HER2 and nectin-4 IHC expression and clinical outcomes with enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma.

827 Background: Enfortumab vedotin and pembrolizumab (EV/P) is the standard of care for metastatic urothelial carcinoma (UC). Outcomes in UC based on HER2 IHC expression and correlation between membranous Nectin-4 and HER2 IHC expression have not been reported. Methods: A retrospective cohort of patients with metastatic UC treated with EV/P at Memorial Sloan Kettering Cancer Center was reviewed. Data were collected by chart review. HER2 and Nectin-4 IHC were performed on patients treated with EV+P and scoring was performed by MSK pathology. Response to EV/P was assessed using RECIST v1.1 and compared using Fisher’s exact test (unordered) and Cochran Armitage (ordered HER2 groups). Progression-free and overall survival (PFS, OS) were estimated from the start of EV+P using the Kaplan-Meier method and compared using logrank tests. Results: Of 232 patients treated with EV/P, 125 underwent both HER2 and Nectin-4 IHC. In the HER2 IHC cohort, the median age was 74 years; 71% were male; 30% had upper tract primary, and 43% had a component of variant histology. Median follow-up was 19 months (95% CI 16, 20). HER2 IHC distribution was 0-1+ 54%, 2+ 23%, and 3+ 23%. HER2 expression was associated with presence of membranous Nectin-4 expression ( P = 0.009). The presence (yes/no) of variant histologic features decreased across ordered HER2 categories, from 53% in HER2 0–1+ tumors to 45% in HER2 2+ tumors and 18% in HER2 3+ tumors (P = 0.0023). There was no significant association between baseline HER2 IHC status and best overall response (P = 0.077, Cochran-Armitage test) or OS (median OS HER2 0–1+: 26 months 95% CI 19, NR, 2+: 27 months 26, NR, 3+: 26 months 14, NR; logrank p = 0.3). Median PFS was 8.1 months in HER2 0–1+ tumors and 12 months in HER2 2+ and HER2 3+ (logrank p = 0.3). Conclusions: In a large real-world cohort, HER2 and membranous nectin-4 co-expression were observed in the majority of tumors by IHC. Tumors with HER2 IHC 0 were also likely to have low Nectin-4 membranous expression. Clinical outcomes in HER2 0-1, 2+, and 3+ subgroups were similar, with no difference in PFS or OS observed based on HER2 clinical status. These data support that HER2 IHC expression is not prognostic for response to EV+P. Further follow-up and additional studies are needed for validation and to understand the landscape of HER2 expression following EV+P exposure. HER2 and nectin-4 IHC expression and clinical outcomes with enfortumab vedotin plus pembrolizumab in metastatic urothelial cancer. Nectin-4 Membranous Expression Characteristic Overall N = 125 1 0 N = 14 1 > 0 N = 111 1 p-value 2 Her2 IHC Score 0.009 0-1 68 (54%) 13 (93%) 55 (50%) 2 29 (23%) 0 (0%) 29 (26%) 3 28 (22%) 1 (7.1%) 27 (24%) Clinical Outcomes with EV+P HER2 IHC Score mPFS p-value mOS p-value 0-1 8.1 m (5.1,10) 0.30 26.0 m (CI 19-NR) 0.30 2 12.0 m (7.1, —) 27.0 m (CI 26-NR) 3