Immune Checkpoints Inhibitors and Chemotherapy as First-Line Treatment for Metastatic Urothelial Carcinoma: A Network Meta-Analysis of Randomized Phase III Clinical Trials

SIMPLE SUMMARY: On the basis of the efficacy and tolerable safety profiles of immune checkpoints inhibitors (ICIs) in second-line metastatic urothelial carcinoma (mUC) patients, some emerging clinical trials focus on the first-line treatment. Thus, we conducted a network meta-analysis (NMA) to assess and compare the response and toxicity of ICIs in naïve-chemotherapy mUC setting. According to our results, combination therapy (either ICIs plus chemotherapy (CTX) or ICIs plus ICIs) had a higher priority in terms of overall survival. Concerning monotherapy, ICIs are not inferior to CTX in terms of OS. In view of the adverse effect, ICIs are very tolerable, and combination therapy did not lead to a higher incidence of grade 3–5 AEs when compared with CTX. ABSTRACT: Immune checkpoints inhibitors (ICIs) were considered as second-line treatments in metastatic urothelial carcinoma (mUC) based on better survival benefit and safety profile than chemotherapy (CTX). We aimed to assess different ICIs regimens in the efficacy and safety for front-line treatments in mUC patients. A comprehensive literature search was performed and Phase II-III randomized controlled trials (RCTs) on ICIs for patients with mUC were included. The outcome was evaluated by overall survival (OS), progression of free survival (PFS), objective response rate (ORR), and grade 3–5 adverse events. Network meta-analysis was used to estimate the effect size. Surface under cumulative ranking curves (SUCRAs) were applied to rank the included treatments for each outcome. Results: The survival benefit of a single ICI was non-inferiority to chemotherapy (CTX). Although no superior effects were indicated, combination therapy (either ICIs plus CTX or ICIs plus ICIs) presented better OS compared with CTX alone. In terms of PFS, combination therapy produced a noticeable benefit over CTX. Regarding the SUCRA ranking, atezolizumab plus CTX was associated with the best ranking for OS and pembrolizumab plus CTX was the best in PFS. In terms of safety, a single ICI had better safety profile than CTX and combination therapy had a similar risk of grade 3–5 adverse events with CTX. Conclusions: Our NMA results revealed that combination therapy has better ranking compared with monotherapy in OS and acceptable AEs. ICIs alone present non-inferior OS but a lower incidence of AEs compared with CTX.