BREAKWATER triplet improves PFS in first-line BRAF V600E metastatic colorectal cancer

Phase 3 BREAKWATER found encorafenib plus cetuximab plus FOLFIRI improved progression-free survival and response in first-line BRAF V600E-mutant metastatic colorectal cancer. According to topline data from the phase 3 BREAKWATER trial (NCT04607421), the regimen produced significant and clinically meaningful improvement in progression-free survival in previously untreated patients with metastatic colorectal cancer harboring a BRAF V600E mutation.

In the latest trial read-out, the encorafenib-based regimen significantly reduced the risk of disease progression or death compared with standard-of-care chemotherapy with or without bevacizumab in cohort 3 of the trial (n = 147). In addition to PFS, the study demonstrated favorable trends in overall survival with the triplet, another key secondary end point, although these data remain immature at the current analysis. The safety profile of the triplet remained consistent with previously reported data for each individual agent, with no new safety signals identified.

Data shared at the 2026 American Society of Clinical Oncology Gastrointestinal Cancers Symposium indicated that the primary end point of objective response rate per blinded independent central review was substantially higher with the triplet (64.4% vs 39.2%; OR, 2.76; 95% CI, 1.42-5.35; P = .001), with responses described as more rapid and durable than those seen with traditional chemotherapy.

BREAKWATER is an open-label, multicenter, randomized phase III study evaluating encorafenib plus cetuximab, with or without chemotherapy, versus standard-of-care therapy in patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer. The BREAKWATER study is a global, randomized, multicenter, open-label phase 3 trial that enrolled a total of 831 treatment-naive patients with BRAF V600E-mutant metastatic colorectal cancer across different treatment cohorts.

In cohort 3, a FOLFIRI backbone was explored, with patients randomized on a 1:1 basis to receive either the triplet (n = 73) or FOLFIRI with or without bevacizumab (n = 74). Those assigned to the triplet arm received 300 mg of encorafenib orally once daily with cetuximab and FOLFIRI. This analysis focuses on progression-free and overall survival with first-line encorafenib plus cetuximab plus FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer.

Detailed results are expected to be presented at an upcoming medical meeting. With detailed data from cohort 3 expected to be shared with the FDA for potential approval of the regimen in this patient population, the latest BREAKWATER findings could further solidify the triplet in frontline treatment for these patients.