Transcript:Keith Flaherty, MD: Rene, let’s switch gears now. As Jeff nicely pointed out before, when we think about immunotherapy, we probably think pretty evenly across our patient population regardless of their mutation status, BRAF mutation present or absent. But sinking in on BRAF-mutant metastatic melanoma, that’s where our treatment decision making algorithm becomes most pressured in terms of—how do we pick the right therapy for the right patient, how far do we go with certain treatments before switching when we have potentially multiple lines of therapy?

I think it even raises an interesting point about PD-1 monotherapy versus PD-1/CTLA4 combination therapy. Is compressing that regimen something that makes sense to do in a BRAF-mutant population? That way you get to next line of therapy if you need to without very much in the way of disease progression and loss of efficacy. So I’m interested in your thoughts now in thinking between the high disease burden/low disease burden end of the spectrum. Where does BRAF inhibitor-based therapy fit?

Rene Gonzalez, MD: I think there’s definitely a role for that. Those drugs are spectacular. There’s no other treatment where you can give a pill to a patient and within hours sometimes, they already feel that the drug is working. So, when you need that kind of response, if the patient has a mutation, I think that’s the way to go. Just to clarify for the audience who may not do this that often, when you say BRAF inhibitors, you mean BRAF and MEK.

Keith Flaherty, MD: Yeah, I wanted to get into that, but why don’t you go ahead and throw that out there now. I think people have been used to the idea that BRAF inhibitor monotherapy was a standard, but now there’s this new evidence with combination therapy. In your mind, is it that simple?

Rene Gonzalez, MD: I can barely think of a role for when a patient would receive just BRAF or MEK inhibitor alone.

Keith Flaherty, MD: Rene, as you commented, the data are pretty compelling for BRAF/MEK combination therapy. On the back of these recent randomized trials, can you just walk the viewers through the design of those trials, what they were set up to try to address?

Rene Gonzalez, MD: There were three studies, COMBI-V, COMBI-D, and coBRIM. The COMBI-D was comparing the trametinib and dabrafenib combination with either vemurafenib in COMBI-V or dabrafenib in COMBI-D. And coBRIM was comparing vemurafenib and cobimetinib to single-agent vemurafenib.

All three of those studies were positive and showed that combination therapy is better than a single-agent BRAF inhibitor. The overall survival is in the range of two years. The combination progression-free survival is 11 to 12 months, which is better than a single-agent BRAF inhibitor. So, they are the new standard of care in terms of targeted agents for melanoma.

Rene Gonzalez, MD: And there are two combination regimens out there, one was more recently approved. And I think they’re fairly similar. They have the rapid responses. The toxicities are probably the distinguishing feature that may guide you towards one versus another.

The Roche-Genentech combination, vemurafenib and cobimetinib, has more phototoxicity, while the trametinib and dabrafenib combination has problems with fever, primarily. And either one of them can be problematic, so you start with one. If that doesn’t work, then I guess you can switch to the other one. They’re both manageable, but it may be a limiting factor in some patients. I think the other point that you brought up is selecting the patients.

So, you’ve got that kind of patient that needs the response yesterday, and I think a harder group is the ones that have just a little bit of tumor, not a high LDH. Those patients will almost certainly respond to this, and they may be the ones that possibly get the longest benefit from it. There are tails to these curves, too. They’re not as far out, but they’re there. So I think that group becomes harder because those have also traditionally been considered the best ones for immunotherapy, and it’s not totally clear to me.

And the other thing that I find the most difficult is when I started a BRAF/MEK combination on a patient and he’s had a great response, when do I switch him? Do I switch him to the ipilimumab/PD-1 combination in the hopes of getting that durable remission? And that is tricky to do.

Jeffrey Weber, MD, PhD: Do you do that, Rene?

Rene Gonzalez, MD: I’ve started doing it. I’ve actually missed the boat on a couple of patients where I was thinking about it. I talk to them about it, but they’re feeling great on the BRAF/MEK combination. And so we think, oh, maybe next cycle we’ll do it, and then they get a brain met or the tumor starts growing quickly, and then I don’t have time. I think that’s a situation where we need a biomarker, BRAF in the blood, something to tell us this patient is not responding anymore, you better start switching. Right now we’re flying by the seat of our pants.

Transcript Edited for Clarity