TY - JOUR
T1 - Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer
AU - Kopetz, Scott
AU - Grothey, Axel
AU - Yaeger, Rona
AU - Van Cutsem, Eric
AU - Desai, Jayesh
AU - Yoshino, Takayuki
AU - Wasan, Harpreet
AU - Ciardiello, Fortunato
AU - Loupakis, Fotios
AU - Hong, Yong Sang
AU - Steeghs, Neeltje
AU - Guren, Tormod K
AU - Arkenau, Hendrik-Tobias
AU - Garcia-Alfonso, Pilar
AU - Pfeiffer, Per
AU - Orlov, Sergey
AU - Lonardi, Sara
AU - Elez, Elena
AU - Kim, Tae-Won
AU - Schellens, Jan H M
AU - Guo, Christina
AU - Krishnan, Asha
AU - Dekervel, Jeroen
AU - Morris, Van
AU - Calvo Ferrandiz, Aitana
AU - Tarpgaard, L S
AU - Braun, Michael
AU - Gollerkeri, Ashwin
AU - Keir, Christopher
AU - Maharry, Kati
AU - Pickard, Michael
AU - Christy-Bittel, Janna
AU - Anderson, Lisa
AU - Sandor, Victor
AU - Tabernero, Josep
N1 - Copyright © 2019 Massachusetts Medical Society.
PY - 2019/10/24
Y1 - 2019/10/24
N2 - BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).
AB - BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects
KW - Benzimidazoles/administration & dosage
KW - Carbamates/administration & dosage
KW - Cetuximab/administration & dosage
KW - Colorectal Neoplasms/drug therapy
KW - Disease Progression
KW - Electrocorticography
KW - Female
KW - Humans
KW - Intention to Treat Analysis
KW - Irinotecan/therapeutic use
KW - Kaplan-Meier Estimate
KW - Male
KW - Middle Aged
KW - Mutation
KW - Proto-Oncogene Proteins B-raf/genetics
KW - Sulfonamides/administration & dosage
KW - Survival Analysis
U2 - 10.1056/NEJMoa1908075
DO - 10.1056/NEJMoa1908075
M3 - Article
C2 - 31566309
VL - 381
SP - 1632
EP - 1643
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 0028-4793
IS - 17
ER -