Hussein A. Tawbi, MD: Patients with metastatic melanoma who present in the first-line setting who have been previously not treated are patients for whom we need to think about testing BRAF mutations. And I do believe that every patient with metastatic melanoma—in fact, with melanoma now even in the adjuvant setting—needs to really know whether their tumor is BRAF mutated or not, because that affects treatment decisions by their oncologist.

One of the issues that does come up is the timing. Sometimes you get a patient who has just been diagnosed with metastatic melanoma, you know they basically are eligible to start immunotherapy immediately, even without the knowledge of a BRAF mutation. And the question is, do you wait before you initiate the immunotherapy until you know if they’re BRAF mutated or not?

From my perspective that’s a situation that is dependent on the clinical picture, and if the patient is basically requiring immediate initiation of therapy, and we don’t have time to wait for the BRAF mutation testing to come back, in those patients we just kind of start with immunotherapy knowing that the BRAF mutation is kind of cooking in the background. However, if it’s a situation in which we have time to learn, from my perspective it’s an important part of the informed consent, so to speak, that the patients have to be aware of all their treatment options at the time they make their treatment decisions. So I make a really significant push to try to know for those patients as early as I can, essentially.

Geoffrey Thomas Gibney, MD: One of the first things when I meet a patient who has advanced melanoma is actually to determine if the BRAF-mutation status has been analyzed. One of the big barriers when we meet patients is that sometimes the BRAF test has been performed up front, and I normally have a discussion with patients that this is a very important process, that we need to have this information before we make a treatment decision. When we have the BRAF status for a patient with advanced unresectable melanoma, and it has a mutation present, in particular the BRAF V600 mutation, we would then have a discussion between BRAF-targeted therapy approach and immunotherapy.

And there are different pros and cons for using each therapy. We currently do not know what is the best starting place or which therapy should we offer to the patient first. There is a cooperative group study that we’re participating in, ECOG [Eastern Cooperative Oncology Group] EA6134. This is a trial looking at the sequence of the 2 drug classes, starting with immunotherapy versus starting with BRAF-targeted therapy and then switching to the other at progression. Currently, there are not clear data on which 1 should be offered first to patients.

In my experience, though, there are some patients for whom I may recommend starting with a BRAF-targeted therapy as their first option. These tend to be patients who have very aggressive disease where the time to response is very critical. We know that the time to response with BRAF-targeted therapy is very short, and the response rate is very high. So the clinical benefit that patients can achieve can happen very early on in their treatment. If that patient is presenting to me who is very symptomatic with very aggressive disease, this may be a treatment strategy that I would recommend.

The other area that the data have shown is that patients with very limited disease can have some of the best results for BRAF-targeted therapy. Those patients who have low-volume disease or an earlier-stage disease that is unresectable, the objective response rate, complete response rate, and durability have been shown in retrospective studies to be greater than the overall data that have been published.

Hussein A. Tawbi, MD: When we identify a BRAF mutation in a patient with first-line metastatic melanoma, we really are in quite a bit of a conundrum at this point in time. Because all our clinical trials that are available that drive our decision making—the phase III studies, which led to FDA approvals—they have all been done in the first-line setting. And so it’s almost if you want to apply the standard of care to your patients, you have to choose either immunotherapy or targeted therapy. And a lot of the time you know that kind of discussion happens with the patient, and we take into account their clinical scenario.

It’s interesting because the data tell us that actually the patients whom we serve the best are the same in immunotherapy or targeted therapy. For instance, we know that lower tumor burden—less than 3 sites of disease, low LDH [lactate dehydrogenase] patients—do fantastic with immunotherapy, but they also do really great with BRAF-targeted therapy as well. And so I take those factors into account to decide which choice of therapy to use. I also have to tell you that I practice in a major academic center. We have several clinical trials that are available for that population, so I also balance the, you know, the clinical trial options that I have at my disposal for those patients. So if sometimes I have the opportunity of having a study that includes both targeted therapy and immunotherapy, personally I consider that the best of all worlds essentially, and that’s what I would end up favoring. But this is, you know, not based on evidence yet. We don’t have results of phase III trials for these combinations of targeted and immunotherapy yet.

Transcript Edited for Clarity.