Association of urothelial carcinoma with squamous differentiation with Nectin-4 expression and outcomes with enfortumab vedotin (EV) treatment.

Abstract

865 Background: The Nectin-4 directed antibody-drug conjugate EV has demonstrated high efficacy in metastatic urothelial carcinoma (mUC), but outcomes in patients with divergent histologies remain poorly characterized. Squamous differentiation represents a clinically challenging subtype with distinct molecular features. We investigated Nectin-4 expression patterns and EV clinical outcomes in patients with urothelial cancer with squamous differentiation versus non-otherwise specified (NOS) histology. Methods: We retrospectively analyzed 127 patients with mUC (squamous differentiation vs NOS urothelial carcinoma) treated with EV as standard-of-care across multiple centers. NECTIN4 gene amplification was assessed by fluorescence in-situ hybridization (FISH), and membranous Nectin-4 protein by immunohistochemistry H-scores. Outcomes including ORR, PFS, and OS were documented by the investigators. Chi-square and log-rank tests were used for statistical comparisons. Results: Among 127 evaluable patients, those with squamous histology (n = 23; 18%) demonstrated significantly lower membranous Nectin-4 expression with a median H-score of 20 (IQR 3.5–85) vs 210 (IQR 97.5–290), p < 0.001. NECTIN4 gene amplification frequency was higher in squamous compared to NOS histology (n = 104): 7.7% vs 34% (p < 0.001). Importantly, patients with squamous histology exhibited inferior clinical outcomes to EV: ORR was lower (20.0% vs 51.6%, p = 0.02), median PFS was 2.8 months vs 6.2 months (HR = 2.52, 95% CI 1.45–4.37, p = 0.001), and median OS was 6.5 months vs 13 months (HR = 2.38, 95% CI 1.26–4.49, p = 0.008). Conclusions: Squamous differentiation in advanced urothelial carcinoma is associated with significantly lower membranous Nectin-4 expression and NECTIN4 amplification frequency, corresponding to markedly inferior responses to EV. These findings highlight the critical need for alternative therapeutic targets and novel treatment strategies in this population.