BREAKWATER makes waves in BRAF V600E-mutant mCRC treatment

First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (mCRC) reduced the risk of death by 51% and doubled the overall survival (OS) and progression-free survival (PFS).

Results from the phase 3 BREAKWATER trial (NCT04607421), presented by Dr Elena Élez (Vall d’Hebron Institute of Oncology, Barcelona, 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 patients with BRAF V600E-mutant mCRC, a targeted combination regimen consisting of a BRAF inhibitor (encorafenib), an anti-EGFR monoclonal antibody (cetuximab), and mFOLFOX6 (a chemotherapy backbone of 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 OS in the combination arm reached 30.3 months, more than double the 15.1 months observed in the control arm. The benefit was mirrored in progression-free survival (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). “These are the first promising survival outcomes ever reported for BRAF-mutant mCRC in the first-line setting, representing a practice-changing breakthrough,” said Dr Élez.

In addition to survival metrics, the objective response rate (ORR) was also significantly improved: 65.7% in the triplet-therapy arm versus 37.4% in the control group. Median duration of response and time to response also favoured the triplet regimen.

“This trial continues to move the needle forward to a more personalised approach to care based on the molecular and genetic characteristics of metastatic colon cancer. These data establish frontline encorafenib, cetuximab, and FOLFOX as the new standard-of-care for BRAF V600E-mutant mCRC,” said 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. 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,” said 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.

Medical writing support was provided by Dr Rachel Giles.
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Posted on 2 June 20252 June 2025