European Commission Approves Erbitux® (cetuximab) in Combination with Encorafenib and FOLFOX for First-Line Treatment of Metastatic Colorectal Cancer with BRAF V600E Mutation

Merck, a leading global science and technology company, today announced that the European Commission (EC) approved an update to the Erbitux (cetuximab) EU label on June 26, 2026. Erbitux is now indicated in combination with encorafenib for patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC) — both in first-line treatment in combination with FOLFOX (BREAKWATER regimen) and for patients who have received prior systemic therapy (BEACON regimen).

The first-line approval is based on results from the Phase 3 BREAKWATER trial, which showed that the cetuximab–encorafenib–FOLFOX combination delivered statistically significant and clinically meaningful improvements in the dual primary endpoints of objective response rate (ORR) and PFS, as well as a significant overall survival benefit — reducing the risk of death by 51% versus chemotherapy with or without bevacizumab.

”The approval of Erbitux in combination with encorafenib and FOLFOX marks an important milestone for patients with BRAF V600E-mutant mCRC who can now benefit from a first targeted treatment option in the first-line setting,” said Matthias Wernicke, Head of Global Therapeutic Area Specialty Care, in the healthcare business sector of Merck. “BRAF V600E-mutant mCRC is associated with a historically poor prognosis and limited effective options. This approval reinforces Erbitux as the backbone of anti-EGFR therapy in colorectal cancer — and reflects our ongoing commitment to addressing unmet needs for patients across the full treatment continuum.”

BREAKWATER (NCT04607421) is a Phase 3, randomized, active-controlled, open-label, multicenter trial evaluating encorafenib in combination with cetuximab and FOLFOX in participants with previously untreated BRAF V600E-mutant mCRC. The trial was conducted by Pfizer, in collaboration with Merck, and Ono Pharmaceutical. The combination of cetuximab, encorafenib and FOLFOX received accelerated FDA approval in December 2024 for treatment-naïve patients based on ORR data, and full FDA approval in February 2026 based on PFS and OS data — with the indication expanded to include fluorouracil-based chemotherapy (FOLFOX or FOLFIRI).

The BREAKWATER regimen demonstrated statistically significant and clinically meaningful improvements across all key endpoints versus standard-of-care chemotherapy (FOLFOX/FOLFOXIRI/CAPOX with or without bevacizumab).1,2 Median PFS was 12.8 months versus 7.1 months (HR 0.53; 95% CI: 0.41–0.68; P<0.001), representing a 47% reduction in the risk of progression or death. Overall survival was likewise significantly improved, with a median OS of 30.3 months versus 15.1 months (HR 0.49; 95% CI: 0.38–0.63; P<0.001) — a 51% reduction in the risk of death, more than doubling median overall survival compared to standard care. Confirmed ORR was 65.7% (95% CI: 59.4–71.4) in the BREAKWATER arm versus 37.4% (95% CI: 31.6–43.7) in the control arm.

Safety profiles were consistent with those previously established for each individual agent; serious adverse events occurred in 46.1% versus 38.9% in the standard-care arm.

The cetuximab–encorafenib–FOLFOX regimen has been endorsed as first-line standard of care by the April 2026 ESMO Clinical Practice Guidelines (Recommendation Grade I, A) for patients with metastatic colorectal cancer harboring the BRAF V600E mutation.3

While the BREAKWATER regimen redefines first-line therapy, the Phase 3 BEACON CRC trial confirmed Erbitux as a standard of care in second-line and beyond. The combination of Erbitux and encorafenib — also approved by the EC on June 26, 2026 for patients with BRAF V600E-mutant mCRC who have received prior systemic therapy — significantly improved OS versus the irinotecan-based control (median 9.3 vs. 5.9 months; HR 0.61; 95% CI: 0.48–0.77; p<0.0001), reducing the risk of death by 39%.4,5 This regimen maintains quality of life with no increase in Grade ≥3 adverse events versus standard chemotherapy.

Erbitux is the first and only anti-EGFR therapy approved for both RAS wild-type and BRAF V600E-mutant mCRC patients — supporting patients throughout their treatment journey and across multiple lines of therapy.
Colorectal cancer remains a major global health challenge. It is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related deaths, with 1.92 million new cases and approximately 900,000 deaths recorded in 2022 alone.6 Projections indicate cases will increase by more than 85% and mortality will double in coming decades. Of patients presenting with metastatic disease — approximately 20% at diagnosis — 5-year survival remains at only 16.2%.

BRAF V600E mutations occur in approximately 8–12% of patients with mCRC and are associated with a particularly poor prognosis, with mortality risk more than double that of patients without the mutation. Extending the indication of Erbitux to this patient population represents a meaningful step toward more personalized and effective treatment — addressing a significant and clinically important unmet need.

With this dual approval — first-line (BREAKWATER) and second-line (BEACON) — Erbitux is now established as the pioneering anti-EGFR backbone across the mCRC treatment continuum. This milestone underscores Merck’s commitment to driving innovation in oncology and improving outcomes for patients with difficult-to-treat cancers.

Local HCP Declaration

Pierre Fabre, which holds the commercialization rights for BRAFTOVI (encorafenib) in Europe, submitted the BREAKWATER data to European Medical Agency (EMA) and received EC approval on June 22,2026. The BEACON regimen was already approved under BRAFTOVI since June 2020.