Bacillus Calmette-Guérin (BCG) with or without immune checkpoint blockade in BCG-naïve high-risk non-muscle-invasive bladder cancer: A systematic review and reconstructed individual patient data meta-analysis.

BACKGROUND

Non-muscle-invasive bladder cancer (NMIBC) accounts for 75% of bladder cancers. Despite standard treatment with transurethral resection followed by BCG instillation, 30-40% of patients relapse. We conducted a meta-analysis evaluating immune checkpoint inhibitor (ICI) plus BCG versus BCG alone in BCG-naïve high-risk NMIBC.

METHODS

We performed a systematic review and reconstructed individual patient data (rIPD) meta-analysis of phase 3 randomized controlled trials (RCTs). Individual patient data were reconstructed from published Kaplan-Meier curves using the IPDfromKM method. The primary endpoint was event-free survival (EFS) for ICI plus BCG induction and maintenance (I+M) versus BCG I + M alone. Secondary endpoints included EFS for ICI plus BCG induction only, overall survival, subgroup analyses (age, sex, BCG strain, concomitant CIS), and safety.

RESULTS

Three phase 3 trials (CREST, POTOMAC, ALBAN; n = 2590) were included. ICI plus BCG I + M significantly improved EFS versus BCG alone (HR 0.77, 95% CI 0.64-0.93; p = 0.006), corroborated by pooled aggregate-data analysis (HR 0.77, 95% CI 0.60-0.97; I²=40%). ICI plus BCG induction only conferred no benefit (HR 1.03, 95% CI 0.85-1.25; p = 0.754). Overall survival data were immature (HR 0.90; p = 0.36). Grade ≥ 3 adverse events were more frequent with combination therapy (24.5% vs 6.1%).

CONCLUSION

ICI combined with full BCG maintenance significantly improves EFS in BCG-naïve high-risk NMIBC. This benefit is contingent on BCG maintenance; induction-only BCG provides no synergistic effect. Incremental toxicity warrants careful patient selection and biomarker-stratified validation before universal adoption.