Genetic Predictors of Response to Zolbetuximab in Gastric Adenocarcinoma: An Exploratory, Retrospective Real-World Study Using the Japanese C-CAT Database

Background/Objectives: The anti-CLDN18.2 antibody zolbetuximab has emerged as a novel therapeutic option for advanced gastric adenocarcinoma. However, robust predictive biomarkers for its efficacy remain an unmet need. Methods: Utilizing the Japanese Center for Cancer Genomics and Advanced Therapeutics database, we retrospectively analyzed the clinical and genomic profiles of 49 patients with gastric adenocarcinoma who received zolbetuximab-containing regimens. In line with Japanese health insurance regulations, these patients were deemed to have CLDN18.2-positive tumors. We explored the association between the objective response rate (ORR) and concurrent genomic alterations, focusing on tumor mutational burden (TMB) and major mutations (TP53, ARID1A, CDH1). Results: The ORR to zolbetuximab-based therapy in this cohort was 22.2%. Statistical analysis revealed a trend toward higher clinical response in patients with lower TMB (median 1.82 in responders vs. 4.0 in non-responders; p = 0.050). Furthermore, patients without a CDH1 single-nucleotide variant also showed a suggestive trend toward better response (p = 0.086). No significant associations were found with TP53 or ARID1A alterations (p = 0.787 and p = 0.239, respectively). Conclusions: Our findings suggest that low TMB and the absence of CDH1 variants may serve as potential predictive biomarkers for response to zolbetuximab in CLDN18.2-positive gastric cancer. Prospective validation is warranted to maximize patient selection for this targeted therapy.