A systematic review and network meta analysis of first-line immunotherapy for advanced urothelial carcinoma

Aim: To compare the efficacy and safety of first-line systemic therapies for advanced urothelial carcinoma (UC) and identify the relative benefit-risk profiles of available regimens. Methods: We conducted a systematic review and Bayesian random-effects network meta-analysis of randomized controlled trials evaluating first-line systemic therapies for advanced UC (INPLASY2025100112). PubMed, Embase, and the Cochrane Library were searched from inception to November 30, 2025. Time-to-event outcomes were summarized as hazard ratios (HRs) with 95% credible intervals (CrIs) for overall survival (OS) and progression-free survival (PFS), and binary outcomes were summarized as odds ratios (ORs) with 95%CrIs for objective response rate (ORR) and grade ≥ 3 adverse events (AEs). Results: Thirteen trials comparing 10 regimens were included. Immune checkpoint inhibitor plus antibody-drug conjugate (ICI+ADC) was associated with the largest estimated improvements in OS, PFS, and ORR (OS: HR 0.47, 95%CrI 0.37-0.63; PFS: HR 0.45, 95%CrI 0.33-0.63; ORR: OR 2.70, 95%CrI 1.60-4.60) and showed consistent improvements across both cisplatin-eligible and cisplatin-ineligible patients. ICI plus chemotherapy (ICI+Chemo) also improved OS (HR 0.83, 95%CrI 0.70-0.96) and PFS (HR 0.78, 95% CrI 0.63-0.95). ICI monotherapy was associated with the lowest odds of grade ≥ 3 AEs (OR 0.11, 95%CrI 0.03-0.44) but ranked lowest for efficacy. Conclusion: ICI+ADC may represent a promising first-line option when available. ICI+Chemo remains an appropriate alternative, whereas ICI monotherapy may be reserved for patients unsuitable for combination therapy.