SynthesisFrontiers in immunology2026
Efficacy and safety of combination versus single-agent immunotherapy for BCG-unresponsive non-muscle-invasive bladder cancer.
Synthesis in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Bacillus Calmette-Guérin (BCG) is the standard adjuvant therapy for high-risk non-muscle-invasive bladder cancer (NMIBC); however, a substantial proportion of patients develop BCG-unresponsive disease with limited bladder-preserving options. The objective of this study was to determine whether combination immunotherapy provides superior clinical efficacy and safety compared with single-agent immunotherapy for patients with BCG-unresponsive NMIBC. Methods: We conducted a systematic analysis of studies retrieved from PubMed, the Cochrane Library, Web of Science, Embase, Google Scholar, and MEDLINE searched up to December 2025. Eligible studies included single-arm trials and randomized controlled trials (RCTs) enrolling patients with pathologically confirmed BCG-unresponsive NMIBC treated with single-agent or combination immunotherapy. The intervention featured eight core drugs, including immune checkpoint inhibitors (PD-1 inhibitors), adenovirus vectors, and IL-15 superagonist Nogapendekin alfa inbakicept (N-803), administered primarily every 3 weeks. Primary outcomes were complete response rate (CRR) and progression-free survival (PFS). Secondary outcomes included high-grade recurrence, bladder preservation rate (BPR), and adverse events (AEs). Pooled analysis utilized fixed or random-effects models based on I Results: Ten studies (7 single-arm, 3 RCTs) involving 768 patients were included. For combination versus single-agent immunotherapy, the 3-month CRRs were 68% (95% CI: 63-75%) and 47% (95% CI: 43-51%), respectively. At 12 months, CRRs were 50% (95% CI: 43-59%) for combination and 28% (95% CI: 23-34%) for monotherapy. The 12-month PFS rate was significantly higher with combination therapy (90%; 95% CI: 85-94%) than with monotherapy (66%; 95% CI: 60-71%). Combination therapy achieved a BPR of 92.5% (95% CI: 87-98%). Regarding safety, any AEs occurred in 29.6% (95% CI: 14-46%) of the combination group compared with 87.4% (95% CI: 85-90%) in the monotherapy group. Limitations include the use of single-arm trial data, which lacks blinded evaluation, and moderate-to-severe heterogeneity in efficacy outcomes. Conclusion: Combination immunotherapy is associated with improved short and intermediate-term oncologic outcomes compared with single-agent immunotherapy in BCG-unresponsive NMIBC, with acceptable safety profiles. These findings support further investigation of combination strategies as bladder-preserving treatments; however, well-designed randomized trials are required before routine clinical adoption. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420251269272.
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