Efficacy and safety of anti-CLDN18.2 therapies in advanced or metastatic gastric, gastro-oesophageal junction, and oesophageal carcinomas with CLDN18.2 positivity: a systematic review and meta-analysis

PURPOSE: The optimal treatment strategy for advanced or metastatic gastric, gastro-esophageal junction or esophageal carcinomas expressing Claudin-18 isoform 2 (CLDN18.2) remains inadequately defined and requires further investigation. METHODS: A systematic search was conducted to identify randomized controlled trials and single-arm studies. RESULTS: Four randomized controlled trials comprising five cohorts compared anti-CLDN18.2-based therapies with chemotherapy or physician's choice. Anti-CLDN18.2 therapy, primarily consisting of first-line zolbetuximab combined with chemotherapy, significantly improved progression-free survival (PFS) (hazard ratios [HR] 0.564; 95% confidence interval [CI]: 0.417-0.711) and overall survival (OS) (HR 0.716; 95% CI: 0.631-0.802), along with enhanced 1- and 2-year survival rates. However, higher rates of nausea, neutropenia, and vomiting were observed in patients treated with zolbetuximab-based regimens. A single-arm meta-analysis, which included ten cohorts from seven trials, demonstrated that antibody-drug conjugates (ADCs) exhibited greater antitumor activity compared to zolbetuximab-based regimens. CONCLUSION: Anti-CLDN18.2 therapies, particularly first-line zolbetuximab plus chemotherapy, significantly improve PFS and OS in advanced gastric, gastro-esophageal junction, or esophageal carcinoma compared to standard treatments. ADCs have shown promising antitumor activity in single-arm studies, suggesting the need for confirmatory randomized trials. Standardized definitions for CLDN18.2 positivity and high expression are urgently needed. PROTOCOL REGISTRATION: www.crd.york.ac.uk/prospero identifier is CRD420251123719.