D. Ross Camidge, MD: Dabrafenib and trametinib got an FDA license because, in the setting of a BRAF V600E mutation, the regimen has something like a 66% response rate and a PFS [progression-free survival] of about 9 months. It’s a classic targetable oncogene. And that’s good enough, but that’s something you prioritize over chemotherapy. That’s why it’s listed as something you would do first. It doesn’t matter what the PD-L1 [programmed death-ligand 1] status is, and it doesn’t matter what else is going on. If you knew that information, you could go for a BRAF/MEK combination up front.

BRAF inhibitor monotherapy is not something you would normally consider. The response rate is about half of that. In fact, it’s actually more toxic than the combination. That feedback loop that you interrupt with the MEK inhibitor, when you use the MEK inhibitor together with the BRAF inhibitor in many people—it actually reduces the adverse effects. It certainly reduces some of the cutaneous adverse effects where people get appearing squamous cancers. And that’s much less with the combination. It’s not the easiest combination to take, however. There are adverse effects. The common things are pyrexias and rigors, and that’s quite a shock to a patient because they suddenly feel as if they have the worst flu they’ve ever had. If that happens, there are very clear instructions for how to manage in the patient information sheet. You probably hold the drug. You can give prophylactic antipyretics like Tylenol. Sometimes you need to give a short course of steroids. Sometimes we’ll even use Demerol. You find a balance that works for that patient. Very few of my patients can stay on it completely uninterrupted. It’s unclear why people will suddenly have a day when they have rigors, and you have to do something about it.

Non—BRAF V600E mutations are very much a work in progress. Some of them clearly don’t respond to BRAF inhibitors. Some of them might respond to MEK inhibitors, but I think most of them are not targetable as yet. There are certainly no approved agents. I think they’re going to go down the chemotherapy or chemoimmunotherapy approach. Something like half the patients with a BRAF mutation are actually smokers, so it’s not your classic never-smoking female Asian that we learned about with an EGFR mutation. That means you should be testing people for it, even if they don’t fit your classic, “They’ve got a driver oncogene” subset. But it also means that even though other driver oncogenes don’t respond quite so well to immunotherapy, this might be a group for which adding an immunotherapy to chemotherapy certainly makes a lot of sense. And if you didn’t use it, you could even use it as monotherapy.

If I find someone with a BRAF V600E mutation, I’m going to try the standard full dose of dabrafenib-trametinib. Then I’ll go down on the dose when they don’t tolerate it. If they don’t have a BRAF V600E mutation, I’m probably going to treat them as if they don’t have an actionable driver oncogene. They’re going to get chemotherapy or chemoimmunotherapy, depending on whether they have any contraindications to any of those elements.

If you knew a patient had a BRAF V600E mutation, and even if they had high PD-L1 expression, you’d still try to prioritize the TKI approach. This has nearly a 70% response rate, even a tumor proportion score of 50%, and is running about a 48% response rate with immunotherapy. It may be about 60% with chemoimmunotherapy plus the adverse effects of chemotherapy. So I think it’s a bit of a no-brainer. You try to prioritize the targeted therapy, and indeed, that’s what most of the guidelines will actually suggest. You would prioritize targeting that BRAF V600E mutation and keep everything else in reserve.

Sometimes somebody might ask, “Can you combine the TKIs with immunotherapy or chemoimmunotherapy?” The answer is, no. In general, TKIs combine very poorly together with immunotherapy. Conceivably, you could combine them together with chemotherapy alone, but I don’t think that’s what we’re currently doing as a first-line option.

If you look at the patient information sheet for the dabrafenib-trametinib combination, you see that the top adverse effects are these rigors and pyrexias. You give antipyretics. You give steroids. Your strategy includes dose holding and dose reduction. And then there’s a list of rarer adverse effects. You can get fatigue, there’s a marginally increased risk of hemorrhaging, there’s a very low risk of cardiomyopathy, and you can get some eye abnormalities. These are all kind of single-figure percentages. If you’re a good clinician, if somebody comes in and says, “I’m getting blurry vision,” you send them to see the ophthalmologist to figure that out. If they’re starting to say, “I’m becoming short of breath,” and you rule out a respiratory cause, think about a cardiac cause. If they start hemorrhaging, that’s a bit of a no-brainer.

The biggest adverse effects that I think affect the acceptability of this regimen are the rigors and the pyrexia. I’ve certainly had some patients, especially more elderly patients, who’ve said, “I can’t put up with this.” And what you have to do is reassure them. You say, “I’ll just hold the drug. We’ll let it settle.” And then you work on a regimen that works for them, whether it’s a lower dose, regular low doses of steroids, Tylenol, etc.

If this is the first time you’ve started a patient on dabrafenib and trametinib, make sure you’ve at least read the patient’s information sheet, so you know how to manage the adverse effects. But I think you have to go in and you have to say to the patient, “This may or may not be tolerable at the initial starting dose and regimen,…so let’s just take it cautiously.” Put them on it, bring them back fairly soon, and reassure them that if it’s bad, you can play around with the dosing schedule and supportive medication.

Transcript Edited for Clarity