Treating BRAF-Mutated Metastatic Melanoma

Jul 26, 2018


Jeffrey S. Weber, MD, PhD: Now we’re in the metastatic mode. We’ve kind of worked our way through adjuvant therapy. In the metastatic mode, Hussein, who gets tested, and what do you test for? Do you test for BRAF in everybody? Do you test a big panel? Do you test a Foundation panel? Do you do PD-L1 testing? How do you test these patients, and how does that help you?

Hussein Tawbi, MD, PhD: That’s a great question. Our approach is to actually cast the net as wide as possible because we need to strategize with metastatic patients. We’re going to start with first-line therapy, which, again, could be on a clinical trial. It may not be biomarker selective, but once they progress, most of our clinical trials in the PD-1 refractory setting are going to be biomarker selective. We test a genomic panel that covers a wide range of genes, obviously with BRAF, as well—a very important aspect for the next choice. We do test with IHC. We do test for PD-L1 and for a few other markers that we find useful for choosing clinical trials after initial progression. Most of these tests, in the first-line setting, are going to be centered around knowing the BRAF status and whether we want to proceed with a combination that involves BRAF/MEK versus PD-1 therapy. The more you know about your patients in that setting, the more you’re likely to find better solutions for them if they do not respond to first-line therapy.

Omid Hamid, MD: From some of the data from KEYNOTE-006, we know that the response rates to ipilimumab were somewhere around 10% to 15%. You’ll be looking for something down the line for your patients. That’s why I feel that we should be doing as much as we can to identify mutations that can be targeted. We have trials like DART, like TAPUR, like MATCH, that can bring those drugs that have shown efficacy in other solid tumors into the melanoma space. Those mutations do exist, although rare.

Jeffrey S. Weber, MD, PhD: You’ve got your metastatic patient. You’ve done your testing. You’ve learned about PD-L1, although that may or may not be useful. You know that they’re BRAF-mutated. What are you going to do with your BRAF-mutated patient, Jason? Are you always going to treat him/her with the BRAF/MEK combination? Are you never going to treat him/her with the BRAF/MEK combination? What determines your decision as to whether you’re going to give a mutated patient a BRAF/MEK combination or whether you’re going to give him/her immunotherapy, whether it’s monotherapy or combination therapy?

Jason J. Luke, MD, FACP: This has been a tough question for years. Fortunately, I think this is the 1 area where our evolving landscape of therapeutics will make this question easier. Whatever you didn’t give them as adjuvant therapy is probably going to be the answer for what you give them when they recur. We’ve been going around and around about this for a couple of years. We’ll just play it out and say that there was no adjuvant therapy. Then, what do you do for this upfront mutated patient? That’s tough. I think there is a population of patients who have high volume disease—maybe brain metastases. It’s fairly clear, and most people agree, that ipilimumab/nivolumab, if they can get it, is what to give them. But if you take your sort of standard patient with a reasonable LDH, who is not rapidly falling apart, there are great data for BRAF- and MEK-targeted therapy in those patients. It actually looks very similar to the PD-1 monotherapy data.

So, then, how do you choose? We have to have this conversation that really lays it out for the patient. What are the pros and cons of each of these approaches? Which of these fits their lifestyle better? Coming to the doctor more often? Less often? The toxicities? The long-term side effects? In this area, for that kind of patient, we think we can do really good things for a very long time. So, how do we optimize that, right? These people are not likely to get sick from cancer in the near future, so how do we set everything up so we’ll have the most available pieces to move forward? I don’t have an absolute answer. Some of it is driven by clinical trials, obviously, at big centers and such. But for an average patient, I think either choice could be reasonable.

Jeffrey S. Weber, MD, PhD: Hussein, if you’re going to make that choice, how long are you going to treat them for?

Hussein Tawbi, MD, PhD: I guess your question relates to PD-1? But I would just say that for the BRAF-mutant patient, if you start a BRAF/MEK therapy, there are no data to support stopping at some point. We continue those patients on treatment as long as they’re responding.

Jeffrey S. Weber, MD, PhD: I would say that most people would agree with you.

Hussein Tawbi, MD, PhD: For the PD-1, with combination therapy, most of the time we stop because the treatment makes us stop. We get toxicity from ipilimumab/nivolumab. Almost half of the patients want us stop therapy. And then, if the patient has derived really great clinical responses, we might observe. Sometimes we may put them back on single-agent therapy. For single-agent PD-1 therapy, obviously the depth of the response, the dynamics of the response…A patient who I give the single-agent treatment to, who experiences no toxicity and 3 months later shows no signs of a tumor, or their tumor burden has decreased dramatically by 70% or 80%—this is a patient for whom I would consider stopping early. The current guidelines or the current treatment recommends going for a full 2 years of therapy. I find myself stopping a lot earlier with patients who are deriving clinical benefit. I think the data support this approach.

Transcript Edited for Clarity

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