{"entity":{"id":"breakwater","kind":"trial","name":"BREAKWATER","aka":[],"tldr":"Doubled survival, from about 15 to about 30 months, in the worst-prognosis genetic subtype of bowel cancer by adding two targeted drugs to first-line chemotherapy.","summary":"EC + mFOLFOX6: PFS 12.8 vs 7.1 months; OS 30.3 vs 15.1 months (HR 0.49; ASCO 2025 LBA3500). The FOLFIRI cohort (ASCO 2026 LBA3503) showed PFS HR 0.44 and OS HR 0.56. FDA accelerated approval December 2024 (first under Project FrontRunner), converted toward full approval in 2026. BRAF V600E disease previously had a median overall survival of around a year.","status":"positive","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04607421","url":"https://clinicaltrials.gov/study/NCT04607421"},{"label":"ASCO 2025 LBA3500","url":"https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA3500"},{"label":"ASCO 2026 LBA3503 (FOLFIRI)","url":"https://ascopubs.org/doi/10.1200/JCO.2026.44.17_suppl.LBA3503"}],"tags":[],"related":[],"cancers":["colorectal","braf-v600e-colorectal"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["braf","egfr"],"drugs":["encorafenib","cetuximab","folfox","folfiri"],"companies":["pfizer"],"institutions":[],"pathways":["ras-mapk"],"terms":["project-frontrunner"],"trials":["swog-s1406"],"people":["scott-kopetz","elena-elez","josep-tabernero"],"bottlenecks":[],"keyPapers":["paper-jones-non-v600-braf-colorectal-jco-2017","paper-breakwater-nat-med-2025"],"journals":[],"dependsOn":[],"notes":[],"nct":"NCT04607421","phase":"3","setting":"First-line BRAF V600E-mutant metastatic colorectal cancer: encorafenib + cetuximab + mFOLFOX6 (or FOLFIRI) vs chemotherapy ± bevacizumab","sponsor":"Pfizer","result":"OS 30.3 vs 15.1 months (HR 0.49); PFS 12.8 vs 7.1 months.","started":"2020-12-21","startedType":"actual","yearReported":2025,"enrolledBasis":"registry","outcomes":[{"endpoint":"Overall survival (EC + mFOLFOX6)","unit":"months","arms":[{"name":"Encorafenib + cetuximab + mFOLFOX6","value":30.3},{"name":"Chemotherapy ± bevacizumab","value":15.1}],"hr":0.49,"source":"https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA3500"},{"endpoint":"Progression-free survival (EC + mFOLFOX6)","primary":true,"unit":"months","arms":[{"name":"Encorafenib + cetuximab + mFOLFOX6","value":12.8},{"name":"Chemotherapy ± bevacizumab","value":7.1}],"source":"https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA3500"},{"endpoint":"Progression-free survival (EC + FOLFIRI cohort)","unit":"months","arms":[{"name":"Encorafenib + cetuximab + FOLFIRI"},{"name":"Chemotherapy ± bevacizumab"}],"hr":0.44,"source":"https://ascopubs.org/doi/10.1200/JCO.2026.44.17_suppl.LBA3503"}],"replication":"Two independent chemotherapy-backbone cohorts within BREAKWATER reproduce the effect; BEACON established the doublet in later lines."},"route":"/trials/breakwater/","neighbours":{"cancer":[{"id":"braf-v600e-colorectal","kind":"cancer","name":"BRAF V600E-mutant colorectal cancer","route":"/cancers/braf-v600e-colorectal/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"technology":[{"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/"}],"drug":[{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"encorafenib","kind":"drug","name":"Encorafenib","route":"/drugs/encorafenib/"},{"id":"folfiri","kind":"drug","name":"FOLFIRI (5-FU, leucovorin, irinotecan)","route":"/drugs/folfiri/"},{"id":"folfox","kind":"drug","name":"FOLFOX (5-FU, leucovorin, oxaliplatin)","route":"/drugs/folfox/"}],"company":[{"id":"pfizer","kind":"company","name":"Pfizer (incl. Seagen)","route":"/companies/pfizer/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"project-frontrunner","kind":"term","name":"Project FrontRunner","route":"/terms/project-frontrunner/"}],"trial":[{"id":"swog-s1406","kind":"trial","name":"SWOG S1406","route":"/trials/swog-s1406/"}],"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":"scott-kopetz","kind":"person","name":"Scott Kopetz","route":"/people/scott-kopetz/"}],"paper":[{"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-breakwater-nat-med-2025","kind":"paper","name":"Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial","route":"/key-papers/paper-breakwater-nat-med-2025/"},{"id":"paper-jones-non-v600-braf-colorectal-jco-2017","kind":"paper","name":"Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer","route":"/key-papers/paper-jones-non-v600-braf-colorectal-jco-2017/"}],"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/"}]}}