Novel therapeutic regimens in previously untreated metastatic urothelial carcinoma: A systematic review and bayesian network meta-analysis.

ABSTRACT

Metastatic urothelial carcinoma (muC) has historically had few effective therapeutic options. Recently, immune checkpoint inhibitors (ICIs), were introduced as therapeutic options for cisplatin-ineligible patients, however, direct head-to-head trials comparing these treatments are lacking. To address this gap, this study employs a Bayesian framework to indirectly compare the performance of ICIs as first-line agents for muC. A systematic review was performed to identify randomized controlled trials evaluating different ICI for mUC. Data was inputted into Review Manager 5.4 for pairwise meta-analysis. Data was then used to build a network in R Studio. These networks were used to model 200,000 Markov Chains via MonteCarlo sampling. The results are expressed as hazard ratios (HR) with 95% credible intervals (CrI). Six studies with 5,449 patients were included, 3,255 received ICI monotherapy or combination. Moreover, a total of 3,006 had PD-L1 positive tumors and 2,362 were PD-L1 negative. Median overall survival (OS) ranged from 12.1 to 31.5 months across the studies, with the combination of enfortumab vedotin and pembrolizumab demonstrating the most substantial reduction in the risk of death (HR 0.47 [95% CrI 0.38, 0.58]), followed by avelumab monotherapy (HR 0.69 [95% CrI 0.56, 0.86]). The limitations of this network meta-analysis include variability in study follow-up duration, lack of standardized methods for assessing PD-L1 positivity, and potential bias introduced by control arms with poorer survival outcomes across included trials. The enfortumab vedotin/pembrolizumab combination significantly improved survival and response rates. Avelumab showed notable single-agent activity. These findings provide a valuable framework to guide clinical decision-making and highlight priority areas for future research, including biomarker refinement and novel combination strategies to enhance antitumor immunity in this challenging malignancy.