CLDN18.2 expression

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...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.

P2, N=143, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: May 2027 --> Nov 2027 | Trial primary completion date: Jul 2026 --> Dec 2026

P2/3, N=126, Not yet recruiting, AstraZeneca AB

Background: Claudin 18.2 (CLDN18.2) has become a clinically relevant therapeutic target in gastric adenocarcinoma (GC), with zolbetuximab now approved for use in CLDN18.2-positive, HER2-negative advanced disease... CLDN18.2 shows excellent intratumoral reproducibility and a stable biological profile in GC, supporting its diagnostic reliability in biopsies and value as a predictive biomarker. A subset with extreme expression demonstrated aggressive features, suggesting a potential "claudin-driven" phenotype requiring further study.

P2, N=90, Recruiting, Innovent Biologics (Suzhou) Co. Ltd. | Not yet recruiting --> Recruiting

Overall, these findings support the recognition of GBASC as a distinct molecular entity potentially requiring dedicated therapeutic strategies.

P3, N=592, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

SOT102 exhibited strong antitumor activity in preclinical models of CLDN18.2-positive cancers and demonstrated a favorable pharmacokinetic and safety profile in non-human primates. These data were used to support clinical evaluation of SOT102 as a potential treatment option for patients with CLDN18.2-expressing solid tumors.

The recent approval by the US Food and Drug Administration (FDA) of the anti-CLDN18.2 monoclonal antibody zolbetuximab marks a significant advancement in the management of locally advanced, unresectable, or metastatic HER2-negative, CLDN18.2-positive G/GEJ adenocarcinoma...Careful selection and evaluation of tumor samples, particularly in small biopsies or cytology specimens, are essential to ensure accurate assessment. Standardization of all aspects of CLDN18.2 immunohistochemistry, from specimen preparation to interpretation, is necessary to achieve accurate, reproducible, and clinically meaningful results that guide therapeutic decisions for patients with G/GEJ and pancreatobiliary cancers.

These results suggest that chemotherapeutic agents upregulate CLDN18.2 in GC cells at least in part through cell cycle arrest, and support combining zolbetuximab with chemotherapy and/or CDK inhibitors for GC treatment.

FGFR2b positivity was observed in 14.1% of patients and was evaluated descriptively due to limited case numbers. CLDN18.2 expression may represent a clinically relevant prognostic biomarker reflecting aggressive tumor biology in locally advanced gastric cancer treated with neoadjuvant therapy.

Despite assay variability, even under stringent clinical trial criteria, a meaningful subset of patients may qualify for CLDN18.2-targeted therapy. These findings highlight the need for standardized testing and further clinical evaluation of CLDN18.2-directed strategies in PDAC.