Impact of Immune Checkpoint Inhibitors as Neoadjuvant Therapy for Muscle-invasive Bladder Cancer: A Systematic Review, Meta-analysis, and Network Meta-analysis.

Background and objective: The availability of immune checkpoint inhibitors (ICIs) has expanded perioperative treatment options for urothelial carcinoma. Our aim was to evaluate the effect of neoadjuvant ICI-based regimens on oncological outcomes for patients with muscle-invasive bladder cancer (MIBC).

Methods: We systematically searched MEDLINE, Embase, Web of Science, and ClinicalTrials.gov in September 2024 for studies on neoadjuvant therapies for MIBC. A proportion meta-analysis and network meta-analysis (NMA) using random-effect models were conducted to evaluate pooled pathological complete response (pCR) rates and to compare overall survival (OS) and adverse events. The review is registered on PROSPERO (CRD42024587964).

Key findings and limitations: We included 12 randomized controlled trials (RCTs; 5004 patients) and 35 non-RCTs (2964 patients). ICI-chemotherapy combination therapy was associated with a significantly higher pCR rate versus chemotherapy alone (40.6% vs 17.9%; p < 0.01). In the two phase 3 RCTs included (1556 patients) there was no significant difference in OS between dose-dense methotrexate + vinblastine + Adriamycin + cisplatin (ddMVAC) and durvalumab + gemcitabine + cisplatin (GC; hazard ratio 1.06, 95% confidence interval [CI] 0.72-1.55; p = 0.8). ddMVAC significantly increased the risk of grade ≥3 anemia (risk ratio [RR] 2.81, 95% CI 1.62-4.88) and asthenia (RR 3.46, 95% CI 1.68-7.14) in comparison to GC, while durvalumab + GC did not. Limitations include data heterogeneity across studies and the limited number of studies included in the NMA.

Conclusions and clinical implications: ICI addition to chemotherapy in the neoadjuvant MIBC setting significantly increased pCR rates in comparison to chemotherapy alone. However, there was no difference in OS between durvalumab + GC and ddMVAC. Further studies are needed to clarify the OS benefit of ICI-based combination therapy in comparison to the current standard chemotherapy regimen.