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Emerging Combination Regimens in Advanced Melanoma

Panelists: Jeffrey S. Weber, MD, PhD, Laura and Isaac Perlmutter Cancer Center; Robert Andtbacka, MD, CM, Huntsman Cancer Institute; Omid Hamid, MD, The Angeles Clinic and Research Institute ; Jason J. Luke, MD, FACP, University of Chicago; Michael A. Postow, MD, Memorial Sloan Kettering Cancer Center; Hussein Tawbi, MD, PhD, UT MD Anderson Cancer Center
Published: Tuesday, Sep 18, 2018



Transcript: 

Jeffrey S. Weber, MD, PhD: Let’s move on, because we still have a few things to discuss. Omid, what other combinations are you excited about? I was told that there are a thousand immunotherapy combination trials, not just in melanoma, but in all histologies. The actual number was 1040 combination trials. So, of those 1040, what excites you? What are your top 3?

Omid Hamid, MD: Well, you can’t go forward without asking, “Where are those combinations?” I would like to talk about what’s available through the Cooperative Groups, because those are available in the community. They’re looking at T-VEC plus PD-1 in patients who have failed single-agent PD-1. They’re looking at ipilimumab and nivolumab in those patients who failed single-agent PD-1. The Nektar drug with nivolumab has shown some initial increases in disease control and response. Again, given what some of these trials have shown, we have to be a little cautious about moving forward and declaring a winner. I think that combination needs to be looked at further.

Jason J. Luke, MD, FACP: That’s a pegylated IL-2 molecule?

Omid Hamid, MD: That’s right. All of these combinations are interesting. What’s really the most important thing to say is that they need to be biomarker heavy. They need to help us understand how to take care of our patients who have not only shown up de novo but have progressed on single-agent therapy. And then, as we move forward, we have to be cautious to move forward in the right way, which would be with randomized phase II studies, to try and find benefit. With all of these combinations, we’ve said that we’re in a different landscape. The numbers may seem better, but we have more therapies. Survival has improved. We’ll be presenting 5-year survivals with PD-1 that indicate how far we’ve really come from what we really thought 5-year survivals were. The data are in flux.

Jeffrey S. Weber, MD, PhD: Hussein, what about the triplets? What do you like there? There are 3 triplet trials—TRILOGY, COMBI-i, and KEYNOTE-022. Which ones do you like? Or, do you like all of them? Are they going to be very similar?

Hussein Tawbi, MD, PhD: The biology for why you should combine BRAF/MEK inhibitors with PD-1 antibodies is quite solid. We know that BRAF-targeted therapy was initially developed with the idea of just targeting the BRAF, the MAP kinase pathway, leading to a direct cell kill. Obviously, it turned out that within a very short period of time, you actually modulated the tumor microenvironment quite significantly by increasing T cell infiltration, changing tumor antigen expression and modulating a lot of the tumor microenvironment cytokines. So, a lot of things point to the fact that there’s an immune mechanism of response to BRAF/MEK. Specifically, there was evidence that demonstrated that PD-1 had an increased expression after BRAF/MEK.

The concept of adding a PD-1 antibody made a lot of sense. The phase I trials that were done, as well as some phase II trials, and, actually, some of our own experience, have been really impressive, in terms of response rates. The response rates have been higher than traditionally known with BRAF combinations, alone. They have been north of 85% for most of those combinations. But, they’ve been taken to the phase III setting now—appropriately so, compared with BRAF/MEK alone.

When I think about which one is going to be my favorite, we need to turn our attention to the next question. Three drugs are definitely going to be more toxic than 2. The toxicity piece has been an important aspect of this. We definitely see an increased rate of fevers, for instance. We just spent some time discussing how BRAF/MEK combinations correspond with fevers in up to 50%, or, possibly, as high as 70% of patients. With the addition of a PD-1, those rates appear to be even higher. Those fevers also tend to be recurrent at what appears to be a higher frequency. There’s some liver toxicity that’s also involved. Once we see the results of these phase III trials, we will be able to have a better sense of a differential activity. Then we will really have to take a close look at the toxicity and its management.

Omid Hamid, MD: Also, to the point that Jason made about the neoadjuvant approach, it also relates to this—the triplets are only in clinical trials. At this time, I would never put a patient in the community on this triplet approach. We don’t know if it’s any better. We don’t know if it’s any worse.

Jeffrey S. Weber, MD, PhD: Well said.

Hussein Tawbi, MD, PhD: I agree with that.

Transcript Edited for Clarity 

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Transcript: 

Jeffrey S. Weber, MD, PhD: Let’s move on, because we still have a few things to discuss. Omid, what other combinations are you excited about? I was told that there are a thousand immunotherapy combination trials, not just in melanoma, but in all histologies. The actual number was 1040 combination trials. So, of those 1040, what excites you? What are your top 3?

Omid Hamid, MD: Well, you can’t go forward without asking, “Where are those combinations?” I would like to talk about what’s available through the Cooperative Groups, because those are available in the community. They’re looking at T-VEC plus PD-1 in patients who have failed single-agent PD-1. They’re looking at ipilimumab and nivolumab in those patients who failed single-agent PD-1. The Nektar drug with nivolumab has shown some initial increases in disease control and response. Again, given what some of these trials have shown, we have to be a little cautious about moving forward and declaring a winner. I think that combination needs to be looked at further.

Jason J. Luke, MD, FACP: That’s a pegylated IL-2 molecule?

Omid Hamid, MD: That’s right. All of these combinations are interesting. What’s really the most important thing to say is that they need to be biomarker heavy. They need to help us understand how to take care of our patients who have not only shown up de novo but have progressed on single-agent therapy. And then, as we move forward, we have to be cautious to move forward in the right way, which would be with randomized phase II studies, to try and find benefit. With all of these combinations, we’ve said that we’re in a different landscape. The numbers may seem better, but we have more therapies. Survival has improved. We’ll be presenting 5-year survivals with PD-1 that indicate how far we’ve really come from what we really thought 5-year survivals were. The data are in flux.

Jeffrey S. Weber, MD, PhD: Hussein, what about the triplets? What do you like there? There are 3 triplet trials—TRILOGY, COMBI-i, and KEYNOTE-022. Which ones do you like? Or, do you like all of them? Are they going to be very similar?

Hussein Tawbi, MD, PhD: The biology for why you should combine BRAF/MEK inhibitors with PD-1 antibodies is quite solid. We know that BRAF-targeted therapy was initially developed with the idea of just targeting the BRAF, the MAP kinase pathway, leading to a direct cell kill. Obviously, it turned out that within a very short period of time, you actually modulated the tumor microenvironment quite significantly by increasing T cell infiltration, changing tumor antigen expression and modulating a lot of the tumor microenvironment cytokines. So, a lot of things point to the fact that there’s an immune mechanism of response to BRAF/MEK. Specifically, there was evidence that demonstrated that PD-1 had an increased expression after BRAF/MEK.

The concept of adding a PD-1 antibody made a lot of sense. The phase I trials that were done, as well as some phase II trials, and, actually, some of our own experience, have been really impressive, in terms of response rates. The response rates have been higher than traditionally known with BRAF combinations, alone. They have been north of 85% for most of those combinations. But, they’ve been taken to the phase III setting now—appropriately so, compared with BRAF/MEK alone.

When I think about which one is going to be my favorite, we need to turn our attention to the next question. Three drugs are definitely going to be more toxic than 2. The toxicity piece has been an important aspect of this. We definitely see an increased rate of fevers, for instance. We just spent some time discussing how BRAF/MEK combinations correspond with fevers in up to 50%, or, possibly, as high as 70% of patients. With the addition of a PD-1, those rates appear to be even higher. Those fevers also tend to be recurrent at what appears to be a higher frequency. There’s some liver toxicity that’s also involved. Once we see the results of these phase III trials, we will be able to have a better sense of a differential activity. Then we will really have to take a close look at the toxicity and its management.

Omid Hamid, MD: Also, to the point that Jason made about the neoadjuvant approach, it also relates to this—the triplets are only in clinical trials. At this time, I would never put a patient in the community on this triplet approach. We don’t know if it’s any better. We don’t know if it’s any worse.

Jeffrey S. Weber, MD, PhD: Well said.

Hussein Tawbi, MD, PhD: I agree with that.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
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