Encorafenib (Braftovi) plus cetuximab (Erbitux) and FOLFIRI (leucovorin calcium [folinic acid], fluorouracil, and irinotecan hydrochloride) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with FOLFIRI with or without bevacizumab (Avastin) in patients with previously untreated, BRAF V600E–mutant metastatic colorectal cancer (mCRC). The final analysis data from cohort 3 of the phase 3 BREAKWATER trial (NCT04607421) were presented at the 2026 American Society of Clinical Oncology Annual Meeting and published simultaneously in Annals of Oncology.1,2
Findings showed the combination of encorafenib, cetuximab, and FOLFIRI (n = 73) reduced the risk of disease progression or death by 56% vs FOLFIRI with or without bevacizumab (n = 74) per blinded independent central review (BICR), with a median PFS of 15.2 months (95% CI, 13.6-not evaluable [NE]) for the experimental regimen vs 8.3 months (95% CI, 6.8-8.9) for the control regimen (HR, 0.44; 95% CI, 0.27-0.70; one-sided P = .0002).
“The cohort 3 data support the use of FOLFIRI as an option with encorafenib and cetuximab as a new standard of care for this BRAF V600E–mutant mCRC population and highlight the importance of prompt biomarker testing to really understand which patients have BRAF V600E mutations prior to starting first-line treatment,” lead study author Scott Kopetz, MD, PhD, said in a presentation of the data. “This really allows for improvements in personalized care.”
Kopetz is the associate vice president for translational integration in the Department of Office of Chief Scientific Officer, Division of Cancer Medicine; medical director of the TRACTION platform in the Therapeutics Discovery Division; and a professor and the deputy chair for translational research in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. Kopetz also received the 2026 Giants of Cancer Care award for gastrointestinal cancer.
In February 2026, the FDA granted 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 This decision was based on prior data from BREAKWATER, including cohort 3. This followed the December 2024 FDA accelerated approval of encorafenib in combination with cetuximab (Erbitux) and modified FOLFOX-6 (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) for patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test, which was also based on prior data from BREAKWATER.4
Key Findings From BREAKWATER Cohort 3
- Encorafenib plus cetuximab and FOLFIRI reduced the risk of disease progression or death by 56% vs FOLFIRI with or without bevacizumab (HR, 0.44; 95% CI, 0.27-0.70; one-sided P = .0002)
- Median OS was not reached in the experimental arm vs 20.3 months in the control arm (HR, 0.56; 95% CI, 0.34-0.94); 18-month OS rates were 72.0% vs 54.9%, respectively.
- 38.4% of patients in the encorafenib plus cetuximab and FOLFIRI arm remained on treatment vs 9.5% in the control arm at data cutoff.
How was the BREAKWATER cohort 3 designed?
BREAKWATER was an open-label, multicenter study evaluating encorafenib plus cetuximab with or without chemotherapy in patients with previously untreated, BRAF V600E–mutant mCRC.1 Cohort 3 enrolled 147 patients who were randomly assigned 1:1 to receive encorafenib plus cetuximab and FOLFIRI (n = 73) or FOLFIRI with or without bevacizumab (n = 74), stratified by ECOG performance status. BRAF V600E mutation was confirmed by local or central laboratory testing, and patients were required to have no prior systemic treatment for metastatic disease and an ECOG performance status of 0 or 1.
The dual primary end points were overall response rate (ORR) and PFS, both by BICR. Previously reported data demonstrated an ORR of 64.4% with encorafenib plus cetuximab and FOLFIRI vs 39.2% with the control regimen (OR, 2.756; 95% CI, 1.420-5.348; P = .0011). The presentation at the 2026 ASCO Annual Meeting reported the final PFS analysis, along with updated overall survival (OS) and safety data.
Baseline characteristics were well balanced between the 2 study arms. The median age was 62 years (range, 28-81) in the encorafenib plus cetuximab and FOLFIRI arm vs 61 years (range, 29-84) in the control arm. Liver metastases were present in 58.9% and 62.2% of patients, respectively. Most patients had an ECOG performance status of 0 (64.4% vs 55.4%) and right-sided tumors (56.2% vs 51.4%).
As of the January 6, 2026, data cutoff, treatment was ongoing for 38.4% of patients in the encorafenib plus cetuximab and FOLFIRI arm vs 9.5% of patients in the control arm. The median treatment durations were 67.9 weeks (range, 2.0-104.1) and 32.1 weeks (range, 2.0-100.1), respectively.
What were the OS and subgroup findings?
At a median OS follow-up of 20.6 months for the experimental arm and 20.7 months for the control arm, median OS had not been reached (95% CI, 21.0-NE) with encorafenib plus cetuximab and FOLFIRI vs 20.3 months (95% CI, 13.2 months-NE) with FOLFIRI with or without bevacizumab (HR, 0.56; 95% CI, 0.34-0.94). The 18-month OS rate was 72.0% and 54.9%, respectively.
Subgroup analyses of PFS by BICR showed a consistent trend favoring encorafenib plus cetuximab and FOLFIRI across all prespecified subgroups, including age, sex, ECOG performance status, number of organs involved, side of tumor, and presence of liver metastases at baseline.
What did the safety analysis show?
The safety profile of encorafenib plus cetuximab and FOLFIRI was consistent with the expected toxicities for each component, and there was no substantial increase in chemotherapy discontinuation due to adverse effects (AEs) compared with control. Among patients with safety data, treatment-emergent AEs (TEAEs) of any grade occurred in 100% of encorafenib plus cetuximab recipients (n = 71) vs 98.5% of control arm recipients (n = 68). Grade 3 or 4 TEAEs were reported in 70.4% vs 80.9% of patients, respectively; grade 3 or 4 treatment-related AEs occurred at rates of 62.0% and 64.7%, respectively.
TEAEs led to permanent discontinuation of any study drug in 15.5% of patients in the experimental arm vs 10.3% of patients in the control arm. The most frequently reported TEAEs, occurring in at least 25% of patients, included nausea, diarrhea, vomiting, anemia, alopecia, fatigue, decreased neutrophil count, constipation, decreased appetite, neutropenia, arthralgia, asthenia, and abdominal pain; these were consistent with the known toxicity profiles of the regimen components. No new safety signals were reported.
References
- Kopetz S, Tabernero J, Lorandi S, et al. BREAKWATER: progression-free and overall survival analyses of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E–mutant metastatic colorectal cancer (mCRC). J Clin Oncol. 2026;44(suppl 17):LBA3503. doi:10.1200/JCO.2026.44.17_suppl.LBA3503
- Kopetz S, Tabernero J, Lorandi S, et al. A randomised study of encorafenib, cetuximab, and FOLFIRI versus FOLFIRI with or without bevacizumab in BRAF V600E–mutant colorectal cancer: BREAKWATER Cohort 3. Ann Oncol. Published online May 31, 2026. doi:10.1016/j.annonc.2026.04.017
- FDA grants traditional approval to encorafenib for metastatic colorectal cancer with a BRAF V600E mutation. FDA. February 24, 2026. Accessed May 31, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-encorafenib-metastatic-colorectal-cancer-braf-v600e-mutation
- 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 31, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf
