At the 2026 Gastrointestinal Cancers Symposium, BREAKWATER Cohort 3 delivered the clearest signal yet that encorafenib plus cetuximab can be paired with FOLFIRI (folinic acid [leucovorin], fluorouracil [5‑FU] and irinotecan) in the first-line treatment of BRAF V600E-mutant metastatic colorectal cancer. In the oral presentation, Scott Kopetz, MD, reported a statistically significant improvement in objective response rate with the targeted regimen plus chemotherapy over standard FOLFIRI with or without bevacizumab, with an early overall survival trend that also favored the experimental arm.
The phase 3, open-label BREAKWATER study has already established the activity of encorafenib and cetuximab with an oxaliplatin backbone. Cohort 3 asked whether the same targeted approach could work with FOLFIRI for patients who are not ideal candidates for oxaliplatin, including those with prior exposure in the adjuvant setting or baseline neuropathy. This cohort enrolled previously untreated patients with microsatellite-stable, BRAF V600E-mutant metastatic colorectal cancer and ECOG performance status 0 or 1. Patients were randomly assigned 1:1 to encorafenib plus cetuximab and FOLFIRI or to control FOLFIRI with or without bevacizumab. The primary endpoint was objective response rate by blinded independent central review. Progression-free survival was the key secondary endpoint, with overall survival, duration of response, and safety among the additional secondary endpoints.
The confirmed objective response rate was 64% with encorafenib, cetuximab, and FOLFIRI compared with 39% in the control arm, meeting the primary endpoint (one-sided P value, .0011; odds ratio, 2.8). Median follow-up was just over 10 months. Median overall survival was not estimable in either arm, but the reported hazard ratio for overall survival was 0.49, favoring the targeted triplet. Progression-free survival follow-up is ongoing and has not yet been reported for this cohort.
No new safety signals emerged, with adverse events consistent with those expected for each study drug. Grade 3 or 4 treatment-related adverse events occurred in 63% of patients on the experimental arm and 71% of patients in the control group. Serious treatment-emergent adverse events were reported in 39% of patients treated with encorafenib, cetuximab, and FOLFIRI and in 37% of those in the control arm. Treatment-emergent adverse events leading to permanent discontinuation of any study treatment was 11% in the encorafenib-containing arm and 9% in the control arm. Skin hyperpigmentation, dry skin, asthenia, weight decrease, arthralgia, palmar-plantar erythrodysesthesia, and rash appeared to occur more commonly on the encorafenib-containing arm.
Overall, these data are encouraging, especially for patients where oxaliplatin is not an ideal fit, but longer follow-up is needed.
References
Kopetz S, Wasan HS, Yoshino T, et al. BREAKWATER: Primary analysis of first-line encorafenib plus cetuximab plus FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer. Presented at: Gastrointestinal Cancers Symposium; 2026. Abstract 13.