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.