John L. Marshall, MD: Let’s first think about the pathway, in general, for signaling through BRAF. We know it starts with an EGFR receptor on the surface. Now, we’ve been targeting EGFR, HER1, for a long time. We have cetuximab, and we have panitumumab—monoclonal antibodies that sit and block that receptor. But we recognized that if you had a BRAF mutation, it didn’t work quite as well. What we figured out is that BRAF is, in fact, downstream of the EGFR receptor.

When we first tried BRAF inhibitors alone in colon cancer, they didn’t work. They certainly didn’t work the way they do in melanoma, where they are a really powerful driver. So it didn’t really make sense why, if we’re hitting the same pathway but just downstream, it didn’t work. But the biology is the biology. This pathway has lots of routes. And so, if you block in 1 place, it has its way of working its way around it. So what we’ve slowly figured out over the last few years is that you hit this pathway in more than 1 setting. First, you hit it with an EGFR monoclonal antibody. Second, you hit it with a BRAF inhibitor. And when we do just those 2 things, we know we’ve already seen an increase in benefit rate. We are seeing benefit, and we are seeing approvals and guideline acceptance of that kind of combination.

But the news is that we can hit it a third time. Downstream from there is MEK. MEK is another part of this pathway. And if we not only hit it at the receptor and at BRAF, but also at MEK, we’re seeing even more activity. And so, this concept of using multiple targeted agents hitting 1 pathway may be a bit counterintuitive to us, but it’s working clinically, day in and day out.

It’s been fascinating to watch drug development in colorectal cancer around this BRAF world. Traditionally, we think of needing to have large phase III randomized studies to change practice. But in the case of BRAF, we’re using medicines that are already on the market. And as we all know, guidelines are maybe just as good as FDA approval when it comes to accessing medicines for us. The payers will provide us these medicines if they make it on the guidelines. What’s really changing the world right now is that with essentially fairly small, randomized phase II studies, we’ve been making, year after year, positive steps in targeting BRAF.

The first person who really did this was Scott Kopetz, MD, PhD, FACP. Scott, a great guy, ran a brilliant study. This was a randomized phase II study of irinotecan and an EGFR inhibitor, cetuximab, versus irinotecan, cetuximab, and vemurafenib, which is a BRAF inhibitor, only in BRAF V600E colon cancer patients. There were 50 patients on each arm. And what we saw is that in the group that got the 3 drugs, there was a significant bump in response rate and progression-free survival, and a trend toward overall survival, of course. But with 50 patients, you can’t make those claims. And what’s nice about that is that in the colon cancer world, where we are in fact desperate for more therapies, the guideline gang got together and said, “You know what? That’s enough. Let’s put that on our guidelines.” And so, very quickly, based on phase II randomized data, we have access to these triplet therapies in BRAF, immediately transforming our entire practice about requiring, really, patients to have BRAF testing now, because you now have a therapy.

So then Ryan Corcoran, MD, PhD, does the same sort of thing in a phase II study. He steals stuff from our melanoma friends and uses trametinib and dabrafenib in combination with an EGFR, in this case panitumumab, and likewise shows that now we’ve got dual inhibition downstream. Now we’ve got not only the BRAF inhibitor, but we’ve got the MEK inhibitor. And so, now we’re hitting this pathway 3 times, and in fact, showed a bump in response rate, which then really sparks the subsequent, larger study called the BEACON trial.

To be honest, this is a larger, more definitive study. It’s a randomized clinical trial. It’s fascinating, from a sort of cultural basis, because it was meant to be a global study. Many of us, including those of us at Georgetown University, opened this clinical trial, but it was open at the same time we were changing guidelines. So if you had a BRAF-positive patient, there was sort of an incentive to not put them on the study because you had 1 of the arms of the study, in essence, available to you.

So they actually closed it down in the United States, and it was done in the rest of world. And this study uses different medicines. It uses the drugs encorafenib and binimetinib in combination with an EGFR monoclonal, cetuximab. And it was randomized against what would be, I guess, the gold standard, or the current standard of care, of an EGFR and irinotecan.

We have the results based on a press release. We expect that to be fully presented soon. But what it showed was that the triplet combination was far superior to the current standard, of irinotecan and cetuximab, in this EGFR-positive, RAS wild-type, but BRAF-mutated tumor. It also proves to us that this BRAF mutation does make a patient resistant to EGFR targeting by itself.

So what this tells us, as practitioners, is that if you don’t know your patient’s BRAF status and you’re considering giving an EGFR targeted therapy, you have to know. Because it won’t work if they have this BRAF V600E mutation.

Transcript Edited for Clarity