# BREAKWATER: encorafenib plus cetuximab with chemotherapy as first treatment for BRAF V600E-mutated colorectal cancer

Source: https://onco.cc/key-papers/paper-breakwater-nejm-2025/  
OnCo record `paper-breakwater-nejm-2025` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Adding a BRAF inhibitor and an EGFR antibody to first-line chemotherapy roughly doubled survival in BRAF V600E-mutated metastatic bowel cancer, one of the worst-prognosis subtypes.

## Summary

Open-label phase 3 trial of patients with untreated BRAF V600E-mutated metastatic colorectal cancer randomised to encorafenib plus cetuximab plus mFOLFOX6, encorafenib plus cetuximab alone (arm later closed), or standard chemotherapy with or without bevacizumab. Primary endpoints were PFS and objective response rate.

The first report (Nature Medicine 2025) showed a response rate of about 61% vs 40%, supporting accelerated FDA approval in December 2024. The 2025 NEJM report showed median PFS 12.8 vs 7.1 months (HR 0.53) and median OS 30.3 vs 15.1 months (HR 0.49). It moved BRAF-targeted therapy from second line (BEACON) to first line and is the largest survival gain ever seen in this subgroup.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2025
- DOI: 10.1056/NEJMoa2501912
- Authors: Elez E, Yoshino T, Shen L, et al.
- Findings: Objective response about 61% vs 40% in the first analysis (Nature Medicine 2025), with longer duration of response.; Median PFS 12.8 vs 7.1 months; HR 0.53.; Median overall survival 30.3 vs 15.1 months; HR 0.49.; Grade 3 or higher adverse events were more frequent with the triplet plus chemotherapy, driven by skin toxicity, gastrointestinal events and neutropenia.; The chemotherapy-free encorafenib plus cetuximab arm was stopped early after emerging data from other studies.
- What it means: Patients with newly diagnosed metastatic colorectal cancer whose tumour carries a BRAF V600E mutation, which is about 8-12% of cases, should now be offered encorafenib and cetuximab together with FOLFOX from the start rather than after chemotherapy fails; median survival has roughly doubled to about two and a half years. BRAF testing at diagnosis is therefore essential, alongside RAS and mismatch repair testing. The regimen is more toxic than chemotherapy alone.
- Caveats: Open-label; some figures come from conference presentations and interim analyses, and long-term follow-up is short.; Most patients had microsatellite-stable tumours; dMMR BRAF-mutated tumours should still receive immunotherapy first.; Combination toxicity and cost are considerable; treatment requires three targeted or antibody agents plus chemotherapy.; Resistance to BRAF/EGFR blockade remains universal; the trial does not address what follows.

## Sources

- PubMed search: BREAKWATER encorafenib NEJM 2025: https://pubmed.ncbi.nlm.nih.gov/?term=BREAKWATER+encorafenib+cetuximab+mFOLFOX6+colorectal
- ClinicalTrials.gov NCT04607421: https://clinicaltrials.gov/study/NCT04607421

## Connected records

- biomarkers: [BRAF V600E (and V600K)](https://onco.cc/biomarkers/braf-v600e/)
- cancers: [BRAF V600E-mutant colorectal cancer](https://onco.cc/cancers/braf-v600e-colorectal/), [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [BRAF](https://onco.cc/targets/braf/), [EGFR](https://onco.cc/targets/egfr/)
- drugs: [Encorafenib](https://onco.cc/drugs/encorafenib/)
- companies: [Pfizer (incl. Seagen)](https://onco.cc/companies/pfizer/)
- institutions: [MD Anderson Cancer Center](https://onco.cc/institutions/md-anderson/), [Vall d'Hebron University Hospital / VHIO](https://onco.cc/institutions/vall-dhebron/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Accelerated approval](https://onco.cc/terms/accelerated-approval/), [Lines of therapy](https://onco.cc/terms/first-line/), [Objective response rate (ORR)](https://onco.cc/terms/orr/), [Overall survival (OS)](https://onco.cc/terms/os/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/)
- people: [Elena Élez](https://onco.cc/people/elena-elez/), [Josep Tabernero](https://onco.cc/people/josep-tabernero/), [Lin Shen](https://onco.cc/people/shen-lin/), [Scott Kopetz](https://onco.cc/people/scott-kopetz/), [Tae Won Kim](https://onco.cc/people/kim-tae-won/), [Takayuki Yoshino](https://onco.cc/people/yoshino-takayuki/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Prices and value](https://onco.cc/bottlenecks/b-drug-pricing/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)

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