胃及胃食管结合部腺癌中靶向 CLDN18.2 的治疗：生物标志物评估、表达动态与治疗排序

Claudin-18 isoform 2 (CLDN18. 2) has rapidly moved from a gastric-lineage surface antigen to an actionable therapeutic target in advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, following the SPOTLIGHT and GLOW Phase 3 trials, which established zolbetuximab plus fluoropyrimidine-platinum chemotherapy as a first-line option for patients with CLDN18. 2-positive, HER2-negative disease. While many existing CLDN18. 2 reviews have centered on target biology, assay development, or individual therapeutic platforms, this review focuses on how CLDN18. 2-directed therapies can be selected and sequenced within a multi-biomarker landscape in which CLDN18. 2 expression is heterogeneous and treatment-modifiable, and its clinical interpretation is modality-dependent.

At the same time, the field has expanded beyond conventional monoclonal antibodies to include antibody-drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies, each with distinct implications for biomarker threshold requirements, toxicity, and clinical positioning. A central unresolved issue is therefore no longer whether CLDN18. 2 can be therapeutically targeted, but how different CLDN18. 2-directed modalities should be positioned across treatment lines and after prior CLDN18.

2 exposure. This review examines the biologic rationale for CLDN18. 2 targeting, current approaches to assay interpretation and patient selection, and the available clinical evidence for the major therapeutic platforms. Particular emphasis is placed on three practice-relevant issues: heterogeneity and sampling in biomarker assessment, treatment-associated modulation of CLDN18. 2 expression, and the consequences of these dynamics for post-zolbetuximab decision-making.

We also compare next-generation platforms according to mechanistic class, expression-threshold assumptions, toxicity trade-offs, and feasibility of integration into real-world treatment algorithms. Collectively, current evidence supports a reassessment-based rather than assumption-based approach to CLDN18. 2 sequencing.

However, key gaps remain, including the optimal interface with PD-1-based first-line therapy, the geographic generalizability of several next-generation datasets, standardized retesting strategies at progression, and prospective validation of modality-specific sequencing after target modulation.