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

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.

Keywords: chemotherapy; immune checkpoints inhibitors; network meta-analysis; urothelial carcinoma.

Figure A1

Quality assessment by the risk of bias (ROB) tool.

Figure A2

Probability to be best treatment for OS, PFS, ORR, and grade 3–5 AEs. (a) Overall survival (HR); (b) progression free survival (HR); (c) overall response rate; (d) risk ratio for grade 3–5 AEs.

Figure A3

Subgroup analysis in OS by age, gender, cisplatin eligibility, and primary tumor site. (a) For age ≥ 65; (b) for age < 65; (c) for male; (d) for female; (e) for cisplatin eligibility; (f) for cisplatin ineligibility; (g) for primary tumor location in the upper tract; (h) for primary tumor location in the lower tract.

Figure 1

PRISMA flow diagram.

Figure 2

Network constructions for comparison in overall survival (OS), progression of free survival (PFS), objective response rate (ORR), and grade 3–5 adverse events (AEs). (a) Network constructions for comparison in OS (hazard ratio (HR)), ORR, grade 3-5 AEs. (b) Network constructions for comparison in PFS (HR).

Figure 3

Summary of effect size for pairwise comparison. (a) Hazard ratio for overall survival, (b) hazard ratio for progression free survival, (c) response ratio for overall response rate, (d) risk ratio for grade 3–5 AEs.

Figure 3

Summary of effect size for pairwise comparison. (a) Hazard ratio for overall survival, (b) hazard ratio for progression free survival, (c) response ratio for overall response rate, (d) risk ratio for grade 3–5 AEs.

Figure 4

Cumulative ranking probability for different interventions. (a) Hazard ratio for overall survival, (b) hazard ratio for progression free survival, (c) response ratio for overall response rate, (d) risk ratio for grade 3–5 AEs.

Figure 4

Cumulative ranking probability for different interventions. (a) Hazard ratio for overall survival, (b) hazard ratio for progression free survival, (c) response ratio for overall response rate, (d) risk ratio for grade 3–5 AEs.