BRAF/MEK Frontline Therapy in Metastatic Melanoma



Ryan J. Sullivan, MD: In patients with metastatic melanoma who have a BRAF mutation, there are a number of options, and those options include BRAF-targeted therapy. Those options include anti—PD-1 [anti–programmed cell death protein 1]-based therapy. There may be other options, too, but for the great majority of patients that’s what we’re deciding upon. In patients who have very severe disease that is life-threatening immediately, we tend to offer BRAF-targeted therapy. In patients for whom there’s a significant contraindication to receive immunotherapy, we offer BRAF-targeted therapy. And then there are data to support the use of BRAF-targeted therapy in patients who have the least amount of disease in the stage IV patients, with good performance status, patients with limited number of disease sites, patients with a normal LDH [lactate dehydrogenase]. So it’s not wrong to offer BRAF-targeted therapy really to any BRAF-mutated melanoma patient as a frontline therapy, but our bias tends to be to offer immunotherapy to those patients. However, it’s appropriate for sure in certain situations and justifiable in others.

The use then or the selection of which BRAF/MEK inhibitor combination pretty much comes down to comfort. For the better part of this past decade, certainly the last half of the decade, dabrafenib and trametinib have been FDA approved. They’re also FDA approved for lung cancer. It’s also FDA approved for anaplastic thyroid carcinoma. So people may have comfort with those drugs. They know how to deal with their fever. Their nurses and other support staff know what calls to expect, and they have their dose modification strategies down, and there’s comfort with dabrafenib and trametinib and that makes complete sense. It’s the one that was first on the market and still the one we use in the adjuvant setting. And so I could imagine that people would want to continue to use that.

Vemurafenib and cobimetinib also have been on the market for a little bit, certainly longer than encorafenib and binimetinib and could be certainly a frontline therapy. Because we were using dabrafenib/trametinib in the phase I and II study and then a phase III study, and then it got approved first, that was our go-to. And when vemurafenib/cobimetinib came on, we really only used it in patients who couldn’t tolerate dabrafenib and trametinib, and we would go to vemurafenib and cobimetinib, outside of a clinical trial, of course.

So we never really made a decision to switch to VEM/COBI [vemurafenib/cobimetinib]. We were happy with dabrafenib/trametinib or at least we were comfortable with it. And as I mentioned before, you get comfortable with a drug or regimen, everybody else is comfortable with it. You know what to do, you know how to react when things happen. With encorafenib/binimetinib, we put a lot of patients on the phase I and phase II study, so we had a decent amount of experience. We felt that it was better tolerated in general than was dabrafenib and trametinib, and so we’ve been interested in seeing whether that’s true. And so many of the patients that we decide to treat with BRAF-targeted therapy either in the frontline or even after they’ve received immunotherapy, we’ve gone to encorafenib and binimetinib.

And I think what we really need to do is get more real-world experience before we’re ready to say this is definitely the least toxic of the 3 regimens by the numbers, by the phase I dosing. Where we settled on a dose that was higher of encorafenib than it was as a single agent, would suggest that it may actually be a little bit better tolerated and could even be a little bit more potent. So there’s rationale to select it and to use it. But as we get more real-world experience, we may decide it’s not really any less toxic, it’s just differently toxic and we felt that it was less toxic because we weren’t seeing the types of adverse effects that we’re now seeing now that we’ve treated not 20 patients or 30 patients but 100 patients.

It’s always the way when you’re using a new drug or a new regimen, even if you’ve had some experience in clinical trials. Of course clinical trials are always different. You have all this support staff and you’re hearing about everything, and patients tend to be more motivated to tell you about stuff, to stop when they’re supposed to stop and continue when they’re supposed to continue as opposed to when the real-world people do what they do. And they either take it or they don’t take it, and they often don’t tell you what they’re doing.

So I don’t know the answer as to whether encorafenib/binimetinib is the best of the 3 regimens, but it’s reasonable to use it and it’s been something that we’ve been doing, in many ways, just to see if it is better tolerated. Because we’ve had such toxicity or because we’ve had to deal with fevers for so long, it would be great if we could have a regimen that didn’t cause that or something else that was equally bad that was substituted for fevers. I think the jury is still out as to whether it should be used in frontline, but it certainly can be used in frontline. And we’ve used it as a frontline BRAF-targeted therapy in a lot of patients to see whether it is like that in the real-world and to get more experience with it.

Geoffrey Thomas Gibney, MD: When I’m meeting with a patient who has BRAF-mutant melanoma, advanced disease that’s unresectable, and we’ve made the decision to move forward with BRAF-targeted therapy, we do have 3 choices with very similar drug regimens; a BRAF inhibitor that’s selectively inhibiting the BRAF V600 protein kinase, and then there’s the MEK inhibitors. Both are taken on a continuous basis, although there are some differences between the dosing schedules. The clinical efficacy among the trials has been very similar. It is difficult to tease out if one truly has better activity over the other. There are some adverse effect profile differences the regimens, including pyrexia and photosensitivity. Those could present challenges for certain patient populations. That may lead you to choosing the encorafenib/binimetinib combination. Patients are also very educated and have done a lot of research a lot of times when they come in. And if they would like to receive encorafenib/binimetinib as opposed to some of the other regimens, I feel very comfortable with prescribing that to the patient.

Hussein A. Tawbi, MD: The decision to treat patients with BRAF-mutated melanoma in the first-line with BRAF-targeted therapy is based on several factors. Again, whether they have immunotherapy options, whether they have clinical trial options as we discussed, particularly at our center, but essentially I consider it a very effective way of managing metastatic melanoma. The evidence that we have is that you can have a progression-free survival of 14.9 months median, which I explain to my patients that means that half of the patients would not have progressed by 14.9 months.

And if we look at the clinical criteria that seem to point in the direction of who does the best, it’s patients who have low volume disease, low LDH, that I would choose this combination for.

I also take into account the potential immunotherapy toxicity. I occasionally have patients that come with a history of autoimmune disorders, or they could be patients who have received immunotherapy in the adjuvant setting and have already progressed on it. And so deciding to start with a BRAF combination makes sense for those patients as well.

Transcript Edited for Clarity.

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