Efficacy of immune checkpoint inhibitors versus chemotherapy in metastatic urothelial carcinoma: A systematic review and meta-analysis.

Abstract

e16560 Background: Metastatic urothelial carcinoma (mUC) is conventionally managed with platinum-based chemotherapy, which might be effective but is often associated with considerable side effects. Recently, immune checkpoint inhibitors (ICIs) have surfaced as a potential alternative. However, their efficacy as monotherapy remains debated. The purpose of the study was to evaluate the efficacy of ICIs as monotherapy compared to chemotherapy in patients with mUC. Methods: We systematically searched MEDLINE/PubMed, Google Scholar, Cochrane Library, ClinicalTrials.gov, PLOS ONE to identify randomized controlled trials (RCTs) (March 1, 2015 - January 6, 2025) comparing ICI monotherapy with chemotherapy in mUC. Patients were randomized to receive ICI monotherapy (atezolizumab, pembrolizumab, or durvalumab, depending on the trial) or chemotherapy (platinum-based chemotherapy or paclitaxel). Studies were eligible if they reported overall survival (OS), objective response rate (ORR), adverse events (AEs). The primary endpoint was OS, and secondary endpoint included ORR and treatment-related grade 3-4 AEs. OS was analyzed using hazard ratios (HRs) with 95% confidence intervals (CIs). We used odds ratio (OR) with 95% CIs to analyze ORR and AEs. Data from the intention-to-treat (ITT) population were utilized in all studies, except for one where the total population was used. Confounding factors, such as Eastern Cooperative Oncology Group (ECOG) performance status and prior treatments, were addressed via stratified randomization, as described in the original trials. The data was analyzed using RevMan 5.4.1. Results: Five phase III RCTs were included, with a total of 3584 patients. Patients receiving ICI monotherapy showed no significant difference in OS when compared to those treated with chemotherapy (HR: 0.89, 95% CI 0.76 - 1.04, p = 0.15, I² = 0%). The random effects pooled estimate for ORR was an OR of 0.68 (95% CI 0.38 - 1.20, p = 0.18, I² = 92%), showing no significant benefit of ICI monotherapy over chemotherapy, with high heterogeneity. The sensitivity analysis reducing heterogeneity (I² = 42%) resulted in an OR of 0.42 (95% CI: 0.33–0.53, p < 0.00001), indicating that certain studies contribute to the initial variability. However, there was lower incidence of treatment-related grade 3-4 AEs in patients receiving ICI monotherapy than those treated with chemotherapy (OR: 0.07, 95% CI 0.03 – 0.15, P < 0.00001, I² = 94%). Conclusions: Our analysis indicates that ICI monotherapy did not show a significant difference in OS and ORR compared to chemotherapy in mUC patients but was associated with significantly fewer AEs. These findings imply that while ICIs alone may not improve survival or response rates, they may help reduce treatment-related toxicity. Further studies are needed to refine patient selection criteria for optimal clinical benefits.