Real-world effectiveness of avelumab, pembrolizumab, and enfortumab vedotin in patients with advanced urothelial carcinoma with squamous differentiation (ARON-2EV)
Journal
Cancer Immunology, Immunotherapy
ISSN
0340-7004
Publisher
Springer Science and Business Media LLC
Date Issued
2026
Author(s)
Mollica, Veronica
Massari, Francesco
Fujita, Kazutoshi
Giannatempo, Patrizia
Grande, Enrique
Büttner, Thomas
Bourlon de los Ríos, María Teresa
Taha, Tarek
Fukuokaya, Wataru
Myint, Zin W.
Pichler, Renate
Binz, Kirstin
Molina‑Cerrillo, Javier
Kopecky, Jindrich
de Liaño, Alfonso Gómez
Kucharz, Jakub
Fiala, Ondřej
Matrana, Marc R.
Kopp, Ray Manneh
Di Civita, Mattia Alberto
Zgura, Anca
Ansari, Jawaher
Kihnel, Randi
De Felice, Francesca
Angel, Martín
Monteiro, Fernando Sabino M.
Soares, Andrey
Urun, Yuksel
Buti, Sebastiano
Santini, Daniele
Santoni, Matteo
Type
text::journal::journal article
Abstract
Introduction: 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. Materials and methods: 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. Results: 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). Conclusions: 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. ©The authors ©Springer.
License
Acceso Abierto
How to cite
Mollica, V., Massari, F., Fujita, K. et al. Real-world effectiveness of avelumab, pembrolizumab, and enfortumab vedotin in patients with advanced urothelial carcinoma with squamous differentiation (ARON-2EV). Cancer Immunol Immunother 75, 119 (2026). https://doi.org/10.1007/s00262-026-04328-9