Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: A randomized phase 3 trial Journal Article
| Authors: | Kopetz, S.; Yoshino, T.; Van Cutsem, E.; Eng, C.; Kim, T. W.; Wasan, H. S.; Desai, J.; Ciardiello, F.; Yaeger, R.; Maughan, T. S.; Beyzarov, E.; Zhang, X.; Ferrier, G.; Zhang, X.; Tabernero, J. |
| Article Title: | Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: A randomized phase 3 trial |
| Abstract: | Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, 2.443; 95% confidence interval (CI): 1.403–4.253; 99.8% CI: 1.019–5.855; one-sided P = 0.0008). Median duration of response was 13.9 versus 11.1 months. At this first interim analysis of overall survival, the hazard ratio was 0.47 (95% CI: 0.318–0.691; repeated CI: 0.166–1.322). Serious adverse event rates were 37.7% versus 34.6%. The safety profiles were consistent with those known for each agent. BREAKWATER demonstrated a significantly improved response rate that was durable for first-line EC+mFOLFOX6 versus SOC in patients with BRAF V600E mCRC. ClinicalTrials.gov identifier: NCT04607421. © The Author(s) 2025. |
| Keywords: | adult; cancer chemotherapy; controlled study; treatment response; aged; aged, 80 and over; middle aged; cancer surgery; gene mutation; major clinical study; overall survival; genetics; mutation; clinical trial; constipation; fatigue; neutropenia; paresthesia; bevacizumab; fluorouracil; diarrhea; drug efficacy; drug safety; side effect; treatment duration; capecitabine; cancer staging; neurotoxicity; antineoplastic agent; cancer diagnosis; c reactive protein; cytology; progression free survival; neutrophil count; sensory neuropathy; anemia; mucosa inflammation; nausea; randomized controlled trial; stomatitis; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; myalgia; peripheral neuropathy; carcinoembryonic antigen; continuous infusion; pathology; cetuximab; histology; irinotecan; abdominal pain; alanine aminotransferase blood level; arthralgia; aspartate aminotransferase blood level; asthenia; fever; hypomagnesemia; pruritus; rash; colorectal neoplasms; alanine aminotransferase; aspartate aminotransferase; drug fatality; hypoalbuminemia; hypokalemia; insomnia; liver metastasis; sulfonamide; multicenter study; colorectal tumor; sulfonamides; folinic acid; microsatellite instability; hyperpigmentation; dermatitis; headache; phase 3 clinical trial; leukocyte count; platinum complex; drug therapy; oxaliplatin; hand foot syndrome; triacylglycerol lipase blood level; dry skin; alopecia; organoplatinum compounds; epistaxis; leucovorin; b raf kinase; carbamic acid; carbamates; proto-oncogene proteins b-raf; braf protein, human; dysgeusia; triacylglycerol lipase; progression-free survival; decreased appetite; metastatic colorectal cancer; colorectal adenocarcinoma; patient-reported outcome; oncological parameters; body weight loss; response evaluation criteria in solid tumors; folfox protocol; time to treatment; very elderly; objective response rate; humans; human; male; female; article; encorafenib; ecog performance status; treatment response time |
| Journal Title: | Nature Medicine |
| Volume: | 31 |
| Issue: | 3 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-03-01 |
| Start Page: | 901 |
| End Page: | 908 |
| Language: | English |
| DOI: | 10.1038/s41591-024-03443-3 |
| PUBMED: | 39863775 |
| PROVIDER: | scopus |
| PMCID: | PMC11922750 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
