BREAKWATER makes waves in BRAF V600E-mutant mCRC treatment

First-line encorafenib plus cetuximab combined with mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (mCRC) reduced the risk of death by 51% and doubled the overall and progression-free survival (PFS) compared to the standard-of-care.

Results from the phase 3 BREAKWATER trial (NCT04607421), presented by Dr Elena Élez (Vall d’Hebron Institute of Oncology, Spain) and published simultaneously in the New England Journal of Medicine, highlight a potential shift in the first-line treatment of mCRC with BRAF V600E mutations [1,2]. Dr Élez explained the rationale: “The BRAF V600E mutation occurs in approximately 8–12% of mCRC cases and is associated with a significantly worse prognosis” [3].

In treatment-naïve participants with BRAF V600E-mutant mCRC, a targeted combination regimen consisting of the BRAF inhibitor encorafenib, plus the anti-EGFR monoclonal antibody cetuximab, with the chemotherapy mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) achieved a 51% reduction in the risk of death compared with standard-of-care chemotherapy (HR 0.49; 95% CI 0.38–0.63; P<0.0001).

Median overall survival in the combination arm reached 30.3 months, more than double the 15.1 months observed in the control arm. The benefit was reflected in PFS: 12.8 months in the experimental group versus 7.1 months in the standard-of-care arm (HR 0.53; 95% CI 0.41–0.68; P<0.0001; see Figure). “These are the first promising survival outcomes ever reported for BRAF-mutant mCRC in the first-line setting, representing a practice-changing breakthrough,” added Dr Élez. In addition to survival metrics, the objective response rate was also significantly improved with 65.7% in the experimental arm versus 37.4% in the control group. The median duration of response and time to response also favoured the triplet regimen.

Figure: Progression-free survival in participants with BRAF V600E mutated metastatic colorectal cancer treated with first-line encorafenib plus cetuximab with or without mFOLFOX6, or standard care [1]



EC, ecorafenib plus cetuximab; mFOLFOX6,  fluorouracil, leucovorin, and oxaliplatin.

“This trial continues to move the needle forward to a more personalised approach to care of metastatic colon cancer based on the molecular and genetic characteristics. These data establish first-line encorafenib plus cetuximab, with mFOLFOX6 as the new standard-of-care for BRAF V600E-mutant mCRC,” acknowledged Dr Joel Saltzman (Cleveland Clinic, OH, USA), speaking as an ASCO-appointed expert.

Safety outcomes were consistent with the known profiles of the included agents, and no new safety signals were identified. The most frequently reported adverse events (≥30%) included nausea, diarrhoea, anaemia, decreased appetite, neutropenia, arthralgia, rash, and vomiting, with a low rate of grade 3–4. Approximately 14% of participants discontinued the BRAF inhibitor due to adverse events.

“This trial demonstrates that understanding the biology of cancer translates into clinically meaningful outcomes,” concluded Dr Élez. “With the right tools and patient selection, we can go beyond modest responses and change the trajectory of this aggressive disease.”

1. Élez E, et al. First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): Progression-free survival and updated overall survival analyses. Abstract LBA3500, ASCO Annual Meeting 2025, 30 May–3 June, Chicago, IL, USA.
2. Elez E, et al. N Engl J Med. 2025;392(1):1–12.
3. Kopetz S, et al. Nat Med. 2025;31(3):901–908.

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Posted on 30 July 2025