# BRAF V600E-mutant colorectal cancer

Source: https://onco.cc/cancers/braf-v600e-colorectal/  
OnCo record `braf-v600e-colorectal` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

BRAF V600E bowel cancer carries the same mutation as many melanomas, but BRAF drugs alone did nothing here because the tumour re-routes its growth signal through EGFR. Blocking both with encorafenib and cetuximab, now given with chemotherapy from the start, has doubled survival in a subtype that used to be the worst.

## Summary

BRAF V600E locks the RAS-MAPK pathway on, and in colorectal cancer it arises in the serrated pathway with CpG island methylation; about a third of localised BRAF-mutant tumours are also mismatch-repair deficient, in which case the immunotherapy of that subtype applies and the outlook is good. Microsatellite-stable BRAF V600E disease is different: it is often right-sided, presents with peritoneal and nodal spread, responds poorly to chemotherapy, and anti-EGFR antibodies alone do not work. Non-V600 BRAF mutations, about 2 percent of cancers, behave as a separate and less aggressive group.

Single-agent vemurafenib failed in 2011 because inhibiting BRAF in bowel cells releases feedback activation of EGFR; blocking both proved the answer. BEACON CRC (2019) randomised 665 previously treated patients to encorafenib and cetuximab with or without binimetinib against chemotherapy plus cetuximab: median survival was 9.3 months with either targeted regimen against 5.9 months, response rates were 20 to 27 percent against 2 percent, and the FDA approved encorafenib with cetuximab in April 2020. BREAKWATER (2024 to 2025) then moved the doublet into first line with mFOLFOX6: the response rate was 61 percent against 40 percent for chemotherapy and median survival 30.3 months against 15.1 months, which brought accelerated approval in December 2024 and full approval in 2026.

The next questions are whether to add a PD-1 antibody (SEAMARK, encorafenib-cetuximab-pembrolizumab in mismatch-repair deficient BRAF disease), how to treat after progression on the targeted doublet, when MAPK reactivation and MET amplification drive resistance, and whether the triplet should be given in the adjuvant setting for stage III disease.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: BRAF-mutant colorectal cancer; BRAF V600E metastatic colorectal cancer; BRAF-mutated bowel cancer
- Tags: subtype-page
- Group: gastrointestinal
- Burden: About 8 to 10 percent of colorectal cancers carry BRAF V600E; they are commoner in older women and right-sided tumours, are often mismatch-repair deficient when localised, and when metastatic and microsatellite-stable have had among the shortest survival of any colorectal subtype.
- Subtypes: BRAF V600E, microsatellite-stable (the aggressive majority; targeted therapy with encorafenib and cetuximab); BRAF V600E with mismatch-repair deficiency (right-sided; immunotherapy first); BRAF non-V600 (class 2 and 3) mutations, a distinct and less aggressive group; Right-sided serrated-pathway tumours with CpG island methylation
- Biomarkers: BRAF V600E by sequencing or VE1 immunohistochemistry; Mismatch repair status (immunotherapy if deficient); RAS wild-type by definition; co-mutations rare; Consensus molecular subtype 1 enrichment; Circulating tumour DNA to track MAPK reactivation on treatment

## Standard of care

- Metastatic, microsatellite-stable, first line: Encorafenib plus cetuximab plus mFOLFOX6 (BREAKWATER); encorafenib plus cetuximab alone for patients unfit for chemotherapy. ([BREAKWATER](https://onco.cc/trials/breakwater/), [Encorafenib](https://onco.cc/drugs/encorafenib/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/))
- Metastatic, previously treated: Encorafenib plus cetuximab (BEACON CRC) if not already given; then trifluridine-tipiracil with bevacizumab, fruquintinib or regorafenib. ([BEACON CRC](https://onco.cc/trials/beacon-crc/), [Encorafenib](https://onco.cc/drugs/encorafenib/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [Trifluridine/tipiracil](https://onco.cc/drugs/trifluridine-tipiracil/), [Fruquintinib](https://onco.cc/drugs/fruquintinib/), [Regorafenib](https://onco.cc/drugs/regorafenib/))
- Metastatic, mismatch-repair deficient: Checkpoint blockade first (pembrolizumab, or nivolumab plus ipilimumab); BRAF-targeted therapy at progression. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/), [CheckMate 8HW](https://onco.cc/trials/checkmate-8hw/))
- Localised: Surgery and stage-based adjuvant FOLFOX or CAPOX as for colorectal cancer; BRAF status does not yet change adjuvant treatment outside trials. ([FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [CAPOX (capecitabine, oxaliplatin)](https://onco.cc/drugs/capox/), [Oxaliplatin](https://onco.cc/drugs/oxaliplatin/))

## State of the art

- Encorafenib plus cetuximab with FOLFOX in first line (BREAKWATER) doubles survival against chemotherapy.
- The EGFR-feedback mechanism explained a decade of failed BRAF monotherapy and is the template for vertical pathway blockade.
- Mismatch-repair deficient BRAF tumours get immunotherapy, not targeted therapy, first.

## Open problems

- No standard therapy after progression on encorafenib and cetuximab.
- Resistance through MAPK reactivation and MET amplification is common and untargeted.
- Adjuvant use of the targeted doublet in stage III disease is untested.
- Non-V600 BRAF mutations have no approved targeted option.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/BRAF_(gene)
- Wikipedia: https://en.wikipedia.org/wiki/BRAF_(gene)
- NCCN Guidelines: Colon Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428

## Connected records

- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [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/), [MEK1/2](https://onco.cc/targets/mek/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Binimetinib](https://onco.cc/drugs/binimetinib/), [CAPOX (capecitabine, oxaliplatin)](https://onco.cc/drugs/capox/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [Encorafenib](https://onco.cc/drugs/encorafenib/), [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [Fruquintinib](https://onco.cc/drugs/fruquintinib/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Oxaliplatin](https://onco.cc/drugs/oxaliplatin/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Regorafenib](https://onco.cc/drugs/regorafenib/), [Trifluridine/tipiracil](https://onco.cc/drugs/trifluridine-tipiracil/)
- pathways: [Colorectal cancer (KEGG map)](https://onco.cc/pathways/colorectal-cancer-signalling/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Consensus molecular subtypes (CMS1-4)](https://onco.cc/terms/cms-subtypes/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/)
- trials: [A Study of Encorafenib Plus Cetuximab Taken Together With Pembrolizumab Compared to Pembrolizumab Alone in People With Previously Untreated Metastatic](https://onco.cc/trials/nct05217446/), [BEACON CRC](https://onco.cc/trials/beacon-crc/), [BREAKWATER](https://onco.cc/trials/breakwater/), [CheckMate 8HW](https://onco.cc/trials/checkmate-8hw/), [Efficacy and Safety of Tunlametinib Plus Vemurafenib in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer](https://onco.cc/trials/nct06008119/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/)
- people: [Elena Élez](https://onco.cc/people/elena-elez/), [Josep Tabernero](https://onco.cc/people/josep-tabernero/), [Scott Kopetz](https://onco.cc/people/scott-kopetz/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)

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