Hussein A. Tawbi, MD, PhD: In terms of the role of the BRAF mutation in melanoma, up to half the patients with melanoma have a BRAF mutation in their tumor. And in those patients, the BRAF mutation actually is oncogenic, which means it actually drives the development of the cancer. We understand very well the pathway that’s involved in that. It’s called the MAP kinase pathway. Because of the mutation, we have a variant signaling for that pathway that drives the cell into continuous proliferation and growth. We also know it affects the tumor microenvironment to make it less immunogenic and less responsive to immune therapy. And so those mutations, again, appear in about half the patients. Specifically, about 80% to 85% of those mutations are V600E. Another 5% to 7% are V600K. Then there’s a smaller percentage of other mutations that could be relevant.

The presence of a BRAF mutation, from my perspective, simply gives us additional alternatives for those patients in terms of using targeted therapy. In the past, there used to be questions about the prognostic significance of having a BRAF mutation, or it seemed to be a bit more of an aggressive disease. But I think the landscape has changed. Now we have therapy that can alter the outcomes of those patients.

The BRAF mutation is a mutation that affects the BRAF gene, which is actually part of the MAP kinase pathway. The MAP kinase pathway is basically a signaling pathway that starts at the cell surface and signals through RAS, then RAF, then MEK, and ERK. ERK is the last protein that actually gets into the nucleus and changes the expression of genes and so on. So that kind of pathway is sequential. When we have a BRAF mutation, the BRAF itself becomes the oncogenic signal, so to speak, and kind of takes over and starts firing through that pathway and activates MEK, activates ERK, and leads to cell proliferation.

The first targeted therapy that was very specific to the mutated BRAF protein was actually vemurafenib, and now we have dabrafenib and encorafenib. Those 3 drugs all go to the mutated BRAF gene, block the signaling through it, and by doing that, shut down the oncogenic signaling through the MAP kinase pathway, leading to cell death. As I discussed a little earlier, this actually changes the tumor microenvironment to be more favorable for immunotherapy as well.

The interesting part is when you inhibit the BRAF gene alone with the BRAF inhibitors. That’s effective and shuts down the oncogenic signaling through the MAP kinase pathway, but the cancer cell tries to figure out ways to bypass it—about 50% through reactivation of MEK, and another 25% also involves activation of MEK, so I usually summarize it at three-quarters of the time. You basically have multiple mechanisms that all kind of hone on MEK and reactivate signaling through MEK cells. That actually makes it a really easy target, because MEK inhibitors were in development as well. So we have trametinib, we have binimetinib, and we have cobimetinib. Those are 3 MEK inhibitors that are capable of shutting down the signaling through that pathway through MEK.

As we started dealing with BRAF inhibitor resistance and figured out that three-quarters of it was driven through MEK, it made a lot of sense to combine BRAF and MEK inhibitors. Obviously, that ended up being more effective—quite significantly more effective. We increased response rates. We increased progression-free survival. And interestingly enough, it ended up being less toxic in general.

It improved the toxicity of BRAF inhibitors, although it kind of generated a few new toxicities that were not as significant before but improved patient outcomes. At this point, we almost never use BRAF inhibitors alone. We always use the combination of a BRAF and MEK inhibitor.

COMBI-AD was a study that looked at the combination of dabrafenib and trametinib compared with dabrafenib alone. It was a large randomized phase III trial that confirmed what we had seen in a smaller randomized phase II trial, which showed that dabrafenib and trametinib had a higher response rate and a better progression-free survival than BRAF inhibition alone with dabrafenib.

We always thought of targeted therapy as something that’s capable of giving you a very quick response. But the progression-free survival is around 10 months, so you kind of figured that within 10 months, you’ll have to find some other therapy for your patient or think about what the next step needs to be.

What people sometimes mistake when we talk about a median progression-free survival is the fact that that’s only the median, which means 50% of patients progress at that time, but the other 50% actually may not progress until later. Some of them may not progress at all. The interesting part from the long-term data is the fact that there is some proportion of patients who don’t progress as they continue on therapy. That proportion can be as high as 20%, 25%, which was really interesting to see, again, because we don’t think about targeted therapy as inducing durable responses. But with 5 years of data, now we actually do.

Transcript Edited for Clarity