Pretreatment Tumor NECTIN4 RNA Expression Is Associated with First-line Enfortumab Vedotin Plus Pembrolizumab...

Enfortumab vedotin (EV) + pembrolizumab (P; EV + P) is the preferred first-line standard-of-care treatment for metastatic urothelial carcinoma (mUC), yet predictive biomarkers remain lacking. We retrospectively investigated whether tumor NECTIN4 RNA expression and tumor mutational burden (TMB) are associated with outcomes in a real-world mUC cohort receiving first-line EV + P (N = 322). NECTIN4-high subgroup showed more favorable overall survival (OS; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.46-0.98; median 21.5 mo [95% CI 16.2-24.3] vs 14.2 mo [95% CI 12.6-23.8]) and best overall response (BOR; odds ratio [OR] 2.98, 95% CI 1.68-5.3; objective response rate [ORR]; 67.4% vs 41.9%) than NECTIN4-low subgroup. TMB-high subgroup also showed more favorable OS (HR 0.57, 95% CI 0.33-0.96; median 22.8 mo [95% CI 21.5 to not reached] vs 15.9 mo [95% CI 13.6-19.1]) and BOR (OR 2.26, 95% CI 1.14-4.47; ORR; 69.2% vs 52.6%) than TMB-low subgroup. In multivariable analyses, NECTIN4 expression independently predicted OS (adjusted HR 0.62, 95% CI 0.41-0.93) and BOR (adjusted OR 2.64, 95% CI 1.4-4.97). Patients with NECTIN4-high and/or TMB-high tumors had more favorable OS (HR 0.61, 95% CI 0.42-0.88) and BOR (OR 3.09, 95% CI 1.72-5.54) than those with double-low tumors. In contrast, NECTIN4 expression was not significantly associated with outcomes in the first-line P monotherapy cohort (N = 232). Overall, pretreatment tumor NECTIN4 RNA expression was associated with EV + P efficacy, with NECTIN4-low and TMB-low tumors showing the lowest likelihood of response.