Results of progression-free survival (PFS) and updated interim overall survival (OS) analyses from the phase 3 BREAKWATER study show that the combination of dual-targeted therapies encorafenib and cetuximab plus a mFOLFOX6 chemotherapy regimen versus standard-of-care (SOC) significantly improved outcomes in previously untreated patients with metastatic colorectal cancer (mCRC) patients harbouring BRAF V600E mutations.

The findings, presented at the 2025 ASCO Annual Meeting by Elena Élez a Medical Oncologist of the Vall d’Hebron University Hospital and Head of the Vall d’Hebron Institute of Oncology’s (VHIO) Colorectal Cancer Group, and published in The New England Journal of Medicine, demonstrated that the investigational combination doubled OS compared to the standard-of-care treatment – chemotherapy with or without bevacizumab.

BRAF V600E mutations occur in 8% to 12% of cases and are associated with a poor prognosis.

In 2019, results from the BEACON study led by Josep Tabernero, Head of the Medical Oncology Department at the Vall d’Hebron University Hospital and VHIO’s Director, demonstrated that targeted therapy including BRAF inhibitor encorafenib and EGFR inhibitor cetuximab significantly prolonged OS and improved response rates compared with SOC in patients with previously treated BRAF V600E-mutant mCRC.

“Based on these results, the combination of encorafenib plus cetuximab was approved in most countries for BRAF V600E-mutant metastatic colorectal cancer in the second and third-line settings. However, first-line strategies have had limited efficacy in the treatment of this patient population,” said Josep Tabernero, co-Principal Investigator of the BREAKWATER phase 3 study along with Scott Kopetz, Professor of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Centre in the U.S.

Median overall survival of 30.3 months

BREAKWATER included 637 patients with previously untreated BRAF V600E-mutant mCRC who were randomly assigned to receive the combination of encorafenib and cetuximab, with or without the mFOLFOX6 chemotherapy regimen with fluorouracil, leucovorin and oxaliplain, or standard therapy.

“Results demonstrate a clinically meaningful and statistically significant overall survival improvement with the investigational combination versus standard-of-care treatment. The median overall survival was 30.3 months in patients assigned to encorafenib and cetuximab plus chemotherapy, compared to 15.1 months in patients who received standard therapy,” observed Elena Élez, BREAKWATER study coordinator at Vall d’Hebron as one of the main recruitment sites for this study.

The investigators also observed improved PFS, with a median of 12.8 months in patients treated with encorafenib and cetuximab plus mFOLFOX6 compared to 7.1 months in those who received standard treatment.

Results also showed a 47% reduction in the risk of disease progression or death and a 51% reduction in the risk of death with the investigational combination compared to standard treatment.

“This new first-line treatment strategy shows unprecedented benefits for patients with BRAF V600E-mutant metastatic colorectal cancer, which will imply a radical change in the prognosis for this patient population,” concluded Élez.

Source: Vall d'Hebron Institute of Oncology