Efficacy and safety of combination versus single-agent immunotherapy for BCG-unresponsive non-muscle-invasive bladder cancer
In brief
Combination immunotherapy lifts 12-month complete response to 50% versus 28% with single-agent
In a pooled analysis of 768 BCG-unresponsive NMIBC patients, combination regimens achieved a 12-month complete response of 50% compared with 28% for monotherapy, and 90% progression-free survival versus 66%. Adverse events were also less frequent (about 30% vs 87%). Results are promising but rely on mixed trial designs, so larger randomized studies are needed before routine use.
- Journal
- Frontiers in immunology (Q1)
- Published
- 28 July 2026
- Study design
- Systematic review / meta-analysis of RCTs
- Evidence level
- Level 1, High (CEBM 1a)
- Authors
- Ying Zhou, Xu Yang, Tingting Tian, Bo Yang, Jinyang Cheng, Yanqing Liu, et al.
- PMID
- 42582256
- DOI
- 10.3389/fimmu.2026.1896444
Why clinicians should know about it
- Picked for Oncology and Radiation Oncology (top studies of the week, 16 August 2026): Combination vs single‑agent immunotherapy for BCG‑unresponsive NMIBC
- Picked for Urology (top studies of the week, 16 August 2026): Combination vs single‑agent immunotherapy for BCG‑unresponsive NMIBC
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 I2 heterogeneity. 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.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.