Michael B. Atkins, MD: For patients with a BRAF mutation, the decision about what to give first has become increasingly complicated. We used to think that BRAF inhibitors were most appropriate for patients with more aggressive disease, with elevated LDH, with multiple tumor metastasis sites, and with symptoms related to their metastatic disease, and that those would be patients who would do less well with immune therapy. But recent data suggest that that’s actually potentially not the case and that patients who have elevated LDH or multiple sites of disease, even though they’ll respond to BRAF/MEK inhibitors very quickly, often respond for a very short period of time. The patients who do the best with BRAF/MEK inhibitor therapy, including those who can respond for long periods of time, tend to be the patients with normal LDH and limited sites of disease. And so, we really don’t know who should get a BRAF inhibitor first and who should get immunotherapy first.
We very strongly recommend that patients with BRAF-mutant melanoma be considered for the Cooperative Group trial, EA6134, being done by ECOG and SWOG, which is formally addressing this question. And it will not only be able to answer this question for the average patient, but also has correlative studies attached to it so that we can look at clinical subsets as well as pathologic subsets of who might be best starting with one treatment or another. In patients who are not candidates for immunotherapy because of autoimmune conditions, because they’re on steroids, because they have symptomatic brain metastases, or who are in the hospital because of symptoms from their disease, those are patients who we sometimes force to start with BRAF inhibitors as their initial treatment. And we look for ways to switch them to immune therapy early on in their treatment course before the resistance fully develops.
Michael A. Postow, MD: When I have a patient with a BRAF mutation, then I know that there are multiple choices for first-line treatment. Treatment can include a BRAF and a MEK inhibitor in combination, such as the combination of vemurafenib and cobimetinib or the combination of dabrafenib and trametinib. But if I have a BRAF-mutant patient and I know that they have a BRAF mutation before we’re planning our first systemic treatment, I also recognize that I could treat this patient with immune therapy. There are a lot of different considerations that go into whether or not a patient with a BRAF mutation should be treated with a BRAF and MEK inhibitor or with initial immune therapy. And so, when I see a patient, how do I think about that?
If I have a patient without that many brain metastases—so, if they have 1 to 3 brain metastases, and those are easily amenable to some type of local treatment approach, such as stereotactic radiosurgery—that would be a patient that I would treat with immune therapy first-line. And the reason I would want a patient getting immune therapy first-line to have a limited number of brain metastases is that if a patient with a BRAF mutation has many, many brain metastases, I think that patient would be better suited for a BRAF and MEK inhibitor because we have more proven efficacy of how well BRAF and MEK inhibitors work in the brain. So, if the patient with a BRAF mutation has just a few brain metastases that are amenable to stereotactic radiosurgery, that’s a patient I would treat with immune therapy. I would also treat patients with immune therapy as an initial treatment if they were not heavily symptomatic with their disease. If a patient comes to see me, they’re generally feeling well, they may have had their metastatic disease picked up by a CAT scan, and then we biopsied something and that proved metastatic disease, but the patient is telling me that they’re feeling great and they don’t even believe that they have metastatic melanoma, that’s a perfect patient for immune therapy, either PD-1 alone or ipilimumab and PD-1 in combination. If I have a patient with a BRAF mutation who’s really, really sick, whose lab tests are abnormal due to their disease burden, or who’s got excruciating pain or some other problem related to their tumor burden, that’s a patient I might think about BRAF and MEK inhibitors first because the response to BRAF and MEK inhibitors first is even more rapid than immune therapy can be.
So, I think it’s really about whether or not the patient has symptoms or not. All patients that are asymptotic, in my mind, should be treated with immune therapy, either PD-1 alone or a combination of ipilimumab and PD-1, and then I think about whether or not this patient has brain metastases. For patients with a few brain metastases that are amenable to local types of treatment, like stereotactic surgery, those are patients I also give immune therapy to as a first-line approach, even if they do have a BRAF mutation.
One thing I would add to this discussion is that many times, we’ll see a patient with metastatic melanoma and we don’t know yet whether they have a BRAF mutation or they don’t have a BRAF mutation. And I think it’s really important that we can start that patient on immune therapy, either PD-1 alone or PD-1/ipilimumab, even before we know whether they have a BRAF mutation or not because immune therapy works similarly for patients with a BRAF mutation and when they don’t have a BRAF mutation. So, many times when we see our patients, we know they have metastatic melanoma. We start them on immune therapy while we’re testing for the BRAF mutation. Most times, we don’t even know if they have a BRAF mutation and we start them on immune therapy initially. So, you don’t have to send a test, get the BRAF result, and then make a decision. You could start many of these patients on PD-1 or ipilimumab/PD-1 while the BRAF test is cooking, before you have the result.