EC Approves Encorafenib/Cetuximab/FOLFOX in 1L BRAF V600E–Mutant mCRC

The European Commission (EC) has approved encorafenib (Braftovi) in combination with cetuximab (Erbitux) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for the first-line treatment of adult patients with BRAF V600E–mutant metastatic colorectal cancer (mCRC), according to a news release from Laboratoires Pierre Fabre.¹ The decision designates this regimen as the first and only BRAF-targeted therapy authorized in the EU for patients with previously untreated disease. The approval is based on results from the phase 3 BREAKWATER trial (NCT04607421).

What is the regulatory history of encorafenib in colorectal cancer?

The EC approval of the BREAKWATER regimen represents the culmination of several regulatory milestones for encorafenib-based therapy in mCRC. In May 2026, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending the first-line indication.² Previously, in February 2026, the FDA granted traditional approval to encorafenib plus cetuximab and fluorouracil-based chemotherapy for the same patient population.³

What were the key efficacy results from the BREAKWATER trial?

In the BREAKWATER trial, encorafenib plus cetuximab and a modified FOLFOX regimen (mFOLFOX6) demonstrated statistically significant improvements across both dual primary end points compared with standard oxaliplatin-based chemotherapy with or without bevacizumab. In the primary analysis set, patients in the encorafenib arm achieved an objective response rate (ORR) of 65.7% vs 37.4% in the control arm (OR, 2.44; 95% CI, 1.40-4.25; P <.001). Median progression-free survival (PFS) was 12.8 months vs 7.1 months (HR, 0.53; 95% CI, 0.41-0.68), representing a 47% reduction in the risk of disease progression or death.

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

“We are extremely pleased to be able to expand the availability of encorafenib in combination with cetuximab and FOLFOX for the first-line treatment of adult patients with BRAF V600E-mutant mCRC,” said Eric Ducournau, chief executive officer of Laboratoires Pierre Fabre.¹ “Today's EC decision for this regimen marks the approval of the only targeted therapy in the EU for this patient population in the first-line setting and an important milestone in that it helps to address a significant unmet need for patients and clinicians, for whom treatment options have been limited.”

Safety was consistent with the known profiles of the individual agents. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 81.5% of all patients who received the experimental regimen, and 4.3% grade 5 AEs were noted.

What was the BREAKWATER trial design?

BREAKWATER is a phase 3, randomized, open-label, multicenter trial evaluating encorafenib in combination with cetuximab and fluorouracil-based chemotherapy in patients with previously untreated BRAF V600E–mutant mCRC. Eligible patients had histologically confirmed BRAF V600E–mutant mCRC, no prior systemic therapy for metastatic disease, measurable disease, and an ECOG performance status of 0 or 1.

In the experimental arm, patients received encorafenib orally once daily with cetuximab and mFOLFOX6 administered every 2 weeks. The dual primary end points were PFS and ORR by blinded independent central review. The key secondary end point was OS.

The median age in the experimental arm was 60 years; 62.3% of patients had liver metastases and 49.6% had 3 or more organs involved.

References

1. Laboratoires Pierre Fabre receives European Commission approval 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. News release. Laboratoires Pierre Fabre. June 22, 2026. Accessed June 22, 2026. https://tinyurl.com/ym83tdxr
2. 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 June 22, 2026. https://tinyurl.com/y7h85ajm
3. FDA grants traditional approval to encorafenib for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. February 24, 2026. Accessed June 22, 2026. https://tinyurl.com/4xr84a6y