Targeting claudin 18.2 in gastric cancer: a review of emerging biologic agents

INTRODUCTION: Zolbetuximab, the first monoclonal antibody targeting claudin 18.2 (CLDN18.2), is approved as first-line treatment for patients with HER2-negative and CLDN18.2-positive gastric or gastroesophageal junction cancers, offering new hope to patients who previously derived limited benefit from molecular targeted therapies or immune checkpoint inhibitors. AREAS COVERED: This review presents clinical insights not fully captured in pivotal phase III trials, examining the clinicopathological characteristics of zolbetuximab-induced gastritis and the dynamics of CLDN18.2 expression during treatment. It further explores key clinical challenges - including standardized patient selection, management of gastrointestinal toxicities, and optimization of treatment sequencing - while providing an overview of recent advances in next-generation CLDN18.2-targeted strategies such as antibody - drug conjugates, bispecific antibodies, and CAR-T cell therapies. EXPERT OPINION: CLDN18.2-targeted therapy has demonstrated the therapeutic feasibility of targeting non-oncogenic drivers, representing a paradigm shift in gastric cancer treatment. Next-generation modalities such as ADCs, bispecific antibodies, and CAR-T cell therapies have shown efficacy even in patients with lower CLDN18.2 expression, suggesting potential to expand treatment eligibility. Moving forward, deeper understanding of gastrointestinal toxicities associated with CLDN-targeted therapies, elucidation of resistance mechanisms, and development of rational combination strategies will be essential to maximize therapeutic benefit in patients with CLDN18.2-positive gastric cancer.