801 Background: Enfortumab vedotin plus pembrolizumab (EV/P) is the standard therapy for metastatic urothelial carcinoma (UC) irrespective of Nectin4 expression. The relevance of membranous (mNectin4) and cytoplasmic (cNectin4) expression remains uncertain. Methods: We retrospectively reviewed an institutional database of patients treated with first line EV/P. Specialized GU pathologists assessed Nectin4 expression by immunohistochemistry and quantified separate mNectin4 and cNectin4 H-scores. Outcomes were compared by high vs low expression (median cutoffs) using Fisher’s exact test (ORR) and Cox models (PFS, OS). Results: Nectin4 was evaluable in 143 of 232 patients. Median age was 74, 72% were male, 31% had upper tract (UTUC) primary, and 43% had UC with divergent histology. Median H-scores were 180 (IQR 100-265) for mNectin4 and 30 (IQR 0-80) for cNectin4. High mNectin4 (≥180) was associated with lower rates of divergent histology (33% vs 54%; p = 0.018), bone (22% vs 38%; p = 0.046) and lung metastases (17% vs 39%; p = 0.003), and higher rates of lymph node (LN) only disease (32% vs 13%; p = 0.009). High cNectin4 (≥30) was less frequently observed in UTUC primary (22% vs 41%; p = 0.018), ECOG 0 (22% vs 48%; p = 0.002), and LN only disease (14% vs 32%; p = 0.010). Outcomes are reported in table 1. Median follow-up was 18 months (95% CI 16-20). mNectin4 and cNectin4 were negatively correlated (spearman correlation -0.48; p < 0.001). High mNectin4 was associated with improved PFS and OS, but not ORR. High cNectin4 was associated with worse ORR, PFS and OS. Given the inverse correlation, further stratification by four combined dichotomized mNectin4/cNectin4 subgroups was conducted. Superior PFS was observed in High mNectin4/Low cNectin4 subgroup (HR 0.41 95% CI 0.22, 0.77; p = 0.006) compared to Low/Low; ORR and OS did not significantly differ between subgroups. Conclusions: High mNectin4/low cNectin4 expression was associated with improved PFS with EV/P and low cNectin4 is associated with improved ORR. Further studies are required to explore the relative contribution of membranous vs. cytoplasmic expression to predict outcomes with EV/P. N Response PFS OS ORR (95% CI) p Median, mo (95% CI) HR 95% CI p Median, mo (95% CI) HR 95% CI p Membranous (M) 0.4 Low (<180) 71 58% (45%, 70%) 6.1 (4.4, 9.4) — — 19 (14, —) — — High (≥180) 72 65% (53%, 76%) 10 (8.4, —) 0.55 0.37, 0.83 0.004 27 (26, —) 0.5 0.28, 0.87 0.014 Cytoplasmic (C) 0.016 Low (<30) 69 72% (60%, 82%) 11 (9.0, 17) — — 27 (26, —) — — High (≥30) 74 52% (40%, 64%) 6.4 (4.5, 8.8) 1.61 1.08, 2.42 0.020 20 (15, —) 1.92 1.10, 3.36 0.022 Subgroups 0.11 M Low/ C
Sternschuss et al. (Sun,) studied this question.