CHMP Recommends BREAKWATER Regimen for Approval in 1L BRAF V600E+ mCRC

The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approving the regimen from the phase 3 BREAKWATER trial (NCT04607421)—encorafenib (Braftovi) in combination with cetuximab (Erbitux) and fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6)—as a treatment for patients with BRAF V600E-mutant metastatic colorectal cancer, according to a press release from the developer, Pierre Fabre Laboratories.¹

Earlier this year, in February 2026, the FDA approved the encorafenib, cetuximab, and mFOLFOX6-based regimen for the aforementioned patient population.² That decision came just a little over a year after the regimen was granted accelerated approval by the FDA in this indication in December 2024.³

In June 2020, the European Commission approved encorafenib plus cetuximab as a treatment for patients with BRAF V600E-mutated metastatic colorectal cancer who were previously treated with systemic therapy.⁴

Similar to the FDA’s regulatory actions, the CHMP made their recommendation based on results from the BREAKWATER trial, which evaluated encorafenib plus cetuximab and mFOLFOX6 compared with oxaliplatin-based chemotherapy, with or without bevacizumab (Avastin), in patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer.

“Today’s positive CHMP opinion marks an important step towards a targeted approach for patients with BRAF V600E-mutant metastatic colorectal cancer. If approved, it would be the only approved targeted therapy in the EU for this patient population in the first-line setting,” said Eric Ducournau, chief executive officer of Pierre Fabre Laboratories, in the press release.¹ “This milestone reflects Pierre Fabre Laboratories’ commitment to advancing meaningful innovation in oncology and to working in close partnership with the scientific and medical community to address areas of high unmet need.”

How effective and safe is encorafenib with cetuximab and mFOLFOX6?

The median progression-free survival (PFS) was 12.8 months with the experimental regimen compared with 7.1 months in the control arm, demonstrating a statistically significant and clinically meaningful improvement (HR, 0.53; 95% CI, 0.41-0.68; P <.001).⁵ The dual primary end point of overall response rate (ORR) was also met, with values of 65.7% (95% CI, 59.4%-71.4%) vs 37.4% (95% CI, 31.6%-43.7%), respectively.

At the interim analysis, the median overall survival was 30.3 months with the encorafenib regimen vs 15.1 months with standard of care, demonstrating a statistically significant improvement and a 51% reduction in the risk of death (HR, 0.49; 95% CI, 0.38-0.63; P <.001).

Regarding safety, the most common treatment-related adverse events (TRAEs) were nausea, anemia, diarrhea, decreased appetite, and vomiting in the encorafenib plus cetuximab and mFOLFOX6 arm. Grade 3 or 4 TRAEs were observed in 81.5% of patients, and grade 5 TRAEs in 4.3%. Notably, investigators stated that the safety profiles were consistent with previously known data.

How was the BREAKWATER trial designed?

BREAKWATER enrolled a total of 637 patients, all of whom were randomly assigned 1:1:1 to receive:⁵

• Arm 1: Encorafenib plus cetuximab (n = 158),
• Arm 2: Encorafenib plus cetuximab and mFOLFOX6 (n = 236)
• Arm 3: Standard of care (n = 243)

Eligible patients were 16 years or older, or 18 years or older based on country, with BRAF V600E-mutant metastatic colorectal cancer, no prior systemic treatment for metastatic disease, measurable disease, and an ECOG performance status of 0 or 1.

The median age of patients in the experimental arm was 60 years (range, 24-81) vs 62 years (range, 28-84) in the standard of care arm, with 49.6% and 57.7% of patients in each respective group having 3 or more organs involved, and 62.3% and 65.8% having liver metastases.

The dual primary end points were PFS and ORR by blinded independent central review, and the key secondary end point was OS.

References

1. 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 BRAFV600E-mutant metastatic colorectal cancer (mCRC). News release. Pierre Fabre Laboratories. May 25, 2026. Accessed May 27, 2026. https://tinyurl.com/y7h85ajm
2. FDA grants traditional approval to encorafenib for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. February 24, 2026. Accessed May 26, 2026. https://tinyurl.com/4xr84a6y
3. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. December 20, 2024. Accessed May 26, 2026. https://tinyurl.com/33jk9usn
4. Pierre Fabre receives European approval for BRAFTOVI® (encorafenib) in combination with cetuximab for the treatment of adult patients with BRAFV600E-mutant metastatic colorectal cancer. News release. Pierre Fabre. June 3, 2020. Accessed May 26, 2026. https://tinyurl.com/4xkdaxj3
5. Elez 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. J Clin Oncol. 2025;43(suppl 17):LBA3500. doi:10.1200/JCO.2025.43.17_suppl.LBA3500