Prevalence of CLDN18.2, HER2 and PD-L1 in gastric cancer samples

Background: 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. Methods: 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. Results: 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. Conclusions: 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. Editorial acknowledgement: Medical writing and editorial assistance provided by Amlan RayChaudhury, PhD (SuccinctChoice Medical Communications Chicago, IL). Legal entity responsible for the study: Astellas Pharma, Inc. Funding: Astellas Pharma, Inc. Disclosure: D. Moran, A. Arozullah: Employee: Astellas. All other authors have declared no conflicts of interest.