OBJECTIVES: Immunotherapies and/or targeted agents in advanced/metastatic gastric cancer (A/MGC) offer more treatment combinations than standard systemic chemotherapies. A systematic literature review (SLR) and network meta-analysis (NMA) was conducted to evaluate the relative efficacy and safety of first-line systemic therapies in A/MGC.

METHODS: PubMed, Embase, Scopus, Cochrane library, ClinicalTrials.gov and the American Society of Clinical Oncology meeting library were systematically searched for phase II or III randomized controlled trials (RCTs) of first-line systemic therapies for A/MGC. Inclusion criteria were trials conducted in western populations and published before March 2022. NMA included regimens recommended in 2022 National Comprehensive Cancer Network guidelines. Outcomes included overall survival (OS), Progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (AEs). Comparative effectiveness results of both direct and indirect evidence in the network structures were summarized with hazard ratios (HR) and odds ratios (OR). P-scores were used to rank treatments. NMA was conducted using R software "netmeta" package (version 4.2.0).

RESULTS: A total of 24 studies were included in the SLR, of which 13 were included in the NMA (6,401 A/MGC patients). Nivolumab-chemotherapy was associated with significantly better OS (HR=0.71, 95% confidence interval [CI]=0.59-0.86) and PFS (HR=0.68, 95%=CI 0.57-0.82) than 5-fluorouracil-oxaliplatin. Docetaxel-cisplatin-fluorouracil showed better ORR (HR=3.22, 95% CI=2.29-3.49) than cisplatin-fluorouracil. Nivolumab-chemotherapy had the highest probability of being best treatment among all included regimens for improvement in OS (P-score=0.948) and PFS (P-score=0.969). Docetaxel-cisplatin-fluorouracil ranked first for ORR (P-score=1.000) and pembrolizumab monotherapy also ranked first for lower odds of grade three/four nausea (P-score=1.000); Cisplatin-S-1 combination ranked highest with lowest odds of grade three/four neutropenia (P-score=1.000) and thrombocytopenia AEs (P-score=0.999). No heterogeneity and inconsistencies were observed.

CONCLUSIONS: Nivolumab-chemotherapy showed better estimates of OS and PFS compared to other treatments. These NMA findings can inform clinical practice decision making and any future comparative trials.