Avelumab, pembrolizumab, and enfortumab vedotin (EV) demonstrated efficacy in mUC following platinum-based chemotherapy. However, real-world data in patients with urothelial carcinoma with squamous differentiation (UCSD) are limited.
The aim of this study is to assess the real-world clinical outcomes of avelumab, pembrolizumab, or EV in mUCSD patients.
The ARON-2EV study is a retrospective, international, multicenter analysis in patients with mUC treated with avelumab, pembrolizumab, or EV across 79 centers in 21 countries. Patients were divided into three cohorts: 1 (avelumab), 2 (pembrolizumab), and 3 (EV). Primary endpoints were overall survival (OS) and time on treatment (ToT). Secondary objectives included evaluating clinical factors associated with outcomes and exploring the impact of UCSD histology on response to therapy. Statistical methods included Kaplan-Meier estimates, log-rank tests, Fisher's exact and chi-square tests, and Pearson's correlation coefficients.
A total of 1918 patients, 1696 with advanced pure UC (pUC) and 222 with mUCSD (36 in cohort 1, 111 in cohort 2, and 75 in cohort 3), were included. Median OS was shorter in patients with UCSD compared to patients with pUC histology in the three cohorts (1: 13.0 vs 26.8 months, HR 2.66, p = 0.003; 2: 10.2 vs 18.5 months, HR 1.52, p = 0.008; and 3: 7.6 vs 13.1 months, HR 1.68, p = 0.011). Median ToT was shorter in patients with UCSD compared to patients with pUC histology in cohort 1 (3.5 vs 5.6 months, HR 1.57, p = 0.044) and 3 (7.6 vs 13.6 months, HR 1.83, p = 0.005) but not in cohort 2 (3.7 vs 4.7 months, HR 1.19, p = 0.177). Response to therapy was negatively correlated with UCSD histology in cohorts 2 (correlation coefficient 0.094, p = 0.008) and 3 (correlation coefficient 0.107, p = 0.021), while response to avelumab was not correlated with UCSD (correlation coefficient 0.072, p = 0.263).
UCSD is a histology with a poor prognosis and response to treatments compared to pUC. Treatments activity and effectiveness in divergent differentiations should be addressed in dedicated prospective studies.
NCT05290038.
Cancer immunology, immunotherapy : CII. 2026 Mar 24*** epublish ***
Veronica Mollica, Francesco Massari, Kazutoshi Fujita, Patrizia Giannatempo, Enrique Grande, Thomas Büttner, Maria T Bourlon, Tarek Taha, Wataru Fukuokaya, Zin W Myint, Renate Pichler, Kirstin Binz, Javier Molina-Cerrillo, Jindrich Kopecky, Alfonso Gómez de Liaño, Jakub Kucharz, Ondřej Fiala, Marc R Matrana, Ray Manneh Kopp, Mattia Alberto Di Civita, Anca Zgura, Jawaher Ansari, Randi Kihnel, Francesca De Felice, Martín Angel, Fernando Sabino M Monteiro, Andrey Soares, Yuksel Urun, Sebastiano Buti, Daniele Santini, Matteo Santoni
Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy., Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy. ., Department of Urology, Faculty of Medicine, Kindai University, Osaka, Japan., Dipartimento Di Oncologia Medica, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy., Department of Medical Oncology, MD Anderson Cancer Center Madrid, Madrid, Spain., Department of Urology, University Hospital Bonn, Bonn, Germany., Department of Hemato-Oncology, Escuela de Medicina, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico-Universidad Panamericana, Mexico City, Mexico., Royal Marsden NHS Foundation Trust, London, UK., Department of Urology, Jikei University School of Medicine, Tokyo, Japan., Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY, USA., Department of Urology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria., Division of Medical Oncology, Department of Internal Medicine, University of Kansas Cancer Center, Kansas, USA., Department of Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain., Department of Clinical Oncology and Radiotherapy, University Hospital Hradec Kralove, Hradec Kralove, Czechia., Medical Oncology Department, CHU Insular-Materno Infantil, Las Palmas, Spain., Department of Uro-Oncology, Maria Sklodowska-Curie National Research Institute of Oncology Warsaw, Warsaw, Poland., Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic., Department of Internal Medicine, Hematology/Oncology, Ochsner Medical Center, New Orleans, LA, USA., Clinical Oncology, Sociedad de Oncología y Hematología del Cesar, Valledupar, Colombia., Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I, University of Rome, Rome, Italy., Department of Obstetrics-Radiotherapy, Alexandru Trestioreanu Institute of Oncology, "Carol Davila" University of Medicine and Pharmacy, Prof. Dr, Bucharest, Romania., Medical Oncology, Tawam Hospital, Al Ain, UAE., Radiation Oncology, Department of Radiological, AOU Policlinico Umberto I, Oncological and Pathological Sciences, "Sapienza" University of Rome, Rome, Italy., Instituto Alexander Fleming, Ciudad De Buenos Aires, Argentina., Latin American Cooperative Oncology Group-LACOG, Porto Alegre, Brazil., Department of Medical Oncology, Faculty of Medicine, Ankara University, 06620, Ankara, Turkey., Medical Oncology Unit, University Hospital of Parma, Parma, Italy., Medical Oncology Unit, Macerata Hospital, Macerata, Italy.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/41874648