CLDN18.2 IHC cutoff and efficacy of anti-CLDN18.2 therapy in gastric and gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis.

Abstract

441 Background: Assay platforms and immunohistochemistry (IHC) cutoffs for CLDN18.2 positivity vary across trials of anti-CLDN18.2 therapy. Whether higher cutoffs are associated with greater treatment effect remains uncertain and has implications for patient selection. Methods: We systematically searched PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov through September 4, 2025, for first-line, HER2-negative advanced/metastatic gastric or gastroesophageal junction adenocarcinoma trials testing anti-CLDN18.2 therapy plus chemotherapy and reporting hazard ratios (HRs) for PFS and/or OS. The risk of bias for randomized trials was assessed using RoB 2. We pooled log-HRs using random-effects models and summarized the results from single-arm cohorts qualitatively. Prespecified exploratory moderators were IHC cutoff (%) and assay platform (e.g., VENTANA RxDx vs CLAUDETECT18.2). Primary endpoints were PFS and OS expressed as hazard ratios; random-effects (DerSimonian-Laird) models pooled log-HRs, heterogeneity was assessed (tau^2 and I^2), small-study bias was not evaluated given k<10, and no imputation was performed; single-arm cohorts were summarized qualitatively. Results: Three randomized trials (k=3; N≈1,233 randomized) met quantitative criteria: two phase 3 studies using VENTANA RxDx with ≥75% cutoff and one phase 2 study using CLAUDETECT18.2 with ≥40% (high-expression subgroup ≥70% reported). Pooled analyses showed improved PFS and OS with anti-CLDN18.2 therapy plus chemotherapy versus control (PFS pooled HR ~0.64; OS pooled HR ~0.71; τ² small–modest). The two phase 3 trials each demonstrated clinically meaningful PFS/OS benefit at ≥75%; the phase 2 trial also favored anti-CLDN18.2, with larger effects in higher-expression subgroups. In phase 3 central testing, CLDN18.2 positivity at ≥75% was observed in ~38% of screened patients, highlighting the enrichment–eligibility trade-off. Safety findings across studies were consistent with the known gastrointestinal adverse-event profile (notably nausea/vomiting) without new safety signals. Exploratory meta-regression suggested that assay/cutoff may influence observed effect sizes, but power was limited (small k). Conclusions: Anti-CLDN18.2 therapy plus chemotherapy improves PFS and OS in CLDN18.2-positive, HER2-negative, first-line gastric and gastroesophageal junction cancer. Evidence supporting the widely used ≥75% VENTANA RxDx definition is strongest (two phase 3 RCTs), while earlier-phase data suggest increased benefit at higher expression. Harmonized IHC methods and standardized reporting, especially outcomes by expression strata, are needed to define an optimal clinical cutoff that balances efficacy with patient eligibility.