Renal safety and clinical outcomes of enfortumab vedotin plus pembrolizumab in urothelial carcinoma patients with chronic kidney disease.

Abstract

e16564 Background: Urothelial carcinoma (UC) predominantly affects older adults with a high burden of comorbidities, particularly chronic kidney disease (CKD), which affects 30–40% of patients at diagnosis and is more prevalent in advanced disease. Enfortumab vedotin plus pembrolizumab (EV+P) has become a frontline standard for advanced UC; however, patients with moderate-to-severe CKD were underrepresented in pivotal trials. Enfortumab vedotin targets Nectin-4 expressed in renal tubular epithelium, and immune checkpoint inhibitors are associated with immune-mediated nephrotoxicity, raising concern for renal vulnerability in patients with reduced renal reserve. Real-world data evaluating renal and clinical outcomes of EV+P in patients with baseline CKD are limited. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, identifying adult patients with UC treated with EV+P between January 2020 and December 2025. Baseline CKD status (stages 3–5; eGFR < 60 mL/min/1.73 m²) was determined by diagnostic codes and laboratory data obtained prior to EV+P initiation.Patients were stratified into CKD and non-CKD cohorts. Propensity score matching (1:1) was performed for demographics, comorbidities, laboratory values, and prior therapies. Outcomes assessed within 180 days of treatment initiation included overall survival (OS), major adverse kidney events (MAKE; composite of acute kidney injury, dialysis initiation or dependence, or death), and selected treatment-related toxicities. Kaplan–Meier and Cox proportional hazards models were used. Results: After matching, 386 patients were included in each cohort (median age 75 years), with well-balanced baseline characteristics (all post-matching standardized mean differences < 0.1). Prior to matching, patients with CKD had a higher burden of cardiovascular comorbidities. Baseline renal function differed by design, with lower mean eGFR and higher serum creatinine in the CKD cohort. Overall survival was similar between CKD and non-CKD cohorts (HR 0.96; 95% CI, 0.69–1.35; p = 0.83), with 180-day survival rates of 79.9% and 79.3%, respectively. Patients with CKD had a higher incidence of MAKE, reflected by lower 180-day event-free survival (49.4% vs 59.1%; HR 1.41; 95% CI, 1.13–1.76; p = 0.002). Treatment-related toxicities were also more frequent in the CKD cohort (HR 1.35; 95% CI, 1.05–1.74; p = 0.020), with a higher mean number of toxicity events (4.3 vs 3.4). Conclusions: In this large real-world analysis, EV+P use was associated with comparable short-term overall survival in UC patients with and without CKD but with higher rates of renal events and treatment-related toxicities among patients with baseline CKD. These findings support the use of EV+P in select UC patients with CKD, with close monitoring of renal function and treatment-related toxicity.