Combination Therapy in BRAF-Mutated mCRC: The BREAKWATER Trial

Shared insight on the BREAKWATER trial, which combined encorafenib, cetuximab, and chemotherapy in patients with BRAF V600E–mutated metastatic colorectal cancer.


Kristen K. Ciombor, MD: Dr Raghav, why don’t you talk to us a bit about the BREAKWATER trial? We talked about HER2 and the MOUNTAINEER study, and now we’re moving tucatinib and trastuzumab up to the first line. Tell us about what BREAKWATER is trying to do.

Kanwal P. Raghav, MD: I think this is good progression when it comes to developing therapies in colorectal cancer. We were talking about when you treat with anti-EGFR [therapy] and chemotherapy, you don’t really acquire these mutations. In some ways I think the chemotherapy is changing the biology of this tumor, whether it’s changing it to more of a stem cell phenotype or a more resistant epithelial-mesenchymal transition phenotype, which is in turn, also affecting resistance to molecular therapies. That’s why when we bring these molecular therapies up in the lines of treatment, you have better responses. If you treated a more refractory population with anti-HER2 [therapy], you may not have as much [of a] response as you would have if you treated it early. I think we already have that example from the MOUNTAINEER study, but BREAKWATER is a similar finding. Clearly, we have not hit a home run with the BEACON trial. Response rates are still around 20%, median survival is still less than 9 months or so.

BREAKWATER is an attempt at movingBRAF and anti-EGFR therapy in combination with chemotherapy right up front. It’s designed as a large phase 3 study with close to 800 patients, with a safety run-in for initial safety with chemotherapy, because we don’t know how to give these drugs with chemotherapy. It’s designed as a 3-arm study in which you’re treating withBRAFplus anti-EGFR therapy, BRAF plus anti-EGFR in combination with chemotherapy, and then whatever would be considered chemotherapy that is standard of care. The safety run-in was reported, and it showed really encouraging response rates. I think the response rates in combination with FOLFOX [folinic acid, fluorouracil, oxaliplatin] and FOLFIRI [folinic acid, fluorouracil, irinotecan] was upward of 60% to 70%, which is great for a tumor type that we know is fairly resistant to chemotherapy up front. You do not see those types of responses in patients with BRAF mutations, even with first-line chemotherapy.

Of course, the follow-up for overall survival and PFS [progression-free survival] is limited, but I think the median PFS was also approaching 7 or 8 months, which is pretty high. Now I think comes the harder part, which is doing the randomized trial and seeing whether the addition of chemotherapy really made a difference, or is it all that we just moved the BRAF therapy. We are eagerly waiting for this study to finish, and hopefully this will help our patients with BRAF mutations much more than BEACON.

Joel R. Hecht, MD: Then you also have the problem of what to do next, because this was sort of the 3-chemotherapy drug problem up front. Let’s say that it’s positive; these are really good results. What do you do then with the patient who has now progressed on chemotherapy plus combination molecular therapy? Is there any benefit to keeping people on, even though we know they have resistance mechanisms? We know they’re going to do poorly once you stop these things. I don’t know, I’m just bringing that up. That’s always been the problem. People brought up, for example, FOLFIRINOX [folinic acid, fluorouracil, irinotecan, oxaliplatin]. What do you do next after that?

Kanwal P. Raghav, MD: I think it’s a valid question. I think the primary end point of the study is overall survival, knowing that we have BRAF [therapy] available to patients who would not get BRAF initially. It is a good question to answer, but if you were to place your money on it, you would say that for an aggressive tumor type, if you bring all your treatment up front, you’re probably going to have that benefit. I would link this more to how we would treat pancreatic cancer, for example. The earlier you can bring the treatments, the better.

Kristen K. Ciombor, MD: Because patients are not guaranteed to get to the next line of therapy otherwise, especially in this subtype….

Joel R. Hecht, MD: The falloff, even in people who do not have BRAF [mutations]. One of the things that as GI [gastrointestinal] oncologists, if you go from trial to trial, you think that everyone who’s in first line goes to second line. Even in people without bad mutations, only about 60% to 70% of people who get first-line therapy ever get second-line therapy. They’re not all patients with BRAF mutations. They fall off for other reasons, and this is a group that falls off really quickly. That makes perfect sense.

Transcript edited for clarity.

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