Real-world effectiveness of avelumab, pembrolizumab, and enfortumab vedotin in patients with advanced urothelial carcinoma with squamous differentiation (ARON-2EV)

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. Trial registration number: NCT05290038.