Malignant Melanoma: Contemporary Management - Episode 11

BRAF/MEK Inhibitors in Metastatic Melanoma


Jeffrey S. Weber, MD, PhD: We’re talking about BRAF/MEK, but what about the new kids on the block? I mean, encorafenib and binimetinib are relatively recently developed drugs. Jason, what can you tell us about encorafenib and binimetinib? Different mode of action, different drugs, different adverse-effect profile.

Jason J. Luke, MD, FACP: Encorafenib and binimetinib are the third BRAF/MEK combination to gain regulatory approval. I think it’s interesting to observe that the development of these drugs was informed by the development of the previous generations of BRAF and MEK inhibitors. Specifically, what I mean by that is that it’s clear from the previous studies that adding the MEK inhibitor decreased the BRAF inhibitor toxicity. We don’t have time to dive into all that, but we know that from other studies.

In the study of encorafenib and binimetinib, in phase I, they pushed the dose of the encorafenib up a little higher than the 1-for-1 dose that you would see with the currently available BRAF inhibitors. That’s very interesting, because we have this hypothesis that if you really suppress BRAF in its downstream signaling, you could get a better benefit.

The randomized phase III data of encorafenib and binimetinib compared with a monotherapy BRAF inhibitor showed a clear improvement as had been the case for the previous combinations. What was interesting, however, was that if you looked on an absolute level, the progression-free survival for encorafenib and binimetinib looked higher than what had historically been reported for other combos.

Whereas around 11 months had been the median progression-free survival for dabrafenib-trametinib and vemurafenib-cobimetinib, for encorafenib and binimetinib, it was about 14.5 months.

It’s not compared head-to-head, and it’s a different era of melanoma therapy, so we don’t know for sure. But there’s now an update for the long-term overall survival from the same study showing similar things, which is that the overall survival looks extended based on the previous phase III trials. This is cross-trial comparison, …but at a minimum it says that these are active drugs. And when you look at the toxicity profile, it actually looks rather favorable compared with the other drugs in the class. I think this is definitely a combination that should be considered when you’re looking at available options for patients.

Jeffrey S. Weber, MD, PhD: Ryan, we will hear about the update on COLUMBUS, which was the randomized 3-arm trial that led to the registration of encorafenib and binimetinib. What can you tell us about that presentation? What do we know about the updated survival?

Ryan J. Sullivan, MD: Essentially what’s happened with the updated survival is the median survival, which at the last time they had a data cut was about 3 years is now about 4 years; an additional year of follow-up. The median hasn’t changed, not surprisingly, because the follow-up was greater than the median. But it does indeed show that the median overall survival of encorafenib plus binimetinib is about 33, 33½ months, something in that ballpark. With single-agent encorafenib, it’s about 23 months, and with single-agent vemurafenib it’s 16 months.

Interesting, that’s about the overall survival for vemurafenib in the early trials with vemurafenib. It does seem that single-agent encorafenib…the combination is definitively better than vemurafenib.

Jeffrey S. Weber, MD, PhD: And compared with what we’ve seen with other combinations whose median survivals were about 25 months, it seems like it might be a little bit better. But rumor has it, sort of the other urban legend, is that it’s less toxic. Hussein, what can you tell us about how you manage the BRAF/MEK toxicity? And do you think any of these regimens really differs in the overall toxicity profile?

Hussein A. Tawbi, MD, PhD: To think about how encorafenib could be different from other BRAF inhibitors, I would highlight the fact that there seems to be a slower dissociation constant, so it seems to actually stick to its target and hold on to it a little longer, which can be part of the reasons it works better. Interestingly, with binimetinib, …1 of the issues that we have in the toxicity of targeted therapy is that MEK inhibitors have significant toxicities in terms of ocular toxicities, pneumonitis incidence, and cardiac toxicities. And binimetinib seems to have the shortest half-life of all MEK inhibitors. Other MEK inhibitors have half-lives that take 2 to 3 weeks to get a complete washout from the MEK inhibitor. Binimetinib has a half-life of just hours, so you can actually get a washout from the MEK inhibitor within a couple of days.

That may be some of the reason we see a better safety profile for this combination, and that helps in the management of the toxicity as we manage those patients. Because when we observe the toxicities; namely fever, fatigue, and ocular toxicities, the first thing we usually do for those patients is hold all their drugs. And typically, especially if it’s a fever situation, you hold all the drugs, and within a day or 2, if the fever dissipates, then you may be able to restart at the full doses without having to dose reduce.

If we face some recurrences of these toxicities, then we start thinking about dose reductions. And with dabrafenib and trametinib, you can dose reduce. If it’s a fever, dose reduce the dabrafenib first. With encorafenib and binimetinib, that gives us the opportunity that you mentioned—that the 450-mg dose is the currently approved dose, but there was, in a phase III trial, a combination of encorafenib at 300 mg with binimetinib that looked better than vemurafenib. You can easily go down to the 300-mg dose without being too fearful about losing efficacy.

And after we go past a couple of dose reductions, if we continue to have toxicities—and now we’re talking 3, 4 months into therapy, you know if your patients are responding and how well they’re responding—we take that into account as well. Occasionally, and I have to say it’s a rare event, we can add a low-dose steroid, such as prednisone 5 mg, to help us maintain those patients on targeted therapy.

Jeffrey S. Weber, MD, PhD: We talked about BRAF/MEK toxicities, but Vern, I think Dirk Schadendorf [, Prof Dr med, University Hospital Essen] is going to present some data [at the American Society of Clinical Oncology Annual Meeting] on quality of life, which we’re finally hearing about from the CheckMate 067 trial, which is a very mature trial with 4, 5 years of follow-up. That was the ipilimumab or nivolumab versus ipilimumab and nivolumab, 945-patient, 3-arm study. What can you tell us about quality of life?

Vernon K. Sondak, MD: We’ve got all these choices. How about asking the patient, “Well, what do you prefer? What’s better for you?” My quality-of-life patients really do focus on that, sometimes more than the physician, who’s focusing on median overall survival, comparing 3 trials from 3 different generations. Ask the patient what’s important to them and then try to find out what happened. And the answer is a really mixed bag. No. 1, our quality-of-life instruments are blunt, they are not precise at really telling us exactly what’s going on. I think the message from this particular trial was pretty clear. Once you get through the initial adverse effects—especially of the ipilimumab-nivolumab combination, which has a lot of them—if you get into a maintenance phase, most of those patients maintain a very reasonable quality of life that’s not dramatically different from what it was before. But every once in a while, a patient has a rare but very lingering complication, and then they say, “Well, if I had known I was going to get that, I wish I had gotten the other drugs.” But we don’t know that, and that remains a major, major limitation.

Now we have a spread of options. We have 3 different BRAF/MEK inhibitor combinations that have 3 different sets of toxicities, all similar but some unique. We’ve got PD-1 [programmed cell death protein 1], which have relatively low toxicity, and the combination of PD-1 and anti—CTLA-4 [cytotoxic T-lymphocyte–associated antigen 4] that really ramps up the early toxicity. We need to be asking our patients, what’s most important? How are you going to weigh and balance the advantages and disadvantages of these regimens?

Transcript Edited for Clarity