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

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.

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.

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.