Novel BCG Combination or Modified BCG Regimens in BCG-Naïve High-risk Non–muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVE: Despite Bacillus Calmette-Guerin (BCG) remaining the standard of care for high-risk non-muscle-invasive bladder cancer (HR-NMIBC), novel combination strategies are being actively investigated. Comparative evidence on the efficacy and tolerability of these regimens in BCG-naïve patients remains limited. The objective of this study was to synthesize and compare the efficacy and safety of treatments for BCG-naïve HR-NMIBC evaluated in randomized controlled trials (RCTs). METHODS: A systematic search of PubMed, Embase, and Web of Science was performed through October 20, 2025, following a registered protocol (PROSPERO CRD420251079219). Eligible studies were phase III RCTs enrolling adults with BCG-naïve HR-NMIBC that reported recurrence-free survival (RFS), event-free survival (EFS), disease-free survival (DFS), and common terminology criteria for adverse events (CTCAE)-graded AEs. Two independent reviewers extracted data following PRISMA guidelines. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Random-effects meta-analyses and a frequentist network meta-analysis (NMA) were performed. Primary outcomes were tumor recurrences, with secondary outcomes including EFS and DFS, AEs, and subgroup analyses. KEY FINDINGS: Five phase III RCTs (n = 3486) met inclusion criteria. Pooled analyses showed 1-yr and 2-yr EFS/DFS for combination therapy of 87% (95% CI 85-89) and 82% (95% CI 79-85) versus 84% (95% CI 82-87) and 78% (95% CI 75-81) with BCG (induction + maintenance [I + M]). In trials with centrally-adjudicated high-grade recurrence, ICI + BCG (I + M) reduced HG-recurrence (RR 0.63; 95% CI 0.41-0.98). Including ALBAN attenuated the effect (RR 0.75; 95% CI 0.50-1.12). Subgroup analyses favored ICI + BCG (I + M) in CIS and T1 disease (HR 0.68; 95% CI 0.50-0.92). Grade ≥3 treatment-related AEs occurred in 25% of combination-treated patients versus 6% with BCG alone. LIMITATIONS: Interpretation is limited by heterogeneity in treatment regimens, diagnostic definitions, and incomplete reporting of key prognostic factors, including variant histology, lymphovascular invasion, programmed cell death ligand 1 status, and transurethral resection of bladder tumor quality, contributing to between-study variability. CONCLUSION AND CLINICAL IMPLICATIONS: The modest, heterogeneity-sensitive recurrence benefit of adding systemic ICI to BCG (I + M), set against a marked increase in toxicity and no demonstrated survival gain, does not justify routine systemic intensification in unselected BCG-naïve HR-NMIBC. Its use should instead be individualized to higher-risk subgroups pending biomarker-driven selection and mature survival data.