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.
Saal et al. (Sun,) studied this question.