First-line treatment with dual-targeted therapies and chemotherapy doubles overall survival in patients with BRAF-mutated metastatic colorectal cancer

• The BREAKWATER open-label, randomized phase 3 study was designed to evaluate first-line treatment with targeted therapies encorafenib and cetuximab plus a mFOLFOX6 chemotherapy regimen compared to standard therapy in patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer.
• Results from second interim analysis show that the investigational combination doubled overall survival compared with standard-of-care (30.3 months versus 15.1 months). It also reduced the risk of death by half in patients who received the new combination.
• These data were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting by first author Elena Élez, a Medical Oncologist at the Vall d’Hebron University Hospital and Head of the Vall d’Hebron Institute of Oncology’s Colorectal Cancer Group.
• Primary analysis of progression-free survival and second interim analysis of overall survival from this international study—co-led by Josep Tabernero, Head of the Vall d’Hebron University Hospital’s Medical Oncology Department and VHIO’s Director, and Scott Kopetz, Professor of Gastrointestinal Medical Oncology at the University of Texas MD Cancer Center in the U.S.—published simultaneously in The New England Journal of Medicine.  

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 harboring 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.

BREAKWATER: supporting a new standard of care for the first-line treatment of patients with BRAF V600E-mutant mCRC

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 Center 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.

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Reference

2025 ASCO Annual Meeting: Corresponding session details

Oral Abstract Session

Track: Gastrointestinal Cancer—Colorectal and Anal

Room: Arie Crown Theater

Date: May 30, 2025

Time: 14:45h (CT)

LBA3500 First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): Progression-free survival and updated overall survival analyses. Elena Elez, MD, PhD, Takayuki Yoshino, MD, PhD, Lin Shen, MD, Sara Lonardi, MD, Eric Van Cutsem, MD, PhD, Cathy Eng, MD, FACP, FASCO, Tae Won Kim, MD, PhD, Harpreet Singh Wasan, MD, Jayesh Desai, FRACP, Fortunato Ciardiello, MD, PhD, Rona Yaeger, MD, Timothy S. Maughan, MD, Van K. Morris, MD, Christina Wu, MD, Tiziana Usari, BSc, Robert Laliberte, MS, Samuel S. Dychter, MD, FFPM, Xiaosong Zhang, MD, PhD, Josep Tabernero, MD, PhD, Scott Kopetz, MD, PhD.

About VHIO

The Vall d’Hebron Institute of Oncology (VHIO), established in 2006 and located within the Vall d’Hebron Campus, is a reference comprehensive cancer center for personalized medicine in oncology. Through our purely translational and multidisciplinary research model, we aim to improve the prevention, early diagnosis and treatment of cancer by transforming the latest scientific discoveries made in the laboratory into early phase clinical trials for the development of more effective therapies to improve the quality of life and survival  of cancer patients.

VHIO forms part of the CERCA – Research Centres of Catalonia system and is accredited as a Severo Ochoa Center of Excellence.

Research at VHIO would not be possible without the support received from our patrons –Generalitat de Catalunya, Fundació Privada CELLEX, "La Caixa" Foundation, Fundación FERO, Fundación BBVA and the CRIS Cancer Foundation– and the public funding it receives as well as the generous support from institutional supporters, private institutions, companies, associations, societies, and individual donors. Only with such continued support will VHIO continue to advance personalized and targeted therapies against cancer.