At the 2026 ASCO Annual Meeting, Scott Kopetz presented results from BREAKWATER Cohort 3, evaluating first-line encorafenib plus cetuximab and FOLFIRI in patients with BRAF V600E-mutant metastatic colorectal cancer. The study was presented as Abstract LBA3503.
FOLFOX- and FOLFIRI-based chemotherapy regimens are commonly used in the first-line treatment of metastatic colorectal cancer. In patients with BRAF V600E-mutant metastatic colorectal cancer, previous BREAKWATER phase 3 data showed improved outcomes with encorafenib plus cetuximab and mFOLFOX6 compared with chemotherapy with or without bevacizumab.
The BREAKWATER safety lead-in had also shown encouraging activity with encorafenib plus cetuximab and FOLFIRI. Cohort 3 was conducted to further evaluate this regimen.
Study Design
Eligible patients had previously untreated BRAF V600E-mutant metastatic colorectal cancer, measurable disease by RECIST 1.1, and an ECOG performance status of 0 or 1.
Patients were randomized 1:1 to receive:
- Encorafenib plus cetuximab and FOLFIRI
- Control treatment with FOLFIRI with or without bevacizumab
The primary endpoint was confirmed objective response rate by blinded independent central review. The key secondary endpoint was progression-free survival by blinded independent central review. Other secondary endpoints included overall survival and safety.
Results
A total of 147 patients were randomized to encorafenib plus cetuximab and FOLFIRI or control.
At the data cutoff of January 6, 2026, median follow-up for progression-free survival was 18.0 months in the encorafenib plus cetuximab and FOLFIRI arm and 14.4 months in the control arm. Median follow-up for overall survival was 20.6 months and 20.7 months, respectively.
Baseline demographics and disease characteristics were generally balanced between treatment arms. The primary endpoint had previously been met. Confirmed objective response rate by blinded independent central review was 64.4% with encorafenib plus cetuximab and FOLFIRI compared with 39.2% with control treatment.
Progression-free survival was significantly improved with encorafenib plus cetuximab and FOLFIRI. Median progression-free survival was 15.2 months with encorafenib plus cetuximab and FOLFIRI compared with 8.3 months with control treatment. The progression-free survival hazard ratio was 0.44 with a 95% confidence interval of 0.27 to 0.70 and a one-sided P value of 0.0002.
Overall survival was prolonged. Median overall survival was not estimable with encorafenib plus cetuximab and FOLFIRI and was 20.3 months with control treatment. The overall survival hazard ratio was 0.56 with a 95% confidence interval of 0.34 to 0.94. The 18-month overall survival rate was 72.0% with encorafenib plus cetuximab and FOLFIRI compared with 54.5%with control treatment.
Safety
The median duration of study treatment was 67.9 weeks with encorafenib plus cetuximab and FOLFIRI and 32.1 weekswith control treatment. Discontinuation of chemotherapy, with or without bevacizumab as appropriate for the treatment arm, due to adverse events was similar between arms: 14% with encorafenib plus cetuximab and FOLFIRI and 10% with control treatment.
Serious treatment-emergent adverse events occurred in 49% and 44% of patients, respectively. Maximum grade 3 or 4 treatment-emergent adverse events occurred in 70% of patients receiving encorafenib plus cetuximab and FOLFIRI and 81% of patients receiving control treatment. The safety profile was consistent with the known safety profile of each agent, with no new safety signals.
Previous BREAKWATER Results From ASCO 2025
The Cohort 3 update builds on previous BREAKWATER data presented at ASCO 2025, where encorafenib plus cetuximab and mFOLFOX6 improved outcomes compared with standard chemotherapy in first-line BRAF V600E-mutant metastatic colorectal cancer. In that analysis, median progression-free survival was 12.8 months with encorafenib plus cetuximab and mFOLFOX6 versus 7.1 months with standard of care. Median overall survival was 30.3 months versus 15.1 months, respectively.
Conclusion
BREAKWATER Cohort 3 showed that first-line encorafenib plus cetuximab and FOLFIRI provided a statistically significant and clinically meaningful benefit in objective response rate and progression-free survival compared with control treatment in patients with BRAF V600E-mutant metastatic colorectal cancer. Overall survival was also prolonged with encorafenib plus cetuximab and FOLFIRI.
The regimen was generally tolerable, with no substantial increase in chemotherapy discontinuation due to adverse events compared with the control arm. The most frequently reported treatment-emergent adverse events were consistent with those expected for the individual regimen components, and no new safety signals were observed.
BREAKWATER Cohort 3 supports the use of FOLFIRI as an option with the encorafenib plus cetuximab backboneas a new standard-of-care approach for patients with BRAF V600E-mutant metastatic colorectal cancer. According to the presentation, results from BREAKWATER Phase 3 and Cohort 3 formed the basis for FDA approval of encorafenib plus cetuximab with fluorouracil-based chemotherapy in this setting.
The study was funded by Pfizer Inc.
The full abstract is available on the official ASCO website.
Read more about CIRCULATE at ASCO 2026 on OncoDaily.
