Immune checkpoint inhibitors or anti-claudin 18.2 antibodies? A network meta-analysis for the optimized first-line therapy of HER2-negative gastric cancer

Abstract

Background: Multiple anti-programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors and zolbetuximab, an anti-claudin 18.2 antibody, have shown efficacy in the first-line treatment of HER2-negative gastric cancers. How to choose the best regimen remains an unsolved question. Objectives: We aimed to conduct a comparative analysis of the therapeutic advantages between immunotherapy and anti-claudin-18.2-targeted therapies in the first-line treatment of HER2-negative, unresectable, or metastatic gastric cancers. Design: Network meta-analysis was employed to systematically compare efficacy and safety data derived from various clinical trials. Data sources and methods: We included phase III randomized controlled trials in PubMed, Embase, Web of Science, Cochrane Library, and major conference abstracts. Network meta-analysis was used to compare the efficacy of each first-line therapeutic agent and to indirectly compare immunotherapy with anti-claudin-18.2-targeted therapy. Results: Eight trials comprising a total of 6455 patients were included. For the overall survival (OS) analysis, no statistically significant differences were observed between pembrolizumab [hazard ratios (HR) = 1.00, 95% CI: 0.94–1.07], sintilimab (HR = 0.99, 95% CI: 0.89–1.09), sugemalimab (HR = 0.98, 95% CI: 0.87–1.10), tislelizumab (HR = 0.97, 95% CI: 0.87–1.09), zolbetuximab (HR = 0.98, 95% CI: 0.91–1.07), and nivolumab (HR = 1.00). For the progression-free survival (PFS) analysis, no statistically significant differences were observed between pembrolizumab (HR = 1.00, 95% CI: 0.93–1.06), sintilimab (HR = 0.91, 95% CI: 0.83–1.00), sugemalimab (HR = 0.92, 95% CI: 0.84–1.02), tislelizumab (HR = 0.93, 95% CI: 0.84–1.03), zolbetuximab (HR = 0.96, 95% CI: 0.88–1.05), and nivolumab (HR = 1.00). For the overall response rate analysis, all regimens presented similar effects on ORR. In addition, anti-claudin-18.2-targeted therapies presented similar OS (HR = 0.99, 95% CI: 0.95–1.04) and PFS (HR = 1.01, 95% CI: 0.91–1.12) compared to immunotherapy, although their toxicity profiles were distinct. Conclusions: Our network meta-analysis showed no significant difference in PFS, OS, or ORR between different checkpoint inhibitors or between immunotherapy and anti-claudin-18.2-targeted therapies in the first-line treatment of HER2-negative, unresectable, or metastatic gastric cancers.