{"entity":{"id":"braf-v600e-colorectal","kind":"cancer","name":"BRAF V600E-mutant colorectal cancer","aka":["BRAF-mutant colorectal cancer","BRAF V600E metastatic colorectal cancer","BRAF-mutated bowel cancer"],"tldr":"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.\n\nSingle-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.\n\nThe 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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/BRAF_(gene)","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/BRAF_(gene)"},{"label":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}],"tags":["subtype-page"],"related":["early-onset-colorectal","her2-amplified-colorectal","kras-g12c-colorectal","msi-high-colorectal","rectal-cancer"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","monoclonal-antibody","checkpoint-inhibitor","liquid-biopsy"],"targets":["braf","egfr","mek","pd1"],"drugs":["encorafenib","cetuximab","binimetinib","folfox","pembrolizumab"],"companies":[],"institutions":[],"pathways":["ras-mapk","colorectal-cancer-signalling"],"terms":["msi","sidedness","cms-subtypes","ctdna"],"trials":["beacon-crc","breakwater","nct05217446","nct06008119"],"people":["scott-kopetz","josep-tabernero","elena-elez"],"bottlenecks":[],"keyPapers":["paper-breakwater-nejm-2025","paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","paper-cms-guinney-nat-med-2015"],"journals":[],"dependsOn":[],"notes":[],"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"],"standardOfCare":[{"setting":"Metastatic, microsatellite-stable, first line","approach":"Encorafenib plus cetuximab plus mFOLFOX6 (BREAKWATER); encorafenib plus cetuximab alone for patients unfit for chemotherapy.","refs":["breakwater","encorafenib","cetuximab","folfox","kinase-inhibitors"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic, previously treated","approach":"Encorafenib plus cetuximab (BEACON CRC) if not already given; then trifluridine-tipiracil with bevacizumab, fruquintinib or regorafenib.","refs":["beacon-crc","encorafenib","cetuximab","trifluridine-tipiracil","fruquintinib","regorafenib"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Metastatic, mismatch-repair deficient","approach":"Checkpoint blockade first (pembrolizumab, or nivolumab plus ipilimumab); BRAF-targeted therapy at progression.","refs":["pembrolizumab","nivolumab","ipilimumab","keynote-177","checkmate-8hw"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}},{"setting":"Localised","approach":"Surgery and stage-based adjuvant FOLFOX or CAPOX as for colorectal cancer; BRAF status does not yet change adjuvant treatment outside trials.","refs":["folfox","capox","oxaliplatin"],"guideline":{"version":"NCCN Guidelines: Colon Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428"}}],"stateOfArt":["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."],"history":[{"year":2002,"title":"BRAF mutations discovered in human cancer (Davies, Nature)","refs":["braf"]},{"year":2011,"title":"Vemurafenib alone fails in BRAF-mutant colorectal cancer; EGFR feedback identified the next year","refs":["braf","egfr","scott-kopetz"]},{"year":2019,"title":"BEACON CRC: encorafenib plus cetuximab improves survival after prior therapy","refs":["beacon-crc","encorafenib","cetuximab"]},{"year":2020,"title":"FDA approves encorafenib with cetuximab, the first targeted therapy for the subtype","refs":["encorafenib"]},{"year":2024,"title":"BREAKWATER: encorafenib-cetuximab-FOLFOX first line; accelerated approval in December","refs":["breakwater"]},{"year":2025,"title":"BREAKWATER overall survival 30.3 versus 15.1 months","refs":["breakwater","scott-kopetz","elena-elez"]},{"year":2026,"title":"Full approval of the first-line triplet","refs":["encorafenib","breakwater"]}],"pipeline":["nct05217446","nct06008119","breakwater","encorafenib"],"openProblems":["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."],"parent":"colorectal"},"route":"/cancers/braf-v600e-colorectal/","neighbours":{"cancer":[{"id":"colon-cancer","kind":"cancer","name":"Colon cancer (adenocarcinoma of the colon)","route":"/cancers/colon-cancer/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"early-onset-colorectal","kind":"cancer","name":"Early-onset colorectal cancer (under 50)","route":"/cancers/early-onset-colorectal/"},{"id":"her2-amplified-colorectal","kind":"cancer","name":"HER2-amplified colorectal cancer","route":"/cancers/her2-amplified-colorectal/"},{"id":"kras-g12c-colorectal","kind":"cancer","name":"KRAS G12C-mutant colorectal cancer","route":"/cancers/kras-g12c-colorectal/"},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/"},{"id":"rectal-cancer","kind":"cancer","name":"Rectal cancer","route":"/cancers/rectal-cancer/"},{"id":"colorectal-serrated-adenocarcinoma","kind":"cancer","name":"Serrated adenocarcinoma of the colon and rectum","route":"/cancers/colorectal-serrated-adenocarcinoma/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"monoclonal-antibody","kind":"technology","name":"Monoclonal antibodies","route":"/technologies/monoclonal-antibody/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"mek","kind":"target","name":"MEK1/2","route":"/targets/mek/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"binimetinib","kind":"drug","name":"Binimetinib","route":"/drugs/binimetinib/"},{"id":"capox","kind":"drug","name":"CAPOX (capecitabine, oxaliplatin)","route":"/drugs/capox/"},{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/"},{"id":"folfox","kind":"drug","name":"FOLFOX (5-FU, leucovorin, oxaliplatin)","route":"/drugs/folfox/"},{"id":"fruquintinib","kind":"drug","name":"Fruquintinib","route":"/drugs/fruquintinib/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"oxaliplatin","kind":"drug","name":"Oxaliplatin","route":"/drugs/oxaliplatin/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"regorafenib","kind":"drug","name":"Regorafenib","route":"/drugs/regorafenib/"},{"id":"trifluridine-tipiracil","kind":"drug","name":"Trifluridine/tipiracil","route":"/drugs/trifluridine-tipiracil/"},{"id":"vemurafenib","kind":"drug","name":"Vemurafenib","route":"/drugs/vemurafenib/"}],"pathway":[{"id":"colorectal-cancer-signalling","kind":"pathway","name":"Colorectal cancer (KEGG map)","route":"/pathways/colorectal-cancer-signalling/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"cms-subtypes","kind":"term","name":"Consensus molecular subtypes (CMS1-4)","route":"/terms/cms-subtypes/"},{"id":"cimp","kind":"term","name":"CpG island methylator phenotype (CIMP)","route":"/terms/cimp/"},{"id":"extended-ras-testing","kind":"term","name":"Extended RAS testing","route":"/terms/extended-ras-testing/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"serrated-pathway","kind":"term","name":"Serrated pathway","route":"/terms/serrated-pathway/"},{"id":"sidedness","kind":"term","name":"Sidedness (left vs right colon)","route":"/terms/sidedness/"}],"trial":[{"id":"nct07506109","kind":"trial","name":"A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colo","route":"/trials/nct07506109/"},{"id":"nct07789210","kind":"trial","name":"A Single-Arm, Phase II, Multicenter Clinical Study of Neoadjuvant Encorafenib Plus Cetuximab N01 and mFOLFOX6 in Patients With Locally Advanced BRAF V600E-Mutan","route":"/trials/nct07789210/"},{"id":"nct07229846","kind":"trial","name":"A Single-arm, Single-center, Phase II Clinical Study of Aipalolitovorelizumab (QL1706) Combined With Bevacizumab and Standard Chemotherapy as First-line Treatme","route":"/trials/nct07229846/"},{"id":"nct06978400","kind":"trial","name":"A Study of Dabrafenib Plus Cetuximab/Panitumumab With FOLFOX in the First Line of Therapy in People With Metastatic Colorectal Cancer","route":"/trials/nct06978400/"},{"id":"nct05217446","kind":"trial","name":"A Study of Encorafenib Plus Cetuximab Taken Together With Pembrolizumab Compared to Pembrolizumab Alone in People With Previously Untreated Metastatic","route":"/trials/nct05217446/"},{"id":"nct07178717","kind":"trial","name":"A Study to Characterize Encorafenib Plus Cetuximab as Rechallenge Treatment for BRAF V600E-mutant Metastatic Colorectal Cancer Patients After Previous Therapy W","route":"/trials/nct07178717/"},{"id":"beacon-crc","kind":"trial","name":"BEACON CRC","route":"/trials/beacon-crc/"},{"id":"breakwater","kind":"trial","name":"BREAKWATER","route":"/trials/breakwater/"},{"id":"checkmate-8hw","kind":"trial","name":"CheckMate 8HW","route":"/trials/checkmate-8hw/"},{"id":"nct06008119","kind":"trial","name":"Efficacy and Safety of Tunlametinib Plus Vemurafenib in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer","route":"/trials/nct06008119/"},{"id":"nct06640166","kind":"trial","name":"Encorafenib + Cetuximab Beyond Progression in Combination With FOLFIRI in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer Progressing on Encorafen","route":"/trials/nct06640166/"},{"id":"nct05706779","kind":"trial","name":"Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer","route":"/trials/nct05706779/"},{"id":"nct06763029","kind":"trial","name":"Irinotecan Liposomes Combined with Cetuximab + Vermofenib in First-line Failure of Advanced Colorectal Cancer","route":"/trials/nct06763029/"},{"id":"nct07809893","kind":"trial","name":"Ivosidenib Plus mFOLFOXIRI and Celecoxib for BRAF-targeted Therapy-refractory BRAF V600E-mutant Colorectal Cancer Patients","route":"/trials/nct07809893/"},{"id":"keynote-177","kind":"trial","name":"KEYNOTE-177","route":"/trials/keynote-177/"},{"id":"nct05786924","kind":"trial","name":"Phase 1/2 Trial of S241656 in Selected RAS/MAPK Mutation- Positive Malignancies","route":"/trials/nct05786924/"},{"id":"nct06425133","kind":"trial","name":"Regorafenib in Combination With Multimodal Metronomic Chemotherapy for Chemo-resistant Metastatic Colorectal Cancers","route":"/trials/nct06425133/"},{"id":"nct07150247","kind":"trial","name":"Safety and Efficacy of IB-FOLFIRI in BRAF V600E-Mutant Metastatic Colorectal Cancer","route":"/trials/nct07150247/"},{"id":"nct06207656","kind":"trial","name":"Study to Evaluate the Efficacy and Safety of Cetuximab in Combination with Encorafenib Plus Binimetinib As Induction Treatment in BRAF V600E Mutated MSS Initial","route":"/trials/nct06207656/"},{"id":"swog-s1406","kind":"trial","name":"SWOG S1406","route":"/trials/swog-s1406/"},{"id":"nct05710406","kind":"trial","name":"Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer","route":"/trials/nct05710406/"},{"id":"nct05275374","kind":"trial","name":"XP-102 and XP-102 in Combination With Trametinib in Advanced Solid Tumor Patients With a BRAF V600 Mutation","route":"/trials/nct05275374/"}],"person":[{"id":"elena-elez","kind":"person","name":"Elena Élez","route":"/people/elena-elez/"},{"id":"josep-tabernero","kind":"person","name":"Josep Tabernero","route":"/people/josep-tabernero/"},{"id":"rona-yaeger","kind":"person","name":"Rona Yaeger","route":"/people/rona-yaeger/"},{"id":"scott-kopetz","kind":"person","name":"Scott Kopetz","route":"/people/scott-kopetz/"}],"paper":[{"id":"paper-breakwater-nejm-2025","kind":"paper","name":"BREAKWATER: encorafenib plus cetuximab with chemotherapy as first treatment for BRAF V600E-mutated colorectal cancer","route":"/key-papers/paper-breakwater-nejm-2025/"},{"id":"paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019","kind":"paper","name":"Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer (BEACON CRC)","route":"/key-papers/paper-kopetz-beacon-encorafenib-braf-colorectal-nejm-2019/"},{"id":"paper-cremolini-tribe-folfoxiri-bevacizumab-lancet-oncol-2015","kind":"paper","name":"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","route":"/key-papers/paper-cremolini-tribe-folfoxiri-bevacizumab-lancet-oncol-2015/"},{"id":"paper-cms-guinney-nat-med-2015","kind":"paper","name":"The consensus molecular subtypes of colorectal cancer","route":"/key-papers/paper-cms-guinney-nat-med-2015/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"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","route":"/roadmaps/colorectal-roadmap/"}],"biomarker":[{"id":"ras-wild-type","kind":"biomarker","name":"RAS wild-type (extended KRAS and NRAS testing)","route":"/biomarkers/ras-wild-type/"}]}}