BREAKWATER Study Shows Superior ORR With Encorafenib-Based Regimen in BRAF V600E-Mutant mCRC

As the first-line (1L) treatment of BRAF V600E-mutant metastatic colorectal cancer (mCRC) using chemotherapy regimens has historically had limited efficacy, the phase III BREAKWATER study presented at the American Society of Clinical Oncology 2025 Gastrointestinal Cancers Symposium evaluated 1L encorafenib plus cetuximab with or without chemotherapy against the standard of care (SOC) of chemotherapy with or without bevacizumab.

Encorafenib with cetuximab was approved by the FDA in 2024 for previously treated patients with BRAF V600E-mutant mCRC based on results of the BEACON phase III study. In BREAKWATER, patients with untreated BRAF V600E-mutant mCRC, measurable disease based on RECIST 1.1 criteria, and ECOG PS 0-1 were randomized 1:1:1 to undergo treatment with encorafenib plus cetuximab, encorafenib plus cetuximab with FOLFOX, or SOC. After a protocol amendment, enrollment for the encorafenib plus cetuximab arm was closed.

The primary endpoints were objective response rate (ORR) by blinded independent central review, overall survival (OS), and safety for the encorafenib plus cetuximab with FOLFOX and SOC arms. A total of 236 patients received encorafenib plus cetuximab with FOLFOX, while 243 patients underwent SOC.

At the data cutoff in December 2023, the encorafenib plus cetuximab with FOLFOX arm demonstrated a meaningful and significant improvement in confirmed ORR at 60.9% over the SOC arm at 40.0% (OR=2.443, P=.0008).

Encorafenib plus cetuximab with FOLFOX provided a rapid and durable response. While OS data were immature, the early results showed a sustained survival benefit with encorafenib plus cetuximab with FOLFOX over the SOC arm.

Serious treatment-emergent adverse events occurred in 37.7% of the encorafenib plus cetuximab with FOLFOX arm versus 34.6% of patients in the SOC arm. Safety profiles were consistent with that known for each treatment.

The BREAKWATER study demonstrated a durable and rapid improved response rate of encorafenib plus cetuximab with FOLFOX in patients with BRAF V600E-mutant mCRC, with manageable toxicities and no new safety signals.