Claudin 18.2-Targeted Therapies in Gastric and Gastroesophageal Junction Cancers: A Narrative Review of the Emerging Therapeutic Landscape

Objective: To survey the emerging therapeutic landscape of Claudin 18.2 (CLDN18.2)-directed agents in gastric and gastroesophageal junction (GEJ) cancers, encompassing CLDN18.2 biology, clinical evidence for approved and investigational therapies, biomarker-driven patient selection, resistance mechanisms, and a practical framework for integrating these agents into evolving treatment algorithms.

Data Sources: A narrative review of the published literature was conducted through searches of PubMed/MEDLINE, Embase, and the Cochrane Library from database inception to 31 May 2026, supplemented by hand-searching of reference lists, ClinicalTrials.gov, and abstracts from the ASCO, ESMO, and ASCO Gastrointestinal Cancers Symposium annual meetings (2022–2026). Search terms combined controlled vocabulary and free-text variants of "claudin 18.2", "CLDN18.2", "zolbetuximab", "gastric cancer", "gastroesophageal junction", "antibody-drug conjugate", "bispecific antibody", and "CAR-T". Sources further included pivotal phase II and III clinical trial data (FAST, SPOTLIGHT, GLOW, CT041-ST-01), phase I/II data for investigational agents, GLOBOCAN 2022 epidemiological data, The Cancer Genome Atlas molecular classification, and FDA regulatory documents pertaining to CLDN18.2-targeted therapies in gastric and GEJ cancers.

Data Summary: Zolbetuximab, a first-in-class anti-CLDN18.2 monoclonal antibody, demonstrated statistically significant improvements in progression-free and overall survival when added to first-line platinum-fluoropyrimidine chemotherapy in CLDN18.2-positive (≥75% viable tumor cells), HER2-negative advanced gastric/GEJ adenocarcinoma, supporting regulatory approval in the United States, Japan, and the European Union. An expanding pipeline of antibody-drug conjugates (IBI343, tecotabart vedotin), bispecific antibodies, and CAR-T cell therapies (CT041/satricabtagene autoleucel) is advancing through clinical development, employing lower IHC expression thresholds to broaden patient eligibility. Key challenges include intratumoral and temporal expression heterogeneity, divergent IHC scoring criteria across trials, and resistance mechanisms including antigen downregulation and tumor microenvironment-mediated immune evasion.

Conclusions: CLDN18.2 represents a clinically validated therapeutic target in gastric and GEJ cancers. Harmonization of IHC scoring criteria, strategies to overcome expression heterogeneity and resistance, and rational sequencing of CLDN18.2-directed agents within multi-modal treatment algorithms are critical priorities to optimize patient outcomes.

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