Treating the untended: Real-world insights into enfortumab vedotin plus pembrolizumab for frail metastatic urothelial carcinoma patients excluded or underrepresented in clinical trials (GUARDIANS).

e16548 Background: Patients with terminal renal failure (GFR <30 ml/min or dialysis), poor performance status (ECOG ≥2), and/or age ≥80 are often excluded or underrepresented in pivotal clinical trials evaluating enfortumab vedotin and pembrolizumab (EV/P) as first-line (1L) treatment in metastatic urothelial carcinoma (mUC). Consequently, data on safety and efficacy in these populations are limited. This study evaluates EV/P outcomes in this high-risk group. Methods: This multicenter, real-world, retrospective study included mUC patients receiving EV/P as 1L treatment who were underrepresented (age ≥ 80) or ineligible for the EV-302 trial due to GFR <30 ml/min, ECOG ≥2. Endpoints included overall and progression free survival (OS, PFS), objective response rate (ORR), and treatment-related adverse events (AE). Descriptive and survival analyses evaluated safety and efficacy in frail patients. Results: A total of 116 patients from 18 German tertiary care centers were treated between May 2022 and December 2024. The median age was 79 years (IQR 68–83), with 20.7% having a GFR <30 ml/min, 44.8% presenting with ECOG ≥2, and 49.1% aged ≥80. The median age-adjusted Charlson Comorbidity Index was 6 (IQR 4–8), highlighting the high burden of comorbidities in this population. The ORR was 54.1%, including an 8.1% complete response rate. The mPFS was 7.5 months (95% CI 5.9–NR), and the mOS was not reached. Any-grade AEs were reported in 72.2% of patients, with ≥grade 3 AEs in 31.3%. The most common treatment-related AEs were peripheral neuropathy (33.0%) and skin toxicity (23.3%). Among patients aged ≥80, 39% required dose reductions, compared to 31% in the overall cohort, occurring after a median of 68 days (IQR 42–137). Of all patients, 18.1% discontinued treatment due to progressive disease, with only 31.3% of them receiving subsequent anti-cancer therapy. In contrary a total of 26.7% of patients permanently discontinued EV/P due to toxicity or non-specified reasons, with a median treatment duration of 89 days (IQR 40–180). Conclusions: This retrospective real-world analysis suggests that EV/P demonstrates promising oncological efficacy, even in highly frail patients, including those with a GFR <30 ml/min, ECOG ≥2, or aged ≥80 years. However, frequent discontinuations in absence of disease progression underscore the need for prospective studies to evaluate more tolerable regimens and treatment interruptions strategies.