Patients with previously untreated BRAF V600E–mutated metastatic colorectal cancer who receive the BRAF inhibitor encorafenib and the EGFR inhibitor cetuximab plus mFOLFOX6 (modified leucovorin, fluorouracil, and oxaliplatin) vs the current standard of care (chemotherapy ± bevacizumab) may live longer, based on progression-free and updated overall survival analyses from the international phase III BREAKWATER trial, reported at a press briefing and during the 2025 ASCO Annual Meeting.¹

“Encorafenib and cetuximab plus mFOLFOX6…is a practice-changing new standard of care for people with metastatic colorectal cancer with a BRAF V600E mutation.”

— Elena Élez, MD, PhD

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“The study previously met one of [its] dual primary endpoints, demonstrating a clinically meaningful and statistically significant improvement in the confirmed overall response rate…,” said lead study author Elena Élez, MD, PhD, of Vall d’Hebron University Hospital, Barcelona. “Therefore, as part of Project FrontRunner, the [U.S. Food and Drug Administration (FDA)] granted accelerated approval for encorafenib and cetuximab plus mFOLFOX6 in this patient population, including in the first-line setting.”

Study Details

The trial included 637 patients with previously untreated BRAF V600E–mutated metastatic colorectal cancer. They had a median age of approximately 60 years, and roughly 50% were women.

Initially, the patients were randomly assigned to one of three treatment regimens: encorafenib and cetuximab alone (n = 158); encorafenib and cetuximab plus mFOLFOX6 (n = 236); or the current standard of care of chemotherapy with or without bevacizumab (n = 243). Enrollment in the encorafenib/cetuximab alone group was closed early because of emerging data from the phase II ANCHOR CRC study, suggesting the efficacy of encorafenib plus cetuximab may be comparable to that of historical standard-of-care chemotherapy and unlikely to be superior. (This type of change to the study design is called a protocol amendment.)

“Key demographic and baseline disease characteristics were well balanced between the arms, with an important proportion of patients with three or more organs involved and presence of liver metastases, which is expected for this poor-prognosis population,” commented Dr. Élez.

The co-primary endpoints were overall response rate and progression-free survival, both assessed by blinded independent central review, comparing the combination of encorafenib and cetuximab plus mFOLFOX6 with the standard of care. Overall survival between these arms was evaluated as the key secondary endpoint. This presentation included the primary analysis of progression-free survival, updated interim analysis of overall survival, updated safety, and other analyses.

Key Results

The median duration of progression-free survival was longer with encorafenib and cetuximab plus mFOLFOX6 vs standard-of-care therapy (12.8 vs 7.1 months; hazard ratio = 0.53; P < .0001); this experimental regimen was found to reduce the risk of disease progression or death by 47%. Those who received encorafenib and cetuximab alone had a median duration of progression-free survival of 6.8 months, which Dr. Élez described as “numerically comparable” to that of the standard of care.

The median duration of overall survival was 19.5 months with encorafenib and cetuximab alone, 30.3 months with encorafenib and cetuximab plus mFOLFOX6, and 15.1 months with standard-of-care therapy. Between the latter two arms, the hazard ratio was 0.49 (P < .0001), indicating a 51% reduction in the risk of death with encorafenib and cetuximab plus mFOLFOX6.

“These survival data are unprecedented,” commented Dr. Élez, “given the historically poor prognosis in BRAF-mutated metastatic colorectal cancer.”

The confirmed overall response rate was 45.6% with encorafenib plus cetuximab alone, 65.7% with encorafenib plus cetuximab and mFOLFOX6, and 37.4% with standard-of-care therapy; according to Dr. Élez, these results are consistent with those of the previous analysis. The percentages of patients with a duration of response of at least 6 months (71.0% vs 41.8%) and 12 months (34.8% vs 17.6%) were approximately twice as high with encorafenib and cetuximab plus mFOLFOX6 vs the standard of care.

According to Dr. Élez, treatment with encorafenib and cetuximab plus mFOLFOX6 was generally tolerable, with a safety profile consistent with that known for each agent. Serious treatment-emergent adverse events were observed in 30%, 46%, and 39% of the encorafenib and cetuximab alone, encorafenib and cetuximab plus mFOLFOX6, and standard-of-care therapy arms, respectively. The most frequently reported side effects with encorafenib and cetuximab plus mFOLFOX6 were nausea, anemia, and diarrhea. “Of note, there was not a substantial increase in dose reductions or modifications in the encorafenib and cetuximab plus mFOLFOX6 group,” Dr. Élez added.

“Encorafenib and cetuximab plus mFOLFOX6…is a practice-changing new standard of care for people with metastatic colorectal cancer with a BRAF V600E mutation,” concluded Dr. Élez. Future studies will investigate the use of encorafenib and cetuximab in combination with the FOLFIRI regimen (leucovorin, fluorouracil, and irinotecan).

DISCLOSURE: The study was funded by Pfizer. Dr. Élez has received honoraria from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cure Teq AG, Janssen, Lilly, Medscape, Merck, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Repare Therapeutics, RIN Institute, Roche, Sanofi/Aventis, Seagan; Servier, and Takeda; has served as a consultant or advisor to Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cure Teq AG, Janssen, Merck, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Repare Therapeutics, RIN Institute, Roche, Sanofi, Seagen, Servier, and Takeda; has received institutional research funding from AbbVie, Amgen, Array BioPharma, AstraZeneca, Bayer, BeiGene, Bioncotech, BioNTech RNA Pharmaceuticals GMBH, BioNTech Small Molecules GMBH, Boehringer Ingelheim, Boehringer Ingelheim Spain, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Debiopharm Group, Genentech, Gercor, HalioDx, Hoffmann–La-Roche Ltd., Hutchison MediPharma, Hutchison MediPharma, Iovance Biotherapeutics, Janssen Research & Development, Janssen-Cilag SA, MedImmune, Menarini, Merck, MSD de España SA, Merus NV, Mirati Therapeutics, Nouscom SRL, Novartis, Novartis Farmacéutica SA, Pfizer, PharmaMar, Pierre Fabre, PledPharma, Redx Pharma, Roche, Sanofi, Scandion Oncology, Seagen, Servier, Sotio, Taiho Pharma USA, Taiho Pharmaceutical, and WntResearch; and received reimbursement for travel, accommodations, and expenses from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cure Teq AG, Janssen, Lilly, Medscape, Merck, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Repare Therapeutics, RIN Institute, Roche, Sanofi, Seagan, Servier, and Takeda. For full disclosures of the other study authors, visit coi.asco.org.

REFERENCE

1. Élez E, Yoshino T, Shen L, et al: First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): Progression-free survival and updated overall survival analyses. 2025 ASCO Annual Meeting. Abstract LBA3500. Presented May 30, 2025.

EXPERT POINT OF VIEW

“The BREAKWATER trial is yet another victory in the march toward precision oncology,” said invited discussant Joel N. Saltzman, MD, FASCO, Vice Chair of Regional Oncology at Taussig Cancer Center, Cleveland Clinic, and an ASCO expert in gastrointestinal cancers. The “dramatic” improvement in overall survival and response rate seen with the targeted encorafenib and cetuximab plus mFOLFOX6 regimen vs standard-of-care therapy will likely translate to improved quality of life for patients with BRAF V600E–mutated metastatic colorectal cancer, he highlighted.

Joel N. Saltzman, MD, FASCO

Julie R. Gralow, MD, FACP, FASCO

“With biomarker testing, we now have three distinct subtypes of metastatic colorectal cancer. It is important to know about [the patient’s] BRAF [mutation] status, RAS mutation status, and microsatellite-stable status when deciding initial therapy…,” Dr. Saltzman remarked. “This study further emphasizes the importance of upfront biomarker testing to find the best available therapies to proceed with in colorectal cancer.”

Also commenting on the BREAKWATER findings was press briefing moderator Julie R. Gralow, MD, FACP, FASCO, Chief Medical Officer and Executive Vice President of ASCO. Dr. Gralow remarked that when a surrogate endpoint (ie, overall response rate) is used to get a regimen or drug approved, it is key that follow-up is showing progression-free and overall survival. “We have locked in the key clinically important endpoints...,”she added.

DISCLOSURE: Dr. Saltzman and Dr. Gralow reported no conflicts of interest.