Tanios Bekaii-Saab, MD, FACP: As we’ve heard, there is a first-line study that is looking at this specific population of BRAF V600E–mutated tumors. The reasoning for this is, as we learned from BEACON, and as we’ve seen with the phase 2 ANCHOR [trial], there’s certainly a potentially larger benefit as we move these agents to earlier lines of therapy. It makes sense that if you hit biology early, you’re going to have your best benefit. And that’s why we move those to the adjuvant setting as well, ultimately, if they work.

The BREAKWATER study is essentially looking at 2 main questions. The main question is, can we move these BRAF-targeted strategies, encorafenib and cetuximab, into the first line and improve outcomes vs standard chemotherapy? And there are 2 arms that are addressing essentially adding those agents. One is just a biologic without chemotherapy. The other question is [should it be] added to FOLFOX [folinic acid, fluorouracil, oxaliplatin] or FOLFIRI [folinic acid, fluorouracil, irinotecan]?

The first data that came out from the BREAKWATER lead-in studies looked incredibly promising with FOLFOX. It was a little more promising with FOLFIRI. But the choice was to proceed with FOLFOX, primarily based on pharmacokinetic parameters that go beyond this discussion. Both do look promising. The response rate is much higher than we would expect for this patient population, although it’s a small number of patients. The overall study is proceeding with FOLFOX, but there will be an add-on arm with FOLFIRI, which I think is very important given the outcomes. So overall, biologics, biologics plus chemotherapy vs standard chemotherapy of choice, whatever you pick for those patients. Just looking at the initial trends [I’m] very excited, potentially, for one of the worst mutations, not that it’s the only bad mutation, this disease has a lot of bad drivers, but this is definitely one of the worst drivers.

John L. Marshall, MD: HER2 used to be that way. In breast cancer you didn’t want to be HER2-positive, and now you want to be HER2+. Not that we’re there yet with BRAF, but we’re heading there. Cathy, another point on that?

Cathy Eng, MD, FACP: To participate in the trial, it does still require RAS testing. As you mentioned earlier, the amendment was for the FOLFIRI arm to be a separate study to be added. But we want to remind people it’s an international study, and we want people obviously to participate so we can complete the clinical trial.

Tanios Bekaii-Saab, MD, FACP: Yes, I would say one of the good aspects of this study, and that’s a good lesson for drug development, I think the sponsor of the study has done a great job allowing us to add liquid biopsies, given the high concordance rate. In fact, the first 2 patients from my clinic who went on this study were found to have their BRAF V600Emutations on a liquid biopsy, which certainly has facilitated access. We’ve got to move fast, especially in the United States, there’s no waiting.

Stacey Cohen, MD: That’s what prompted us to start doing liquid biopsy. I had a patient who came back later on a tissue sample, and I realized it was a missed opportunity. We want to always be offering these opportunities to patients, especially with [those with] poor prognostic disease.

John L. Marshall, MD: Dr Cohen, I’m going to come back to you on the topic of toxicity with these drugs. Back to drug development and wise drug development, our second-line, third-line indication came off the backs of an investigator-initiated study that was initiated and driven around this idea that we need to hit these pathways more than once. We need to hit the swamp, if you will, in more than one place. It was 2 drugs vs 3 drugs vs [what] you could argue was not the best control arm at the end of the day. It served its purpose [as an] ethical control arm in the end, but it always surprises me that this was in a way better tolerated than either drug separately. [Can you] talk about the toxicities that are observed? A lot of our doctors listening may not have given this combination in colorectal cancer.

Stacey Cohen, MD: Yes. Like many drug therapies, we anticipate that a lot of patients will have some level of toxicity, but the level of grade 3 toxicity was fairly manageable. Patients have a peak of symptoms in first 1 to 2 months, but they don’t seem to have a long duration of symptoms. So there seems to be sort of some getting used to the drugs and then a tolerance, and patients do fairly well. Unlike with a lot of our cytotoxic [drugs], there are not severe cytopenias and severe GI [gastrointestinal] effects. You can have diarrhea, and I think that was one thing [considered] as they were deciding about FOLFIRI or FOLFOX. For patients with especially sensitive GI tracts, it’s something we always are looking out for. But it seemed to be fairly well tolerated, and my patients would far prefer to be on these targeted inhibitors. [There’s] no pump that they have to take home, they can manage the pills, they’re only in the clinic every couple of weeks. They’d rather be on that than on chemotherapy.

John L. Marshall, MD: There is much less rash, but my first patient developed early melanomas. I went to my melanoma friends and they [told me to add] a MEK inhibitor. It went away, which was remarkable. I think that was a cool idea.

Transcript edited for clarity.