• Thomas Powles, Begoña P Valderrama, Shilpa Gupta, Jens Bedke, Eiji Kikuchi, Jean Hoffman-Censits, Gopa Iyer, Christof Vulsteke, Se Hoon Park, Sang Joon Shin, Daniel Castellano, Giuseppe Fornarini, Jian-Ri Li, Mahmut Gümüş, Nataliya Mar, Yohann Loriot, Aude Fléchon, Ignacio Duran, Alexandra Drakaki, Sujata Narayanan, Xuesong Yu, Seema Gorla, Blanca Homet Moreno, Michiel S van der Heijden, and EV-302 Trial Investigators.
• From Barts Cancer Institute Biomedical Research Centre, Queen Mary University of London, London (T.P.); Hospital Universitario Virgen del Rocio, Seville (B.P.V.), Hospital Universitario 12 de Octubre, Madrid (D.C.), and Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla, Santander (I.D.) - all in Spain; Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland (S. Gupta); Klinikum Stuttgart Katharinen Hospital, Stuttgart, Germany (J.B.); St. Marianna University School of Medicine, Kawasaki, Japan (E.K.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (J.H.-C.); Memorial Sloan Kettering Cancer Center, New York (G.I.); Integrated Cancer Center Ghent, AZ Maria Middelares, Ghent, and the Center for Oncological Research, University of Antwerp, Antwerp - both in Belgium (C.V.); Samsung Medical Center, Sungkyunkwan University School of Medicine (S.H.P.), and Severance Hospital, Yonsei University Health System (S.J.S.) - both in Seoul, South Korea; Scientific Institute for Research, Hospitalization, and Healthcare Ospedale Policlinico San Martino, Genoa, Italy (G.F.); Taichung Veterans General Hospital, Taichung, Taiwan (J.-R.L.); Istanbul Medeniyet University Goztepe Training and Research Hospital, Istanbul, Turkey (M.G.); the University of California, Irvine Medical Center, Orange (N.M.), and the University of California, Los Angeles Medical Center, Los Angeles (A.D.); Institut Gustave Roussy, Université Paris-Saclay, Villejuif (Y.L.), and Centre Léon Bérard, Lyon (A.F.) - both in France; Seagen, Bothell, WA (S.N., X.Y.); Astellas Pharma US, Northbrook, IL (S. Gorla); Merck, Rahway, NJ (B.H.M.); and the Netherlands Cancer Institute, Amsterdam (M.S.H.).
• N. Engl. J. Med. 2024 Mar 7; 390 (10): 875888875-888.

BackgroundNo treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma.MethodsWe conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival.ResultsA total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group.ConclusionsTreatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.).Copyright © 2024 Massachusetts Medical Society.

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