Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer

Author(s): Thomas Powles, M.D., Begoña P. Valderrama, M.D., Shilpa Gupta, M.D., Jens Bedke, M.D., Eiji Kikuchi, M.D., Ph.D., Jean Hoffman-Censits, M.D., Gopa Iyer, M.D., Christof Vulsteke, M.D., Ph.D. https://orcid.org/0000-0002-4607-5660, Se Hoon Park, M.D., Ph.D., Sang Joon Shin, M.D., Ph.D., Daniel Castellano, M.D., Giuseppe Fornarini, M.D., Jian-Ri Li, M.D., Ph.D., Mahmut Gümüş, M.D., Nataliya Mar, M.D., Yohann Loriot, M.D., Ph.D., Aude Fléchon, M.D., Ignacio Duran, M.D., Ph.D., Alexandra Drakaki, M.D., Sujata Narayanan, M.D., Xuesong Yu, Ph.D., Seema Gorla, M.D., Blanca Homet Moreno, M.D., Ph.D., and Michiel S. van der Heijden, M.D., Ph.D., for the EV-302 Trial Investigators*
Source: DOI: 10.1056/NEJMoa2312117
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

This antibody doublet is essentially the new SOC in met-urothelial cancer. The anti-PD1 and ADC combination is compelling in many ways and the survival outcomes compared to chemo were very significant. This combination is on NCCN, as well.


No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma.


We 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.


A 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.


Treatment 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.)

Author Affiliations

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.).

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