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Managing Disease Progression in Metastatic 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: Friday, Sep 14, 2018



Transcript: 

Jeffrey S. Weber, MD, PhD: Hussein, you’ve got your BRAF wild-type patient who’s failed frontline immunotherapy, whether it be PD-1 alone or ipilimumab/nivolumab. What’s your next step, if they’re BRAF wild-type?

Hussein Tawbi, MD, PhD: Most of the time, I would put them on a clinical trial. Actually, that highlights the fact that this population is actually here and is growing. We may have great responses in most of our patients. At this point, we’re probably giving a long-term benefit to about half of our metastatic patients. However, there’s the entire other half that continues to have no options. Those patients, to your point, will actually burn through therapies relatively quickly. We work really hard in trying to establish clinical trials that can capture those populations. I will bring you back to the biomarker question in those patients. We have started trying to learn as much as we can about other mutations that could be in their tumors. We’ve been doing IHC, for instance, for PTEN loss because we have a clinical trial directed specifically at patients who have PTEN loss and immunotherapy resistance, where we could potentially reverse that with a PI3-kinase inhibitor. We’re trying to become smarter about those studies, but we really do need to do a lot more work in this setting.

Jeffrey S. Weber, MD, PhD: The other equivalent question is, they’re BRAF-mutated. They blow through ipilimumab/nivolumab. I assume that you’re going to go to BRAF/MEK therapy?

Hussein Tawbi, MD, PhD: That’s the standard of care. It’s proven to improve overall survival and can give long-term durable responses. And so, in those patients, that would be my usual approach. Again, I’m very clinical trial inclined, so most of my clinical trials are going to be BRAF/MEK combinations, and then I would add something else in. If a patient fails immunotherapy upfront and is BRAF-mutated, we should consider BRAF therapy for the long-term potential outcomes.

Jeffrey S. Weber, MD, PhD: Omid, is there any place for high-dose IL-2? This is a drug that was approved in 1998. That’s 20 years ago. Do you use it? Does anybody use it? Is there a place for it?
Omid Hamid, MD: I think about using IL-2 with some of these adoptive T-cell therapies. There are clinical trials looking at bringing adoptive T cell to the masses. There is a trial where the tumor harvest is done locally. It’s sent, the TILs are grown, the patient is admitted, and then they get the TIL therapy and IL-2. This makes a lot of sense for those patients who have not responded to anything. They have blown through and have exhausted their targeted and immunotherapy options. So, that’s where I look for it.

I wouldn’t know, and have never come across a patient who has gone through everything and has the performance status to get high-dose IL-2 in the third- or fourth-line setting. I think that’s a rare subgroup of patients. In that scenario, you have to have a long discussion regarding the fact that we don’t have a lot of experience here. There was data presented that suggested that initial PD-1 or checkpoint therapy may decrease the efficacy of the TILs that you have, and that’s a question that we’ll have to come across. It may decrease the efficacy of high-dose IL-2. We’re not sure about that. For traditional high-dose IL-2, the patient would have to be someone with such a good performance status that they could withstand it but not the time to undergo some form of a TIL procedure.

Transcript Edited for Clarity 

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Transcript: 

Jeffrey S. Weber, MD, PhD: Hussein, you’ve got your BRAF wild-type patient who’s failed frontline immunotherapy, whether it be PD-1 alone or ipilimumab/nivolumab. What’s your next step, if they’re BRAF wild-type?

Hussein Tawbi, MD, PhD: Most of the time, I would put them on a clinical trial. Actually, that highlights the fact that this population is actually here and is growing. We may have great responses in most of our patients. At this point, we’re probably giving a long-term benefit to about half of our metastatic patients. However, there’s the entire other half that continues to have no options. Those patients, to your point, will actually burn through therapies relatively quickly. We work really hard in trying to establish clinical trials that can capture those populations. I will bring you back to the biomarker question in those patients. We have started trying to learn as much as we can about other mutations that could be in their tumors. We’ve been doing IHC, for instance, for PTEN loss because we have a clinical trial directed specifically at patients who have PTEN loss and immunotherapy resistance, where we could potentially reverse that with a PI3-kinase inhibitor. We’re trying to become smarter about those studies, but we really do need to do a lot more work in this setting.

Jeffrey S. Weber, MD, PhD: The other equivalent question is, they’re BRAF-mutated. They blow through ipilimumab/nivolumab. I assume that you’re going to go to BRAF/MEK therapy?

Hussein Tawbi, MD, PhD: That’s the standard of care. It’s proven to improve overall survival and can give long-term durable responses. And so, in those patients, that would be my usual approach. Again, I’m very clinical trial inclined, so most of my clinical trials are going to be BRAF/MEK combinations, and then I would add something else in. If a patient fails immunotherapy upfront and is BRAF-mutated, we should consider BRAF therapy for the long-term potential outcomes.

Jeffrey S. Weber, MD, PhD: Omid, is there any place for high-dose IL-2? This is a drug that was approved in 1998. That’s 20 years ago. Do you use it? Does anybody use it? Is there a place for it?
Omid Hamid, MD: I think about using IL-2 with some of these adoptive T-cell therapies. There are clinical trials looking at bringing adoptive T cell to the masses. There is a trial where the tumor harvest is done locally. It’s sent, the TILs are grown, the patient is admitted, and then they get the TIL therapy and IL-2. This makes a lot of sense for those patients who have not responded to anything. They have blown through and have exhausted their targeted and immunotherapy options. So, that’s where I look for it.

I wouldn’t know, and have never come across a patient who has gone through everything and has the performance status to get high-dose IL-2 in the third- or fourth-line setting. I think that’s a rare subgroup of patients. In that scenario, you have to have a long discussion regarding the fact that we don’t have a lot of experience here. There was data presented that suggested that initial PD-1 or checkpoint therapy may decrease the efficacy of the TILs that you have, and that’s a question that we’ll have to come across. It may decrease the efficacy of high-dose IL-2. We’re not sure about that. For traditional high-dose IL-2, the patient would have to be someone with such a good performance status that they could withstand it but not the time to undergo some form of a TIL procedure.

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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