Key Considerations for Detecting and Targeting BRAF Mutations - Episode 9

Selecting Therapy & Managing Patients With BRAF+ Melanoma


Hussein A. Tawbi, MD, PhD: In the adjuvant treatment of melanoma, at this point, I wouldn’t say that we suffer from this, but we have a bit of an embarrassment of riches. Finally, we have several therapies that can actually improve our patients’ outcomes, and they are safe and tolerable. Again, just to go through the therapies, we have 2 single-agent anti—PD-1 [programmed cell death protein 1] antibodies, nivolumab and pembrolizumab, that have proven safe—about 15% grade 3/4 toxicity and highly effective, decreasing the risk of recurrence by about half, with a hazard ratio that is in the range of 0.5. And then we have targeted therapy, which is at this point dabrafenib and trametinib for patients who have a BRAF mutation. This decreases the risk of relapse by about half.

It should be noted that the 3 different studies that were done to approve each of the therapies were different. Pembrolizumab was compared with placebo, whereas nivolumab was compared with active therapy with ipilimumab. Dabrafenib and trametinib was also compared with placebo, but none of these 3 agents were compared head-to-head. All we can do at this point is get a general sense of how effective they are. As you heard me say, they all have about a 50% reduction in the risk of relapse.

Really, when we have to make a choice in the adjuvant setting, the first thing I always do is test for BRAF. I feel that’s an important consideration and an option that our patients should know about—whether they have it or not. I tend to insist on getting the BRAF result before we start immunotherapy, although I have patients who feel strongly about receiving immunotherapy. It’s clear that they don’t want to have targeted therapy, so I wouldn’t delay their therapy specifically for that. But generally speaking, to have a fuller conversation with your patients, I think knowing the BRAF result is very important.

Then we have the conversation. That conversation is now extended at this point, because we share with them all the data, basically again highlighting that with immunotherapy you have a decreased risk of relapse. The grade 3/4 toxicity is only 15%, and most of the toxicities are manageable. There have been no deaths on study.

However, what we always need to highlight to those patients is that some of those toxicities are actually long-lasting toxicities, specifically endocrinopathies and sometimes neuropathies as well.

That’s an aspect for someone who you’re trying to cure, and that could actually be cured with surgery alone. There’s a chance your therapy may not have been needed. We feel pretty strongly about not giving those patients too much toxicity. And so that is always a discussion with the patient.

When it comes to targeted therapy, we point out that it seems, in general, to be more toxic than immunotherapy. We have about a 30%, or slightly higher than that, rate of grade 3/4 toxicities, and 26% of patients actually stop because of toxicity.

However, that’s where you have some differential depending on the patient’s preference. The toxicity from targeted therapy actually stops the minute you stop the drug. So it’s very limited in time, and it doesn’t induce any long-term toxicities. With those choices that patients have and with this overall discussion of what the benefit is and what the toxicities are, that’s how we end up making decisions with patients.

I just want to share with you that as we design the next adjuvant trial, I tell my patients that I am actually comfortable flipping a coin and deciding which 1 they go for because, technically, there is no proved difference in efficacy. So from an efficacy perspective, these approaches seem to be equally favorable.

The concept of whether patients are compliant with their therapy, or with targeted therapy, is a really important consideration. We’ve learned that from the early days. We really try to highlight that patients need to adhere to their therapy. In the adjuvant setting, that’s probably even more difficult because patients know they’re taking it for prevention of the risk of relapse. It’s not that they’re treating an active tumor, and I think that plays in on the psychology of the situation.

The way we handle this most of the time is really by telling our patients to communicate with us in case they’re having toxicity. Most of the time, they are not going to be compliant, because the drugs are not making them feel good. They’re giving them fevers, fatigue, and some of the adverse effects that are not pleasant. That tends to be the major reason. We always discuss with our patients whether the first step would be to actually decrease the doses or modify the doses so that they’re more tolerable. But in general, I don’t think we have clear data regarding how much those patients comply with their therapy, at least in the adjuvant setting.

Transcript Edited for Clarity