Outcomes of immune checkpoint inhibitor rechallenge in advanced urothelial carcinoma: results from a global real-world evidence study

BACKGROUND: Several immune checkpoint inhibitors (ICIs) are approved for urothelial carcinoma (UC), but limited information is currently available regarding the efficacy of rechallenging ICIs in patients with previous ICI exposure. PATIENTS AND METHODS: A retrospective study was carried out using the TriNetX® database for a large-scale search of patients with advanced UC (aUC) who had received two separate courses of ICIs (either alone or in combinations). Kaplan-Meier analysis was used to estimate progression-free and overall survival (PFS, OS) of ICI rechallenge. Propensity score matching analysis was run to balance and compare groups based on the duration of ICI rechallenge and stage at diagnosis. RESULTS: Out of 35 789 patients, a cohort of 292 (0.81%) treated with ≥2 ICI-including lines between 2014 and 2024 was identified. There were 86% bladder versus 14% upper tract UC. At initial diagnosis, 49% had stage IV, whereas 51% had stage I-III disease. The median time on prior ICI treatment was 19.5 months; the median time from the end of ICI to the start of ICI rechallenge was 9.4 months. After a median follow-up of 21.7 months, the median OS of ICI rechallenge was 20.5 months, the median PFS was 10.3 months. Previous use of an ICI in a nonmetastatic setting was associated with longer median OS than both lines given in aUC (P < 0.001). Among those who received a previous ICI in a metastatic setting, a cut-off of 12 months for the ICI rechallenge was associated with a longer median OS (P = 0.027). The longest duration of rechallenge treatment was achieved with anti-programmed cell death protein 1 given after anti-programmed death-ligand 1 therapy (18.2 months, P < 0.001). CONCLUSIONS: Although it is an uncommon and not standard strategy, previous ICI in nonmetastatic UC and a period of ≥12 months after previous ICI in the metastatic setting were associated with better outcomes after ICI rechallenge in patients with aUC.