The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the approval of encorafenib (Braftovi) in combination with cetuximab (Erbitux) and FOLFOX (fluorouracil, leucovorin, and oxaliplatin) for the first-line treatment of adult patients with BRAF V600E–mutant metastatic colorectal cancer (mCRC).1 A final marketing authorization decision from the European Commission (EC) is anticipated later in 2026.
The positive opinion is supported by results from the phase 3 BREAKWATER trial (NCT04607421), in which encorafenib combined with cetuximab and modified FOLFOX6 (mFOLFOX6) generated a statistically significant improvement in progression-free survival (PFS) compared with oxaliplatin-based chemotherapy with or without bevacizumab (Avastin). At a median follow-up of 16.8 months (95% CI, 15.1-18.4) for the experimental arm and 9.8 months (95% CI, 8.5-13.0) for the standard of care (SOC) arm, patients treated with encorafenib plus cetuximab and mFOLFOX6 (n = 236) achieved a median PFS of 12.8 months (95% CI, 11.2-15.9) compared with 7.1 months (95% CI, 6.8-8.5) for those given SOC (n = 243; HR, 0.53; 95% CI, 0.41-0.68; P < .0001).2
The encorafenib regimen also produced a statistically significant improvement in the dual primary end point of objective response rate (ORR) in the primary analysis set and reduced the risk of death by 51% vs the control arm.1
“Today’s positive CHMP opinion marks an important step towards a targeted approach for patients with BRAF V600E–mutant mCRC,” Eric Ducournau, chief executive officer of Pierre Fabre Laboratories, stated in a news release. “If approved, it would be the only approved targeted therapy in the [European Union] for this patient population in the first-line setting.”
Encorafenib Plus Cetuximab and mFOLFOX6: A First-Line First in the European Union
- The European Medicines Agency’s CHMP issued a positive opinion recommending encorafenib plus cetuximab and mFOLFOX6 for first-line BRAF V600E–mutant mCRC.
- In the BREAKWATER trial, the combination reduced the risk of disease progression or death by 47% vs chemotherapy with or without bevacizumab (median PFS, 12.8 months vs 7.1 months, respectively; HR, 0.53; 95% CI, 0.41-0.68; P <.001).
- If approved by the EC, encorafenib plus cetuximab and FOLFOX would become the first and only BRAF-targeted regimen approved in the EU for the first-line treatment of patients with BRAF V600E–mutant mCRC.
What was the design of BREAKWATER?
BREAKWATER was a randomized, active-controlled, open-label, multicenter trial enrolling treatment-naive patients with mCRC who displayed a BRAF V600E mutation.3 In the phase 3 portion, patients were randomly assigned 1:1:1 to 1 of 3 arms to receive:
- Encorafenib orally once daily with intravenous (IV) cetuximab infusion every 2 weeks (arm A)
- Encorafenib orally once daily with cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks (arm B)
- mFOLFOX6 or FOLFOXIRI (leucovorin calcium, fluorouracil, oxaliplatin, and irinotecan hydrochloride) every 2 weeks or CAPOX (capecitabine and oxaliplatin) every 3 weeks, each with or without bevacizumab (arm C)
Upon amendment to the trial to limit randomization to arms B and C, a new cohort was initiated. In cohort 3, patients were randomly assigned 1:1 to receive 1 of the following 2 regimens:
- Encorafenib orally once daily with IV cetuximab IV infusion every 2 weeks and FOLFIRI every 2 weeks (arm D)
- FOLFIRI every 2 weeks, with or without bevacizumab (arm E)
Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death.
The primary efficacy outcomes in the phase 3 portion were PFS in the overall population and ORR in the first 110 patients randomly assigned to each arm per blinded independent central review (BICR). OS in all patients was an additional end point. The major efficacy outcome measure in cohort 3 was ORR per BICR.
What additional efficacy data with encorafenib plus cetuximab and mFOLFOX6 have been reported from BREAKWATER?
Previously reported data from the primary analysis of BREAKWATER showed that the ORR rate was 61% (95% CI, 52%-70%) with the investigational combination vs 40% (95% CI, 31%-49%) with SOC (P = .0008) among the first 110 patients treated in each arm.3,4 The median durations of response (DORs) were 13.9 months (95% CI, 8.5-not estimable [NE]) and 11.1 months (95% CI, 6.7-12.7), respectively.4
Findings presented ahead of the 2025 ASCO Annual Meeting and published in the New England Journal of Medicine demonstrated that encorafenib plus cetuximab and mFOLFOX6 generated a median overall survival (OS) of 30.3 months (95% CI, 21.7-NE) vs 15.1 months (95% CI, 13.7-17.7) for SOC (HR, 0.49; 95% CI, 0.38-0.63 P < .0001).2 The estimated 12- and 24-month OS rates in the experimental arm were 80.1% and 52.0%, respectively. These respective rates were 66.0% and 29.0% in the SOC arm.
What was the safety profile of the BREAKWATER regimen?
Regarding safety, investigators deemed the encorafenib/cetuximab/mFOLFOX6 regimen to be generally tolerable.2 All patients experienced any-grade adverse effects (AEs) in the encorafenib/cetuximab/mFOLFOX6 arm vs 99.1% of patients in the SOC arm and 97.4% of patients in the encorafenib/cetuximab arm. The rates of grade 3/4 AEs were 81.5%, 66.8%, and 42.5% in these respective arms. The respective rates of grade 5 AEs were 4.3%, 4.4%, and 2.6%. Only 1 grade 5 AE was deemed treatment-related in the SOC arm.
What are the current indications and future readouts planned for the BREAKWATER regimens?
In December 2024, the FDA granted accelerated approval to encorafenib plus cetuximab with or without mFOLFOX6 for the treatment of patients with BRAF V600E–mutant mCRC, making it the first BRAF-targeted regimen approved in the first-line setting in the United States.4
In February 2026, the FDA expanded upon this decision by granting traditional approval to encorafenib in combination with cetuximab and fluorouracil-based chemotherapy for the treatment of adult patients with mCRC harboring a BRAF V600E mutation, as detected by an FDA-approved test.3 Both regulatory decisions were supported by data from BREAKWATER.
Notably, PFS and OS data from cohort 3 of BREAKWATER will be shared at the upcoming 2026 ASCO Annual Meeting on May 31.5
References
- Pierre Fabre Laboratories receives CHMP positive opinion for Braftovi (encorafenib) in combination with cetuximab and FOLFOX for the first-line treatment of adult patients with BRAFV600E-mutant metastatic colorectal cancer. News release. PR Newswire. May 25, 2026. Accessed May 26, 2026. https://www.prnewswire.com/news-releases/pierre-fabre-laboratories-receives-chmp-positive-opinion-for-braftovi-encorafenib-in-combination-with-cetuximab-and-folfox-fluorouracil-leucovorin-and-oxaliplatin-for-the-first-line-treatment-of-adult-patients-with-brafv600-302781057.html
- Elez E, Yoshino T, Shen L, et al. Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer. N Engl J Med. Published online May 30, 2025. doi:10.1056/NEJMoa2501912
- FDA grants traditional approval to encorafenib for metastatic colorectal cancer with a BRAF V600E mutation. FDA. February 24, 2026. Accessed May 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-encorafenib-metastatic-colorectal-cancer-braf-v600e-mutation?utm_medium=email&utm_source=govdelivery
- FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed May 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf
- Pfizer showcases oncology innovation and next-generation pipeline at ASCO 2026. News release. Pfizer. April 21, 2026. Accessed May 26, 2026. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-showcases-oncology-innovation-and-next-generation
