Checkpoint blockade as neoadjuvant strategy: A single-arm meta-analysis of dual PD-1/PD-L1 and CTLA-4 inhibition in urothelial cancer.

783 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is the standard treatment for muscle-invasive urothelial cancer (MIUC). In patients who are ineligible or deny chemotherapy, upfront surgery is typically preferred. Immune checkpoint inhibitors, such as anti-PD-1/PD-L1 and anti-CTLA-4 antibodies, have emerged as potential neoadjuvant alternatives for these patients. This single-arm meta-analysis evaluates the efficacy and safety of combining anti-PD-1/PD-L1 with anti-CTLA-4 in MIUC. Methods: A systematic review of PubMed, Cochrane, ClinicalTrials.gov, and EMBASE identified clinical trials assessing neoadjuvant anti-PD-1/PD-L1 plus anti-CTLA-4 therapy in resectable, non-metastatic high-risk or muscle-invasive urothelial cancer. Outcomes included pathological complete response (pCR), pathological downstaging (<ypT2N0), recurrence-free survival (RFS), mortality, progressive disease (PD), and treatment-related adverse events (TRAEs). Pooled proportions and 95% confidence intervals (CI) were calculated using a random-effects model. Heterogeneity was assessed using I² statistics. Results: 137 patients were included from 4 clinical trials, encompassing 6 cohorts. Two cohorts received Durvalumab plus Tremelimumab (D+T), and four cohorts received Nivolumab plus Ipilimumab (N+I). Of these, 73.7% were cisplatin-ineligible, and 15.3% had upper tract urothelial carcinoma (UTUC). The overall pooled pCR rate was 35% (CI: 27–44%, I² = 11%), with no significant subgroup difference between in muscle-invasive bladder cancer (MIBC)-only studies compared to studies that included patients with UTUC (p-interaction = 0.33). The downstaging rate was 47% (CI: 36–58%, I² = 41%). One-year RFS was 81% (CI: 64–92%, I² = 44%), while PD occurred in 19% of patients (CI: 9–36%, I² = 44%). The mortality rate was 16% (CI: 10–26%, I² = 11%). Grade ≥3 TRAEs were reported in 29% of patients (CI: 18–44%, I² = 61%). Additionally, TRAEs grade ≥ 3 were numerically less common in the D+T group (22%, 95% CI: 12–35%, I² = 0%) compared to the N+I group (33%, 95% CI: 16–56%, I² = 68%), although this difference was not statistically significant (p-interaction = 0.33). Conclusions: Neoadjuvant anti-PD-1/PD-L1 combined with anti-CTLA-4 therapy demonstrates promising pCR, pathological downstaging rates and 1-year RFS in patients with MIUC. Despite Grade ≥3 TRAEs occurring in nearly one-third of patients, the majority were manageable. While these results highlight the potential of this combination for patients who are ineligible or deny NAC, randomized controlled trials are needed to refine patient selection and validate these findings.