• Scott Kopetz, Axel Grothey, Rona Yaeger, Eric Van Cutsem, Jayesh Desai, Takayuki Yoshino, Harpreet Wasan, Fortunato Ciardiello, Fotios Loupakis, Yong Sang Hong, Neeltje Steeghs, Tormod K Guren, Hendrik-Tobias Arkenau, Pilar Garcia-Alfonso, Per Pfeiffer, Sergey Orlov, Sara Lonardi, Elena Elez, Tae-Won Kim, Schellens Jan H M JHM From the University of Texas M.D. Anderson Cancer Center, Houston (S.K., V.M.); West Cancer Center and Research Institute, OneOncology, Germantown, , Christina Guo, Asha Krishnan, Jeroen Dekervel, Van Morris, Aitana Calvo Ferrandiz, L S Tarpgaard, Michael Braun, Ashwin Gollerkeri, Christopher Keir, Kati Maharry, Michael Pickard, Janna Christy-Bittel, Lisa Anderson, Victor Sandor, and Josep Tabernero.
• From the University of Texas M.D. Anderson Cancer Center, Houston (S.K., V.M.); West Cancer Center and Research Institute, OneOncology, Germantown, TN (A. Grothey); Memorial Sloan Kettering Cancer Center, New York (R.Y., A.K.); University Hospital Gasthuisberg and University of Leuven, Leuven, Belgium (E.V.C., J. Dekervel); the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (J. Desai, C.G.); National Cancer Center Hospital East, Kashiwa, Japan (T.Y.); Hammersmith Hospital, Division of Cancer, Imperial College London (H.W.), and the Sarah Cannon Research Institute and University College London Cancer Institute (H.-T.A.), London, and the Christie NHS Foundation Trust/National Institute for Health Research Manchester Biomedical Research Centre, Manchester (M.B.) - all in the United Kingdom; the University of Campania Luigi Vanvitelli, Naples (F.C.), and Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua (F.L., S.L.) - both in Italy; Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea (Y.S.H., T.-W.K.); the Netherlands Cancer Institute, Amsterdam (N.S., J.H.M.S.); Oslo University Hospital, Oslo (T.K.G.); Hospital Gregorio Marañón, Madrid (P.G.-A., A.C.F.), and Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, UVic, IOB-Quiron, Barcelona (E.E., J.T.) - both in Spain; Odense University Hospital, Odense, Denmark (P.P., L.S.T.); Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia (S.O.); and Array BioPharma, Boulder, CO (A. Gollerkeri, C.K., K.M., M.P., J.C.-B., L.A., V.S.).
• N. Engl. J. Med. 2019 Oct 24; 381 (17): 1632-1643.

BackgroundPatients 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.MethodsIn 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.ResultsThe 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.ConclusionsA 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.).Copyright © 2019 Massachusetts Medical Society.

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