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

Year: 2026

Type: article

Abstract: 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.

Source: Cancer Immunology Immunotherapy

DOI: 10.1007/s00262-026-04535-4