BRAF V600E mutations occur in 8%-12% of metastatic colorectal cancer (mCRC).¹ Initial data from the BREAKWATER safety lead-in established that encorafenib + cetuximab (EC) + FOLFIRI was tolerable with encouraging antitumor activity, supporting evaluation as a first-line treatment in cohort 3.¹ In cohort 3, EC + FOLFIRI achieved a significantly higher objective response rate (ORR) by blinded independent central review (BICR) compared with control therapy (64.4% vs. 39.2%; odds ratio [OR] = 2.76; 95% CI: 1.42-5.35; one-sided p=0.0011).¹

At the 2026 ASCO Annual Meeting, Dr. Scott Kopetz from the University of Texas MD Anderson Cancer Center, United States, presented the final analysis of the key secondary endpoint, progression-free survival (PFS) by BICR for cohort 3 of the BREAKWATER trial.¹ Results from the phase 3 and cohort 3 portion of the trial formed the basis for the Food and Drug Administration (FDA) approval of EC + fluorouracil-based chemotherapy for the treatment of BRAF V600E-mutant mCRC.¹

BREAKWATER is an open-label, multicenter study evaluating EC + chemotherapy vs. control in patients with previously untreated BRAF V600E-mutant mCRC.¹ The cohort 3 portion of BREAKWATER included patients aged ≥16 years (or ≥18 years according to country requirements) with previously untreated BRAF V600E-mutant mCRC, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and adequate bone marrow, hepatic, and renal function.¹ Patients were randomized 1:1 to receive EC + FOLFIRI (n=73) or FOLFIRI ± bevacizumab (n=74), stratified by ECOG PS.¹

Baseline demographic and disease characteristics were generally similar between treatment arms.¹ The median age was 62 years in the EC + FOLFIRI arm and 61 years in the control arm, and approximately half of the patients in each treatment group were female.¹ Most patients had an ECOG PS of 0 or 1, and baseline tumor characteristics, including primary tumor location, liver metastases, and biomarker levels, were generally balanced across treatment groups.¹ At the January 6, 2026 data cutoff, 38.4% of patients remained on treatment with EC + FOLFIRI vs. 9.5% in the control arm, with a median treatment duration of 67.9 weeks vs. 32.1 weeks, respectively.¹

After a median PFS follow-up of 18.0 months, EC + FOLFIRI met the key secondary endpoint by demonstrating a 56% reduction in the rate of disease progression or death, significantly improving PFS vs. the control regimen (mPFS: 15.2 months vs. 8.3 months; HR=0.44; 95% CI: 0.27-0.70; one-sided p=0.0002).¹ Clinical benefit was observed across key prespecified patient subgroups, including age, sex, ECOG performance status at baseline, number of organs involved per BICR, tumor laterality, and presence of liver metastases at baseline.¹ Updated OS analysis at the median OS follow-up of 20.6 months also favored the EC + FOLFIRI arm, with mOS not estimable (NE) vs. 20.3 months in the control arm, corresponding to a 44% reduction in the risk of death (HR=0.56; 95% CI: 0.34-0.94).¹

The safety profile of EC + FOLFIRI was generally consistent with that expected for the study drugs, with no new safety signals observed.¹ The incidence of treatment-related adverse events (TRAEs) was comparable between treatment groups (98.6% vs. 95.6%) despite the longer treatment exposure with EC + FOLFIRI, and the addition of EC did not substantially increase chemotherapy discontinuation due to adverse events (14.1% vs. 10.3%).¹ Grade 3 or higher anemia and grade 1/2 arthralgia occurred more frequently with EC + FOLFIRI, whereas rates of gastrointestinal toxicities such as nausea and diarrhea were similar between treatment groups.¹

In conclusion, BREAKWATER cohort 3 demonstrated statistically significant and clinically meaningful improvements in PFS by BICR with EC + FOLFIRI vs. control therapy in patients with previously untreated BRAF V600E-mutant mCRC.¹ EC + FOLFIRI was also associated with prolonged OS and showed a generally tolerable safety profile.¹ Collectively, these results support EC + FOLFIRI as a potential new standard-of-care option in this patient population, while underscoring the critical role of timely biomarker testing and individualized treatment strategies.¹