Association of Claudin18.2 expression, PD-L1, and prognostic implications in gastric and gastroesophageal junction cancers.

Abstract

e16094 Background: CLDN18.2-targeted therapies and immune checkpoint inhibitors (ICIs) are promising approaches for gastric and gastroesophageal junction cancers (GC/GEJ). CLDN18.2 expression and PD-L1 CPS serve as potential biomarkers, yet their interplay and joint prognostic impact remain unclear. Methods: We retrospectively analyzed 56 patients with metastatic GC or GEJ cancer who progressed after 1L treatment. CLDN18.2 IHC expression was classified as positive (≥75%) or negative (< 75%), while PD-L1 CPS was evaluated using cutoffs of < 10 and ≥10. Relationships between CLDN18.2 expression, PD-L1 CPS, histological subtypes, molecular features, and metastasis patterns were examined. Progression-free survival (PFS) and overall survival (OS) were analyzed using log rank tests and Cox multivariable models. Categorical variable associations were assessed using chi-square test. Results: CLDN18.2-positive tumors were identified in 57% (32/56) of patients. CLDN18.2-positivity was associated with younger age (median 55 vs. 66.5 years, p = 0.008), increased non-regional lymph node-only metastases, and fewer liver-only metastases. The CLDN18-ARHGAP26/6 fusion occurred in 9% of CLDN18.2-positive tumors and 11% of diffuse-type tumors with signet-ring cell features. PD-L1 expression was significantly higher in CLDN18.2-negative tumors (41.7% vs. 9.4%, p = 0.005). CLDN18.2-negative status was linked to improved OS (median OS NR vs. 28 months; p < 0.02), a finding which remained significant in multivariate models adjusting for PD-L1 (HR 0.19, 95% CI 0.04-0.85; p = 0.03). No significant PFS difference was seen between CLDN18.2-negative and -positive tumors (median PFS 9.5 vs. 8.5 months; p = 0.4). Conclusions: Our findings highlight biomarker complexity and heterogeneity in GC/GEJ cancers. The inverse relationship between CLDN18.2 and PD-L1 CPS suggests CLDN18.2-positive tumors may be less likely to engage PD-L1-mediated immune evasion mechanisms, providing a rationale for combining CLDN18.2-targeted therapies with ICIs. These results also underscore the potential of CLDN18.2 as a prognostic marker for overall survival in the setting of metastatic gastric cancer. Baseline characteristics. CLDN+ (n=32) CLDN- (n=24) p Age, median (range) 55 (38–82) 66.5 (42–84) 0.008 Male 16 (50%) 18 (75%) 0.06 Diffuse histology 27 (84.4%) 12 (50%) 0.006 ARHGAP26/6 Fusion 3 (9.4%) 0 0.26 PD-L1 expression PD-L1>=10 3 (9.4%) 10 (41.7%) 0.005 Metastatic siteLung-onlyLiver-onlyPeritoneum-onlyNon-regional lymph node-onlyMulti-organ 3 (9.4%)1 (3.1%)16 (50%)4 (12.5%)8 (25.0%) 1 (4.2%)8 (33.3%)11 (45.8%)04 (16.7%) 0.02