Real-world outcomes and prognostic determinants of enfortumab vedotin plus pembrolizumab in urothelial carcinoma with squamous divergent differentiation and pure squamous cell carcinoma

Urothelial carcinoma (UC) with squamous divergent differentiation and pure squamous cell carcinoma (SCC) are aggressive subtypes with limited prospective data on enfortumab vedotin plus pembrolizumab (EV/Pembro). We evaluated outcomes and exploratory correlates. We conducted a retrospective cohort study of adults with pure SCC or UC with squamous divergent differentiation treated with EV/Pembro across Mayo Clinic sites. Best overall response was retrospectively adjudicated from heterogeneous routine-care CT, MRI, and PET reports rather than through uniform prospective RECIST 1.1 assessment. Overall survival (OS), progression-free survival (PFS), duration of response (DoR), and factors associated with OS were evaluated. Forty-nine patients were included; 35 (71.4%) received EV/Pembro as first-line metastatic therapy. Best response included complete response in 29 (59.2%), partial response in 4 (8.2%), stable disease in 4 (8.2%), and progressive disease in 12 (24.5%), yielding a retrospectively adjudicated objective response rate of 67.3%. Median DoR was 23.7 months (95% CI 16.0–not reached [NR]). Median OS was 24.5 months (95% CI 11.1–NR), and median PFS was 23.8 months (95% CI 7.8–NR). In multivariable analysis, greater metastatic burden was associated with shorter OS (HR per additional metastatic site, 2.37; 95% CI 1.55–3.62; p < 0.001). No statistically discernible survival differences were observed by extent of squamous divergent differentiation, although subgroup analyses were underpowered. Pretreatment Nectin-4 analyses were limited to 12 patients and were descriptive. EV/Pembro demonstrated clinically meaningful activity. Greater metastatic burden was associated with shorter OS; histology- and Nectin-4–based findings require prospective validation.