Enfortumab vedotin plus pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma: 2.5-year median follow-up of the phase III EV-302/KEYNOTE-A39 trial

T B Powles; M S Van der Heijden; Y Loriot; J Bedke; B P Valderrama; G Iyer; E Kikuchi; J Hoffman-Censits; C Vulsteke; A Drakaki; S Rausch; W Arafat; S H Park; U Swami; J-R Li; I Duran; S Gorla; B Homet Moreno; X Yu; Y-T Lu; S Gupta

doi:10.1016/j.annonc.2025.05.536

Enfortumab vedotin plus pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma: 2.5-year median follow-up of the phase III EV-302/KEYNOTE-A39 trial

Ann Oncol. 2025 Jun 1:S0923-7534(25)00762-8. doi: 10.1016/j.annonc.2025.05.536. Online ahead of print.

Authors

T B Powles¹, M S Van der Heijden², Y Loriot³, J Bedke⁴, B P Valderrama⁵, G Iyer⁶, E Kikuchi⁷, J Hoffman-Censits⁸, C Vulsteke⁹, A Drakaki¹⁰, S Rausch¹¹, W Arafat¹², S H Park¹³, U Swami¹⁴, J-R Li¹⁵, I Duran¹⁶, S Gorla¹⁷, B Homet Moreno¹⁸, X Yu¹⁹, Y-T Lu¹⁹, S Gupta²⁰

Affiliations

¹ Department of Genitourinary Oncology, Barts Cancer Centre NIHR Biomedical Research Centre, Queen Mary University of London, London, UK. Electronic address: thomas.powles1@nhs.net.
² Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
³ Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France.
⁴ Department of Urology & Transplantation Surgery, Eva Mayr-Stihl Cancer Center, Klinikum Stuttgart, Stuttgart, Germany.
⁵ Medical Oncology Department, Hospital Universitario Virgen del Rocio, Seville, Spain.
⁶ Department of Genitourinary Oncology, Memorial Sloan Kettering Cancer Center, New York, USA.
⁷ Department of Urology, St. Marianna University School of Medicine, Kawasaki, Japan.
⁸ Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Center, Baltimore, USA; Department of Urology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Center, Baltimore, USA.
⁹ Department of Integrated Cancer Center Ghent, AZ Maria Middelares and Center for Oncological Research (CORE), Antwerp University, Antwerp, Belgium.
¹⁰ Division of Hematology Oncology, David Geffen School of Medicine, Department of University of California, Los Angeles Medical Center, Los Angeles, USA.
¹¹ Department of Urology, Eberhard Karls University, Tübingen, Germany.
¹² Division of Hematology and Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, USA.
¹³ Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
¹⁴ Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, USA.
¹⁵ Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
¹⁶ Medical Oncology Department, Hospital Universitario Marques de Valdecilla, IDIVAL Santander, Spain.
¹⁷ Department of Medical Oncology, Astellas Pharma, Inc., Northbrook, USA.
¹⁸ Department of Medical Oncology, Merck & Co., Inc., Rahway, USA.
¹⁹ Oncology Division, Pfizer Inc., Bothell, USA.
²⁰ Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, USA.

PMID: 40460988
DOI: 10.1016/j.annonc.2025.05.536

Abstract

Background: At the primary analysis of the EV-302 trial, enfortumab vedotin plus pembrolizumab (EV+P) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC).

Patients and methods: We present an updated analysis of efficacy and safety in the overall population, with a median follow-up of 2.5 years, providing an additional year of follow-up since the primary analysis.

Results: The median PFS by blinded independent central review was 12.5 months [95% confidence interval (CI) 10.4-16.6 months] for the EV+P arm and 6.3 months (95% CI 6.2-6.5 months) for the chemotherapy arm [hazard ratio (HR) 0.48, 95% CI 0.41-0.57]. The median OS was 33.8 months (95% CI 26.1-39.3 months) for the EV+P arm and 15.9 months (95% CI 13.6-18.3 months) for the chemotherapy arm (HR 0.51, 95% CI 0.43-0.61). Safety data with an additional year of follow-up were consistent with those of the primary analysis.

Conclusion: The continued survival benefit with EV+P compared with chemotherapy in this updated analysis reinforces EV+P as the standard of care for the first-line treatment of patients with la/mUC.

Keywords: EV-302; antibody-drug conjugate; enfortumab vedotin; overall survival; pembrolizumab; progression-free survival.