In gastric cancer (GC) there is a need for therapeutic targets/biomarkers beyond HER2 and PD-L1; Claudin 18.2 (CLDN18.2) is a promising target. In healthy tissue, CLDN18.2 is confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to exposure of CLDN18.2 on the surface of GC cells. In a randomized clinical study (FAST; NCT01630083), patients with CLDN18.2-positive advanced GC and gastroesophageal junction (GEJ) cancers treated with EOX and zolbetuximab (an anti-CLDN18.2 monoclonal antibody) had prolonged survival compared with EOX alone. The CLDN18.2, HER2, and PD-L1 prevalence in global GC/GEJ tissue samples were assessed in this study.
FFPE GC/GEJ tissue samples were stained using antibodies against CLDN18.2, PD-L1, and HER2. IHC assays were run on an automated platform; HER2 amplification was determined by HER2 CISH. Stained samples were evaluated by a trained pathologist using established scoring criteria.
A total of 298 GC/GEJ tissue samples (North America, n = 100; Asia, n = 100; Europe, n = 98) were assessed; 148 (50%) were histologically classified as intestinal, 123 (41%) diffuse, 18 (6%) mixed, and 9 (3%) other. In American samples, intestinal histology was the most prevalent; diffuse and intestinal were similar within Asian and European samples. Of the 286 evaluable samples, 30% (n = 86/286) were CLDN18.2high (moderate-to-strong CLDN18.2 membrane staining in ≥75% of tumor cells). CLDN18.2high prevalence ranged from 24% (n = 22/92) in Asian samples to 34% (n = 33/97) in American samples. CLDN18.2high prevalence was 30% (n = 35/115) in diffuse and 28% (n = 40/145) in intestinal subtypes. HER2+ and PD-L1+ (≥1% membrane-stained tumor cells) occurred in 10% (n = 29/291) and 37% (n = 107/289) of the evaluable samples, respectively. Of CLDN 18.2high samples with evaluable status for HER2, CLDN18.2 overlapped with HER2 in 12% (n = 10/83) of cases.
CLDN18.2 was found globally to be a high prevalence target in GC/GEJ cancer with limited overlap with HER2. In light of the clinical activity observed for zolbetuximab, CLDN18.2 may serve as a therapeutic target for a large subgroup of patients with GC/GEJ cancer.
Clinical trial identification
Legal entity responsible for the study
Astellas Pharma, Inc.
Astellas Pharma, Inc.
Medical writing and editorial assistance provided by Amlan RayChaudhury, PhD (SuccinctChoice Medical Communications Chicago, IL).
D. Moran, A. Arozullah: Employee: Astellas. All other authors have declared no conflicts of interest.