Effectiveness and safety of combined therapy versus monotherapy based on immune checkpoint inhibitors and/or targeted drugs as salvage treatment for advanced urothelial carcinoma: a systematic review and meta-analysis

Background: The standard salvage regimen for the patients with advanced urothelial carcinoma (UC) is uncertain, although lots of novel agents are recommended, including immune checkpoint inhibitors (ICIs) and targeted drugs (TDs). We aimed to compare the effectiveness and safety of combined therapy of novel agents (CNA) and monotherapy of novel agents (MNA) as salvage therapy for advanced UC. Methods: Studies exploring CNA and/or MNA for advanced UC in second-line setting were searched from PubMed, Embase, Cochrane Library, and Web of Science. The data of objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), median overall survival (OS), and grade 3-4 adverse effects rate (grade 3-4 AEs%) were pooled for analyses. Cochrane risk of bias tool was applied for the quality judgment of randomized controlled studies (RCTs). Results: Forty-one arms from 37 studies including 4,691 patients were included. Significant differences were presented in pooled ORR (22.9% versus 12.2%, OR=1.88, P<0.001) and DCR (62.7% versus 37.5%, OR=2.53, P<0.001) between CNA and MNA groups. The pooled median PFS was 3.66 months in CNA group versus 2.16 months in MNA group (WMD=1.50, P=0.028). No significant difference in pooled median OS was found between two groups (7.93 versus 7.50 months, WMD=0.43, P=0.449). 63.7% versus 25.4% of pooled grade 3-4 AEs% could be seen in CNA and MNA groups (OR=3.52, P<0.001). Additionally, the pooled results of PFS-6m and OS-6m in CNA group demonstrated significant advantages over MNA group (31.5% versus 28.7%, OR=1.31, P=0.049; 66.0% versus 56.7%, OR=1.34, P=0.029, respectively). In the subgroup analysis of CNA, use of ICIs, the positive expression of PD-L1 and ECOG-PS=0 were significantly associated with superior clinical outcomes (P<0.05). Discussion: For advanced UC patients after first line agents, CNA had potential benefits than MNA in terms of ORR, DCR, median PFS, PFS-6m and OS-6m. However, CNA was associated with a significantly higher grade 3-4 AEs%. Furthermore, potential advantages were presented in CNA patients with ICIs usage, positive PD-L1 expression and ECOG-PS=0.