BREAKWATER
In BRAF V600E-mutated metastatic colorectal cancer, does encorafenib plus cetuximab and mFOLFOX6 improve outcomes over standard care?
One underlying study; aliases and follow-up reports consolidated. Primary discipline: Medical.
637 patients with previously untreated BRAF V600E-mutated metastatic colorectal cancer.
Confirmed BRAF V600E metastatic disease; not applicable to BRAF wild-type or non-metastatic disease.
637 randomised; primary comparison n=236 vs 243 randomised/evaluable as reported.
Encorafenib plus cetuximab with mFOLFOX6.
Standard care chemotherapy with or without bevacizumab according to protocol.
Endpoints and results
Primary endpoints included ORR and PFS; OS key secondary endpoint.
- Median PFS 12.8 vs 7.1 months.
- Interim median OS 30.3 vs 15.1 months; HR 0.49 (95% CI 0.38–0.63; p<0.001).
- ORR 65.7% vs 37.4%. Serious AEs during treatment 46.1% vs 38.9%.
Absolute Effect and outcome visualisation
Median OS
months (median, not fixed-time rate) · Interim OS analysis. Bars compare reported medians only; they are not fixed-time survival probabilities.
Interpretation: No fixed-time OS rates reproduced here; NNT not calculated. Never derive NNT from median survival difference.
Toxicity, discontinuation and quality of life
Trial-specific harms: Serious AEs 46.1% vs 38.9%; chemotherapy neuropathy/cytopenias and targeted-agent GI/skin toxicities require monitoring.
Treatment burden/discontinuation: Intensive multi-agent treatment with cumulative oxaliplatin neuropathy, dose modifications and monitoring.
Quality of life: No numerical QoL advantage asserted without the PRO report.
Subgroups, maturity and limitations
Subgroups: Molecularly defined BRAF V600E population; molecular confirmation is essential.
Maturity: Primary report published 2025; OS was interim.
Limitations: Open-label trial and control regimens could vary; update with later OS and current regulatory/guideline status.
BREAKWATER is a major first-line targeted-therapy-plus-chemotherapy advance in BRAF V600E mCRC, with improved PFS, response and interim OS but greater serious toxicity.
Use current regional guidelines, patient fitness, biomarkers, competing risks, alternatives and regulatory status before clinical application. Clinical freshness review and browser-rendered QA remain pending.
Primary sources and registry
Registry: NCT04607421
The Absolute Effect · Updated 26 October 2026 · Never derive NNT from median survival.