# Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer (BEACON CRC)

Source: https://onco.cc/key-papers/paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019/  
OnCo record `paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

BRAF V600E bowel cancer had a median survival of four to six months after first-line failure. Blocking BRAF and EGFR together took it to nine, and made the doublet a standard.

## Summary

Kopetz, Grothey, Yaeger and colleagues enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had progressed after one or two previous regimens, randomising them 1:1:1 to encorafenib, binimetinib and cetuximab (triplet), encorafenib and cetuximab (doublet), or the investigators' choice of cetuximab with irinotecan or with FOLFIRI (control). The primary end points were overall survival and objective response in the triplet group against control, with overall survival in the doublet group against control as a secondary end point; this is the prespecified interim analysis.

Inhibition of BRAF alone has limited activity in colorectal cancer because the pathway reactivates through EGFR signalling, which is the reason the EGFR antibody is in every arm of the experimental design.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Journal: New England Journal of Medicine
- Year: 2019
- DOI: 10.1056/NEJMoa1908075
- Authors: Kopetz S, Grothey A, Yaeger R, et al.
- Findings: Median overall survival 9.0 months in the triplet group against 5.4 months in the control group: hazard ratio 0.52 (95 percent CI 0.39 to 0.70, p<0.001).; Confirmed response 26 percent (95 percent CI 18 to 35) with the triplet against 2 percent (0 to 7) with control (p<0.001).; Median overall survival in the doublet group 8.4 months: hazard ratio against control 0.60 (0.45 to 0.79, p<0.001).; Grade 3 or higher adverse events in 58 percent (triplet), 50 percent (doublet) and 61 percent (control).
- What it means: Encorafenib with cetuximab became the standard second-line treatment for BRAF V600E disease, and the platform BREAKWATER later moved into first line with chemotherapy added, doubling survival again.
- Caveats: The MEK inhibitor added toxicity without a clear survival gain over the doublet, which is why the doublet was approved.; BRAF V600E disease is 8 to 10 percent of colorectal cancer; the trial says nothing about non-V600E BRAF alterations.; Interim analysis; the final report confirmed the direction with slightly different medians.

## Sources

- N Engl J Med 2019: https://doi.org/10.1056/NEJMoa1908075
- PubMed: https://pubmed.ncbi.nlm.nih.gov/31566309/

## Connected records

- key papers: [FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of TRIBE](https://onco.cc/key-papers/paper-cremolini-tribe-folfoxiri-bevacizumab-lancet-oncol-2015/)
- cancers: [BRAF V600E-mutant colorectal cancer](https://onco.cc/cancers/braf-v600e-colorectal/), [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [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: [Binimetinib](https://onco.cc/drugs/binimetinib/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [Encorafenib](https://onco.cc/drugs/encorafenib/), [FOLFIRI (5-FU, leucovorin, irinotecan)](https://onco.cc/drugs/folfiri/), [Irinotecan (and liposomal irinotecan)](https://onco.cc/drugs/irinotecan/)
- companies: [Pfizer (incl. Seagen)](https://onco.cc/companies/pfizer/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- trials: [BEACON CRC](https://onco.cc/trials/beacon-crc/), [BREAKWATER](https://onco.cc/trials/breakwater/)
- people: [Eric Van Cutsem](https://onco.cc/people/eric-van-cutsem/), [Josep Tabernero](https://onco.cc/people/josep-tabernero/), [Scott Kopetz](https://onco.cc/people/scott-kopetz/), [Takayuki Yoshino](https://onco.cc/people/yoshino-takayuki/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/)

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