Clinicopathological significance and immunotherapeutic outcome of claudin 18.2 expression in advanced gastric cancer: A retrospective study

Abstract

<sec><b>Objective</b>Immunotherapeutic outcomes and clinical characteristics of claudin 18 isoform 2 positive (CLDN18.2-positive) gastric cancer (GC) vary in different clinical studies, making it difficult to optimize anti-CLDN18.2 therapy. We conducted a retrospective analysis to explore the association of CLDN18.2 expression with clinicopathological characteristics and immunotherapeutic outcomes in GC.</sec><sec><b>Methods</b>A total of 536 advanced GC patients from 2019 to 2021 in the CT041-CG4006 and CT041-ST-01 clinical trials were included in the analysis. CLDN18.2 expression on ≥40% of tumor cells (2+, 40%) and CLDN18.2 expression on ≥70% of tumor cells (2+, 70%) were considered the two levels of positively expressed GC. The clinicopathological characteristics and immunotherapy outcomes of GC patients were analyzed according to CLDN18.2 expression status.</sec><sec><b>Results</b>CLDN18.2 was expressed in 57.6% (cut-off: 2+, 40%) and 48.9% (cut-off: 2+, 70%) of patients. Programmed death-ligand 1 (PD-L1) and CLDN18.2 were co-expressed in 19.8% [combined positive score (CPS)≥1, CLDN18.2 (cut-off: 2+, 40%)] and 17.2% [CPS≥5, CLDN18.2 (cut-off: 2+, 70%)] of patients. CLDN18.2 expression positively correlated with younger age, female sex, non-gastroesophageal junction (non-GEJ), and diffuse phenotype (P&lt;0.001). HER2 and PD-L1 expression were significantly lower in CLDN18.2-positive GC (both P<i>&lt;</i>0.05). Uterine adnexa metastasis (P&lt;0.001) was more frequent and liver metastasis (P&lt;0.001) was less common in CLDN18.2-positive GC. Overall survival and immunotherapy-related progression-free survival (irPFS) were inferior in the CLDN18.2-positive group.</sec><sec><b>Conclusions</b>CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.</sec>

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