Clinical trialPhase 3Colorectal cancer

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer

N Engl J Med · 2025637 patients in the phase 3 part (158 EC, 236 EC + mFOLFOX6, 243 standard of care)

Elez E, Yoshino T, Shen L, et al. N Engl J Med. 2025. 392:2425-2437

Study type: Clinical trial
Study name: BREAKWATER
Phase: Phase 3
Design: International, open-label, three-arm randomised trial (1:1:1 randomisation to EC, EC + mFOLFOX6 or standard of care)
Sample size: 637 patients in the phase 3 part (158 EC, 236 EC + mFOLFOX6, 243 standard of care)
Source: N Engl J Med · 2025
Trial registration: NCT04607421

In plain words

About 8 to 12 percent of bowel cancers that have spread carry a mutation called BRAF V600E, which usually makes the disease more aggressive and less responsive to chemotherapy. In this study, adding a targeted tablet (encorafenib) and an anti-EGFR drug given by infusion (cetuximab) to FOLFOX chemotherapy from the very start of treatment almost doubled the time the disease stayed under control and raised median survival from about 15 months to about 30 months. Serious side effects were a little more common but are usually manageable. This is why testing for the BRAF mutation is so important when cancer that has spread is first diagnosed.

Key results

12.8 vs 7.1 months

Median progression-free survival

HR 0.53 (95% CI 0.41–0.68); P<0.001

30.3 vs 15.1 months

Median overall survival (interim analysis)

HR for death 0.49 (95% CI 0.38–0.63); P<0.001

65.7% vs 37.4%

Objective response (all randomised patients, updated)

Primary response analysis (first 110 patients in each group): 60.9% vs 40.0%; odds ratio 2.44

46.1% vs 38.9%

Serious treatment-emergent adverse events

Grade 3 or 4 adverse events: 81.5% vs 66.8%

Drugs in this study:Bevacizumab (Avastin)Capecitabine (Xeloda)Cetuximab (Erbitux)Fluorouracil (5-FU)Irinotecan (Camptosar)Oxaliplatin (Eloxatin)

Dose and schedule cards

Encorafenib + cetuximab + mFOLFOX6 (BREAKWATER)

BRAF V600E-mutant metastatic colorectal cancer; first-lineEach drug’s schedule in the tableOn the page “Colorectal cancer” · pMMR/MSS metastatic colorectal cancer: first-line

BRAF V600E-mutant metastatic colorectal cancer; first-line

Drug	Dose	Route	Schedule
Encorafenib	300 mg once daily	Oral	Continuous
Cetuximab	500 mg/m²	IV	Day 1 (every 2 weeks)
Oxaliplatin	85 mg/m²	IV over 2 h	Day 1 (every 2 weeks)
Leucovorin	400 mg/m²	IV over 2 h	Day 1 (every 2 weeks)
Fluorouracil (bolus)	400 mg/m²	IV bolus	Day 1 (every 2 weeks)
Fluorouracil (infusion)	2400 mg/m²	IV, continuous 46-h infusion	Starting day 1 (every 2 weeks)

Cycle schedule: Cetuximab and mFOLFOX6 every 2 weeks (28-day cycles); encorafenib daily and continuously
Duration: Until disease progression or unacceptable toxicity

Doses from BREAKWATER and the FDA label for encorafenib, which also covers the combination with biweekly cetuximab and FOLFIRI; results of the combination with FOLFIRI in cohort 3 of the same trial.

Encorafenib: dose reductions in colorectal cancer to 225 mg and then 150 mg daily; discontinue if 150 mg is not tolerated. QTcF greater than 500 ms with an increase of ≤60 ms → withhold until ≤500 and resume at a lower dose; QTcF greater than 500 with an increase of more than 60 ms → discontinue permanently.

On the page “Colorectal cancer” · pMMR/MSS metastatic colorectal cancer: first-line

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Encorafenib + cetuximab + mFOLFOX6

Encorafenib 300 mg orally once daily (continuous) + cetuximab 500 mg/m² IV over 120 minutes every 2 weeks + mFOLFOX6 every 2 weeks: oxaliplatin 85 mg/m² IV over 120 minutes, leucovorin 400 mg/m² IV over 120 minutes, fluorouracil 400 mg/m² IV bolus, then 2400 mg/m² by continuous infusion over 46 to 48 hours; 28-day cycle; until disease progression or unacceptable toxicity.

2Encorafenib + cetuximab (EC)

Encorafenib 300 mg orally once daily + cetuximab 500 mg/m² IV over 120 minutes every 2 weeks. (Enrolment in this arm was closed early.)

3Standard of care (control group)

Investigator's choice, each with or without bevacizumab (per label; 81.1% of patients received bevacizumab):

• mFOLFOX6 every 2 weeks: oxaliplatin 85 mg/m² over 120 minutes, leucovorin 400 mg/m² over 120 minutes, fluorouracil 400 mg/m² bolus, then 2400 mg/m² over 46 to 48 hours.

• FOLFOXIRI every 2 weeks: irinotecan 165 mg/m² over 90 minutes, oxaliplatin 85 mg/m², leucovorin 400 mg/m², fluorouracil 2400 or 3200 mg/m² by continuous infusion over 46 to 48 hours (no bolus).

• CAPOX every 3 weeks: oxaliplatin 130 mg/m² over 120 minutes, capecitabine 1000 mg/m² orally twice daily, days 1 to 14.

Source of the regimen details: Full text of the paper (PMC12197837, Methods) and ClinicalTrials.gov NCT04607421 (infusion durations and doses of the control regimens)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 16 years or older (where locally permitted) with BRAF V600E-mutated metastatic (stage 4) colorectal adenocarcinoma and measurable disease who had received no prior systemic therapy for metastatic disease. Patients with MSI-H/dMMR tumours (unless not candidates for immunotherapy), RAS mutations, symptomatic brain metastases or prior BRAF or EGFR inhibitor therapy were excluded.

Endpoints

Dual primary endpoints (EC + mFOLFOX6 versus standard of care, by blinded independent central review): objective response (reported previously) and progression-free survival.

Key secondary endpoint: overall survival.

Safety and side effects

Serious treatment-emergent adverse events occurred in 46.1% of the EC + mFOLFOX6 group and 38.9% of the standard-of-care group (30.1% in the EC group). Grade 3 or 4 adverse events occurred in 81.5% and 66.8% respectively (42.5% in the EC group), and fatal (grade 5) events in 4.3% and 4.4% (2.6% with EC). The safety profile was consistent with the known toxic effects of each drug.

Clinical significance and place in guidelines

The early response results of this trial led to accelerated FDA approval (according to the full paper). The current FDA label for BRAFTOVI includes the indication "in combination with cetuximab and fluorouracil-based chemotherapy for adults with metastatic colorectal cancer with a BRAF V600E mutation". EC + mFOLFOX6 is now considered the preferred first-line option in this subgroup. Approval status may differ in other countries.

Limitations

Open-label design; overall survival data from an interim analysis (81.5% of expected events); patients with MSI-H/dMMR tumours (for whom immunotherapy is the first choice) were largely excluded; enrolment in the EC arm was closed early.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.