Immunotherapy in bladder cancer: a systematic review of clinical trials and therapeutic advances

Bladder cancer poses significant morbidity, mortality, and healthcare burdens globally. While non-muscle-invasive bladder cancer often initially responds to intravesical Bacillus Calmette-Guérin, many patients become unresponsive to Bacillus Calmette-Guérin, resulting in recurrence or progression. Emerging immunotherapies, including checkpoint inhibitors (Pembrolizumab, Atezolizumab, Durvalumab), intravesical gene therapies (Nadofaragene Firadenovec, Cretostimogene Grenadenorepvec), and novel cytokine-based therapies, present promising alternatives. This systematic review thoroughly synthesizes existing clinical evidence from phase 2 and 3 trials, critically assessing immunotherapeutic options for bladder cancer treatment.

A comprehensive search was systematically conducted across four databases: PubMed, Cochrane, Web of Science and Scopus strictly adhering to PRISMA guidelines and retrospectively registered. Included studies evaluated immunotherapies in non-muscle-invasive bladder cancer and selected muscle-invasive bladder cancer populations. Two reviewers independently performed study screening, data extraction, and risk-of-bias assessments using the Cochrane Risk-of-Bias tool. Results were synthesized both qualitatively, incorporating detailed comparative analyses and robust statistical descriptions.

A total of 778 studies were initially identified. Intravesical Cretostimogene Grenadenorepvec demonstrated the highest complete response [1] rate (75.2%), with impressive durability (83% maintaining response ≥ 12 months). Intravesical Nadofaragene Firadenovec also exhibited notable efficacy (CR 53.4%, median duration 9.69 months). Nogapendekin Alfa Inbakicept combined with Bacillus Calmette-Guerin achieved a robust CR (71%) and a remarkably sustained response (median 26.6 months). Systemic Pembrolizumab showed moderate efficacy (43.5% 12-month disease-free survival) but raised significant toxicity concerns (14% grade ≥ 3 adverse events). Intravesical therapies consistently provided superior cystectomy avoidance (≥ 89% at 12 months) compared to systemic treatments. Safety profiles significantly favored intravesical therapies, which had predominantly mild (grade 1–2) adverse events, while systemic therapies reported notable severe toxicities and treatment-related fatalities.

Intravesical immunotherapies, particularly Nogapendekin Alfa Inbakicept and Bacillus Calmette-Guerin and Nadofaragene, demonstrate superior efficacy, significant response durability, and favorable safety profiles in treating bladder cancer compared to systemic checkpoint inhibitors, which display moderate efficacy and notable safety concerns. These findings strongly support prioritizing intravesical therapies in non-muscle-invasive bladder cancer management, especially for patients who are unresponsive to Bacillus Calmette-Guerin. Future research should focus on head-to-head randomized controlled trials and biomarker-driven patient selection to optimize clinical outcomes.