BREAKWATER Trial: Encorafenib Plus Cetuximab With FOLFIRI Shows Strong Efficacy in BRAF V600E-mutant mCRC

Updated results from the phase 2 BREAKWATER trial’s safety lead-in (SLI) cohort presented at the European Society for Medical Oncology Congress 2024 demonstrate the efficacy and tolerability of the combination of encorafenib and cetuximab with FOLFIRI chemotherapy in BRAF V600E-mutant metastatic colorectal cancer (mCRC).

Building on the phase 3 BEACON study, which led to the approval of encorafenib and cetuximab for previously treated mCRC, this trial assesses the combination as a first-line treatment option.

The BREAKWATER trial included patients with BRAF V600E-mutant mCRC confirmed by either blood or tumor tissue testing. Participants who had received up to one prior systemic therapy for mCRC but no previous exposure to BRAF inhibitors, EGFR inhibitors, or both oxaliplatin and irinotecan were included. All patients had an ECOG performance status of 0 or 1.

In this cohort, patients received encorafenib 300 mg once daily plus cetuximab 500 mg/m² intravenously (IV) every two weeks, in combination with either FOLFIRI or mFOLFOX6 in 28-day cycles. The primary endpoint of the study was the incidence of dose-limiting toxicities (DLTs). Secondary endpoints included safety, pharmacokinetics, and antitumor activity.

As of the data cutoff (December 22, 2023), 30 patients were enrolled (12 first-line and 18 second-line). The confirmed overall response rate by blinded independent central review (BICR) was 83.3% in the first-line group and 44.4% in the second-line group. The median progression-free survival (PFS) was not estimable in the first-line group, while it was 12.6 months in the second-line group. Median overall survival was not estimable for first-line patients and 19.7 months for second-line patients.

The pharmacokinetic analysis showed a 24% to 28% reduction in exposure to irinotecan and its active metabolite SN-38 in the presence of encorafenib, consistent with predicted CYP3A-mediated interactions.

Regarding safety, encorafenib plus cetuximab with FOLFIRI was generally tolerable, with only one dose-limiting toxicity of grade 4 neutropenia lasting more than seven days. Serious adverse events occurred in 46.7% of patients, but no new safety signals were identified.

Combining encorafenib and cetuximab with FOLFIRI chemotherapy demonstrated strong antitumor activity, especially as a first-line treatment for BRAF V600E-mutant mCRC, with a manageable safety profile. These findings support continued evaluation of this combination in subsequent cohorts of the BREAKWATER trial and underscore its potential as a key treatment option for this patient population.