C Ciccarese, D Occhipinti, P Troisi, N D Shore, M De Santis, P Gontero, A Stenzl, S T Assumma, M Racioppi, T Powles, B Rocco, R Iacovelli
Adding ICIs to intravesical BCG in BCG-naïve high-risk NMIBC increases treatment-related toxicity, mainly due to immune-mediated adverse events, without substantially worsening local urinary tolerability. Careful patient selection and multidisciplinary management are essential when adopting this treatment optimization.
BACKGROUND: Intravesical bacillus Calmette-Guérin (BCG) is the standard of care for BCG-naïve high-risk non-muscle-invasive bladder cancer (NMIBC). Recent phase III trials showed reduced disease recurrence with the addition of immune checkpoint inhibitors (ICIs) to BCG induction plus maintenance but with increased toxicity. We carried out a systematic review and meta-analysis to assess the safety of this treatment intensification.
PATIENTS AND METHODS: Randomized phase II-III trials comparing BCG plus anti-programmed cell death protein 1/programmed death-ligand 1 ICIs with BCG alone in BCG-naïve high-risk NMIBC were identified through MEDLINE/PubMed, American Society of Clinical Oncology, and European Society for Medical Oncology databases up to November 2025. Outcomes included the incidence and relative risk (RR) of treatment-related adverse events (TRAEs), immune-related adverse events (irAEs), serious adverse events (SAEs), treatment discontinuation, and the impact of the BCG schedule.
RESULTS: Three phase III trials including 1895 patients were analyzed. Compared with BCG alone, BCG plus ICIs significantly increased the risk of any-grade TRAEs [RR 1.25, 95% confidence interval (CI) 1.20-1.31, P < 0.00001], grade ≥3 TRAEs (RR 4.02, 95% CI 3.06-5.30, P < 0.00001), SAEs (RR 4.54, 95% CI 2.09-9.85, P = 0.0001), any-grade irAEs (RR 15.18, 95% CI 4.34-53.14, P < 0.0001), grade ≥3 irAEs (RR 9.99, 95% CI 2.12-47.14, P = 0.004), and treatment discontinuation (RR 2.87, 95% CI 1.50-5.52, P = 0.002). Toxicity was mainly driven by systemic immune-mediated events, whereas local BCG-related urinary adverse events were largely comparable between groups.
CONCLUSIONS: Adding ICIs to intravesical BCG in BCG-naïve high-risk NMIBC increases treatment-related toxicity, mainly due to immune-mediated adverse events, without substantially worsening local urinary tolerability. Careful patient selection and multidisciplinary management are essential when adopting this treatment optimization.