Addressing Challenges With BRAF Inhibitors in Melanoma
Insights From: Geoffrey Thomas Gibney, MD, MedStar Georgetown University Hospital; Ryan J. Sullivan, MD, Massachusetts General Hospital Cancer Center; Hussein A. Tawbi, MD, University of Texas MD Anderson Cancer Center
Hussein A. Tawbi, MD: BRAF inhibitors, specific BRAF inhibitors—in that case specific to the BRAF V600E mutations—transformed the care of patients with melanoma because we managed to induce really high response rates really quickly in those patients. But we also learned, as soon as we started doing that, that it does come at the expense of toxicity. And so patients with experience with a single-agent BRAF inhibitor would experience significant skin rashes, skin photosensitivity, which means that when they kind of go out in the sun, they would be easily burned. They also experienced some almost echinacea-formed rashes that were quite significant.
So there were a bunch of those, including also developing new cutaneous squamous cell carcinomas. Which was really shocking in that we were kind of creating another form of cancer—a lot more benign, a lot easier to manage, but it was still kind of another form of cancer that happened because of that treatment. So that was 1 thing we learned very quickly.
We also learned that the effect of BRAF inhibitors doesn’t really last very long and that we can induce a really rapid response, get those patients to feel better very quickly. However, a median of 6 months, or kind of on average about 6 months later, those patients’ tumors would start growing back again.
So in trying to understand what was happening in those patients—both why they were experiencing the toxicity and why they were experiencing the progression—we ended up learning very quickly that in normal tissues, a BRAF inhibitor actually activates the MAP kinase pathway and causes the skin toxicity and can cause some liver toxicity and other things. And then we also learned that you know when the tumor progressed, it was also reactivating the MAP kinase pathway. And then putting those 2 things together, you know the next step was actually to think about adding a MEK inhibitor to a BRAF inhibitor.
And you know, MEK is actually kind of a little lower in the pathway than BRAF. It basically gets activated, you know, in normal tissues, and gets reactivated in the tumor that’s progressing. So it made a lot of sense to add a MEK inhibitor to a BRAF inhibitor. And that really—again, speaking of transformation—just by doing that 1 additional thing, we added new drugs, 1 more drug to a drug that was already effective. And it was really fascinating to us because what ended up happening is the combination ended up being a lot more effective, which we were happy with. It prolonged the time before a tumor progresses. But it was really surprisingly a lot less toxic. And so we ended up having way fewer of these skin toxicities and some of those, again, liver toxicities as well. And so it was really good to see that happening, and it quickly became the standard of care for patients with BRAF-mutated melanoma.