’d like to get final thoughts from each of you. Dr. Gonzalez, what do you see as being this near-term next breakthrough in the field? We discussed a lot of these currently available treatments.

Rene Gonzalez, MD: To start, I’d like to put it a little bit in perspective. As you said, in the last five years, there have been either 12 new drugs or combinations or indications approved in melanoma. Before that, we had nothing, really. So there’s a lot of work that remains to be done, a lot of schedule, and dosing, and biomarkers, and other targets, and resistant mechanism of sequencing, etc. So, I think it’s an exciting time for melanoma, and I think there will be research in progress at a pace like we’ve never seen before.

Keith Flaherty, MD: I think the take-home point is that we’re still doing research in this field. We’re not done. Jason, you’ve done a lot of work in your early career here in terms of real unmet need populations. We didn’t talk very much today about that, such as unique histologies, and so on. What’s your hope or sense in terms of where we could make impact, uveal melanoma, acral mucosal, these types.

Jason Luke, MD, FACP: Uveal melanoma is a particular interest of mine and an area where, unfortunately, we have not made the kind of progress we’ve seen with cutaneous melanoma. But I wonder about the advances we could make if this broader understanding we have, to things like the inflamed tumor microenvironment and how that applies to PD-1 and other checkpoint blockade, is applied to uveal melanoma.

These larger genomic approaches have really helped us to better understand BRAF inhibitor therapy. Knowing what kind of targeted therapies could we then apply in that uveal space will start to turn things, and we’ll really start to make progress. Similarly, these drugs have some activity in mucosal and acral melanomas. It’s somewhat less, but that’s also an area where we can start to think, perhaps a specific biology around that. I think broadly speaking, we have a lot of work to do. We just have these tools now.

This is just the tip of the iceberg, and we have so many other things that we need to learn about the drugs that we already have and about the pipeline. So, we really do need to continue to accrue patients to clinical trials, and, if we don’t do that, we’re basically saying that our 20% ipilimumab long-term survival is good enough, or our combination is good enough, despite the fact that half the patients end up with high-grade toxicity. And I would really push that message out that we really need to continue to do this research.

Keith Flaherty, MD: I agree. So, Dr. Weber, I want your closing comments. I also want you to take an additional burden on your shoulders. We haven’t discussed adjuvant use of ipilimumab, and I think this audience is probably aware of the fact that, very recently,the FDA approved adjuvant ipilimumab on the basis of the EORTC trial, 10 mg/kg, which is higher than what we use in standard practice in the overt metastatic setting. There is a positive relapse-free survival result that we looked at, now, a year-and-a-half ago, but we still don’t know about the overall survival impact. So, two tasks for you: one is how do you think about that data? Does it move the field forward beyond our long plateau of kind of an unsatisfying standard in interferon? And, then, give me your forward looking, what’s the game changer?

Jeffrey Weber, MD, PhD: On the adjuvant scene, I think we are making incremental progress. I think that even though the RFS data show a statistically significant and moderate benefit, I think that you’re going to see a significant and more striking advantage in survival to ipilimumab at 10 per kilo versus placebo, and ultimately, in the ECOG 1609 trial versus interferon. I would suspect over the next couple of years, it will get a fair bit of traction in the community.

Doctors will take the plunge and use ipilimumab at 10 per kilo in spite of what I would estimate to be a 1 in 3 grade 3/4 side effect rate. But, a lot of that is going to be biochemical—pancreatitis, hepatitis, endocrinopathies. Those are easily overcome and treated. Yes, there will be some more toxicity, but I agree, in exchange, there will be some benefit in survival that I think is significant. In a couple of years, we’ll know the results of the CheckMate 238 trial of nivolumab versus ipilimumab.

On the basis of my own experience with both drugs in pilot adjuvant trials, I have a suspicion that nivolumab is going to look better than ipilimumab. And the next frontier is what we’ve already piloted when I was at Moffitt and we’ll continue at NYU, which is combination adjuvant therapy. But because of the toxicity, we flipped the doses giving one of ipilimumab and three of nivolumab, which is very well-tolerated with a pretty good track record, admittedly, in a small study. So, I think that we’ve gone from interferon, we’ll go to ipilimumab, we’ll go to nivolumab, and eventually end up at ipilimumab plus nivolumab, over the next five years, which brings us to where we’re going in metastatic treatment.

I think we’re going to see triple combinations. On the one hand, it’s scientifically fascinating, extremely complex with paradoxically a bar that’s now so high, it’s going to be very difficult to get combinations approved. You’re going to need to see major incremental advantages, which I think you probably will see with some of the drugs my colleagues have mentioned. But they’re also going to be very expensive, so pharmacoeconomics is also going to play a huge role in what we do. Right now, I would estimate that the cost of ipilimumab plus nivolumab therapy for a year is about $250,000. So, I would ask where does this all end?

Keith Flaherty, MD: Maybe I’ll take the prerogative of making a closing comment. Our colleagues in lymphoma, for years, have developed a concept of concoctions of therapy that are highly effective, can be administered in the short-term and induce remissions, and then watch. And I would argue that our ambitions are high enough now that I think we actually can start to think about these high order of combinations with a goal of durations of some number of months of induction therapy, and stop, either with complete or deep partial responses. I think that’s the sustainable path, but, of course, we have a ways to go before we have any notion that we’ve got the confidence to be able to move to that. I think that’s the way we’re going to make this, ultimately, a strategy that can play in the long-term and be cost-manageable.

Well, on behalf of our panel, we thank you for joining us, and we hope you found this peer exchange discussion to be useful and informative.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Keith Flaherty, MD:
It’s interesting. I think we’re all of the mindset now, that with the progress over the past five years, we’re aiming for complete responses and long-lasting durable responses. We’ve totally adjusted our expectations such that a promising new regimen, a PD-1-based combination, a BRAF/MEK plus another agent triplet, needs to produce a ≥20% complete response rate, or we’re not going to follow that up. It’s a fascinating shift, and I think folks in the community who have begun to see these therapies emerge are getting that sense also that we’re really starting to shift our expectations for patients.

Well, this has been a great discussion. We’ve reviewed and discussed a lot of the information that’s emerged just within the past year, in terms of new treatment strategies, as well as future directions. To close, I’d like to get final thoughts from each of you. Dr. Gonzalez, what do you see as being this near-term next breakthrough in the field? We discussed a lot of these currently available treatments.

Rene Gonzalez, MD: To start, I’d like to put it a little bit in perspective. As you said, in the last five years, there have been either 12 new drugs or combinations or indications approved in melanoma. Before that, we had nothing, really. So there’s a lot of work that remains to be done, a lot of schedule, and dosing, and biomarkers, and other targets, and resistant mechanism of sequencing, etc. So, I think it’s an exciting time for melanoma, and I think there will be research in progress at a pace like we’ve never seen before.

Keith Flaherty, MD: I think the take-home point is that we’re still doing research in this field. We’re not done. Jason, you’ve done a lot of work in your early career here in terms of real unmet need populations. We didn’t talk very much today about that, such as unique histologies, and so on. What’s your hope or sense in terms of where we could make impact, uveal melanoma, acral mucosal, these types.

Jason Luke, MD, FACP: Uveal melanoma is a particular interest of mine and an area where, unfortunately, we have not made the kind of progress we’ve seen with cutaneous melanoma. But I wonder about the advances we could make if this broader understanding we have, to things like the inflamed tumor microenvironment and how that applies to PD-1 and other checkpoint blockade, is applied to uveal melanoma.

These larger genomic approaches have really helped us to better understand BRAF inhibitor therapy. Knowing what kind of targeted therapies could we then apply in that uveal space will start to turn things, and we’ll really start to make progress. Similarly, these drugs have some activity in mucosal and acral melanomas. It’s somewhat less, but that’s also an area where we can start to think, perhaps a specific biology around that. I think broadly speaking, we have a lot of work to do. We just have these tools now.

This is just the tip of the iceberg, and we have so many other things that we need to learn about the drugs that we already have and about the pipeline. So, we really do need to continue to accrue patients to clinical trials, and, if we don’t do that, we’re basically saying that our 20% ipilimumab long-term survival is good enough, or our combination is good enough, despite the fact that half the patients end up with high-grade toxicity. And I would really push that message out that we really need to continue to do this research.

Keith Flaherty, MD: I agree. So, Dr. Weber, I want your closing comments. I also want you to take an additional burden on your shoulders. We haven’t discussed adjuvant use of ipilimumab, and I think this audience is probably aware of the fact that, very recently,the FDA approved adjuvant ipilimumab on the basis of the EORTC trial, 10 mg/kg, which is higher than what we use in standard practice in the overt metastatic setting. There is a positive relapse-free survival result that we looked at, now, a year-and-a-half ago, but we still don’t know about the overall survival impact. So, two tasks for you: one is how do you think about that data? Does it move the field forward beyond our long plateau of kind of an unsatisfying standard in interferon? And, then, give me your forward looking, what’s the game changer?

Jeffrey Weber, MD, PhD: On the adjuvant scene, I think we are making incremental progress. I think that even though the RFS data show a statistically significant and moderate benefit, I think that you’re going to see a significant and more striking advantage in survival to ipilimumab at 10 per kilo versus placebo, and ultimately, in the ECOG 1609 trial versus interferon. I would suspect over the next couple of years, it will get a fair bit of traction in the community.

Doctors will take the plunge and use ipilimumab at 10 per kilo in spite of what I would estimate to be a 1 in 3 grade 3/4 side effect rate. But, a lot of that is going to be biochemical—pancreatitis, hepatitis, endocrinopathies. Those are easily overcome and treated. Yes, there will be some more toxicity, but I agree, in exchange, there will be some benefit in survival that I think is significant. In a couple of years, we’ll know the results of the CheckMate 238 trial of nivolumab versus ipilimumab.

On the basis of my own experience with both drugs in pilot adjuvant trials, I have a suspicion that nivolumab is going to look better than ipilimumab. And the next frontier is what we’ve already piloted when I was at Moffitt and we’ll continue at NYU, which is combination adjuvant therapy. But because of the toxicity, we flipped the doses giving one of ipilimumab and three of nivolumab, which is very well-tolerated with a pretty good track record, admittedly, in a small study. So, I think that we’ve gone from interferon, we’ll go to ipilimumab, we’ll go to nivolumab, and eventually end up at ipilimumab plus nivolumab, over the next five years, which brings us to where we’re going in metastatic treatment.

I think we’re going to see triple combinations. On the one hand, it’s scientifically fascinating, extremely complex with paradoxically a bar that’s now so high, it’s going to be very difficult to get combinations approved. You’re going to need to see major incremental advantages, which I think you probably will see with some of the drugs my colleagues have mentioned. But they’re also going to be very expensive, so pharmacoeconomics is also going to play a huge role in what we do. Right now, I would estimate that the cost of ipilimumab plus nivolumab therapy for a year is about $250,000. So, I would ask where does this all end?

Keith Flaherty, MD: Maybe I’ll take the prerogative of making a closing comment. Our colleagues in lymphoma, for years, have developed a concept of concoctions of therapy that are highly effective, can be administered in the short-term and induce remissions, and then watch. And I would argue that our ambitions are high enough now that I think we actually can start to think about these high order of combinations with a goal of durations of some number of months of induction therapy, and stop, either with complete or deep partial responses. I think that’s the sustainable path, but, of course, we have a ways to go before we have any notion that we’ve got the confidence to be able to move to that. I think that’s the way we’re going to make this, ultimately, a strategy that can play in the long-term and be cost-manageable.

Well, on behalf of our panel, we thank you for joining us, and we hope you found this peer exchange discussion to be useful and informative.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 13th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®Apr 28, 20182.0
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
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