New frontier in the treatment of BRAF V600E-mutated metastatic colorectal cancer: Results of the BREAKWATER Study

BRAF V600E-mutated metastatic colorectal cancer (mCRC) represents one of the greatest challenges in the field of oncology due to its aggressiveness and poor prognosis. This mutation, present in 8%-12% of cases, is known to confer dysregulated signaling in the MAPK pathway, promoting exacerbated cell proliferation and resistance to traditional chemotherapies.

Encorafenib is a BRAF inhibitor with long pharmacodynamic activity and, combined with the anti-EGFR monoclonal antibody cetuximab, has demonstrated efficacy when used in advanced lines of treatment in the BEACON study (NCT02928224). The phase 3 BREAKWATER study, presented at the ASCO® Gastrointestinal (GI) Cancers Symposium 2025, brought new data evaluating this first-line combination and compared its efficacy with standard therapy (chemotherapy with or without bevacizumab).

The BREAKWATER study (NCT04607421) is a global, open-label, randomized clinical trial that included 479 patients with previously untreated BRAF V600E mutation metastatic colorectal cancer (mCRC). Participants were divided into three arms: encorafenib + cetuximab (EC), encorafenib + cetuximab + FOLFOX (EC+FOLFOX), and standard therapy (SOC). After an amendment to the protocol, inclusion in the EC arm was terminated, focusing on the comparison between EC+FOLFOX and SOC. The primary outcomes analyzed were objective response rate (ORR) assessed by independent central review (BICR) and progression-free survival (PFS). Additional data included duration of response, time to response, and overall survival (OS).

The EC+FOLFOX arm demonstrated a statistically significant improvement in ORR compared to SOC (60.9% vs. 40.0%, odds ratio=2.443; P=0.0008). The response was rapid and sustained, with the first signs of benefit observed early in the treatment. OS analysis is still at an early stage, but preliminary data suggest a trend toward prolonged benefit in the EC+FOLFOX arm.

Treatment-related serious adverse events occurred in 37.7% of patients in the EC+FOLFOX arm and in 34.6% in the SOC arm. No new safety signals were identified, and the toxicity profile remained consistent with the known effects of encorafenib, cetuximab, and FOLFOX.

The BREAKWATER study highlighted the potential of encorafenib combined with cetuximab and FOLFOX as a new standard of care for patients with first-line BRAF V600E mCRC, providing a significantly higher response rate and a manageable toxicity profile. These results represent a promising advance for patients facing this aggressive form of colorectal cancer, expanding the possibilities of treatment with efficacy and safety.