Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer

Abstract

Background: We conducted comprehensive clinical and molecular characterization of claudin 18.2 expression (CLDN18.2) in advanced gastric or gastroesophageal junction cancer (GC/GEJC).

Patients and methods: Patients with advanced GC/GEJC who received systemic chemotherapy from October 2015 to December 2019 with available tumor specimens were analyzed. We evaluated clinicopathological features of CLDN18.2 expression with four molecular subtypes: mismatch repair deficient, Epstein-Barr virus-positive, human epidermal growth factor receptor 2-positive, and others. In addition, programmed death-ligand 1 (PD-L1) combined positive score (CPS), genomic alterations, and the expression of immune cell markers were assessed. Clinical outcomes of standard first- or second-line chemotherapy and subsequent anti-programmed cell death protein 1 (anti-PD-1) therapy were also investigated according to CLDN18.2 expression.

Results: Among 408 patients, CLDN18.2-positive (moderate-to-strong expression in ≥75%) was identified in 98 patients (24.0%) with almost equal distribution in the four molecular subtypes or CPS subgroups. CLDN18.2-positive was associated with Borrmann type 4, KRAS amplification, low CD16, and high CD68 expression. Overall survival with first-line chemotherapy was not significantly different between CLDN18.2-positive and -negative groups [median 18.4 versus 20.1 months; hazard ratio 1.26 (95% confidence interval 0.89-1.78); P = 0.191] regardless of stratification by PD-L1 CPS ≥5. Progression-free survival and objective response rates of first- and second-line chemotherapy, and anti-PD-1 therapy also showed no significant differences according to CLDN18.2 status.

Conclusions: CLDN18.2 expression in advanced GC/GEJC was associated with some clinical and molecular features but had no impact on treatment outcomes with chemotherapy or checkpoint inhibition. CLDN18.2-positive also had no impact on overall survival. This information could be useful to interpret the results from currently ongoing clinical trials of CLDN18.2-targeted therapies for advanced GC/GEJC and to consider a treatment strategy for CLDN18.2-positive GC/GEJC.

Keywords: Epstein–Barr virus; claudin 18.2; gastric cancer; mismatch repair deficiency; zolbetuximab.

Figure 1

Association between CLDN expression and molecular characteristics. CLDN, claudin; CPS, combined positive score; EBV, Epstein–Barr virus; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; MMR-D, mismatch repair deficient; MMR-P, mismatch repair proficient; PD-L1, programmed death-ligand 1. ^aCLDN+, 2+/3+ ≥75%; EGFR+, 2+/3+ ≥50%; MET+, 2+/3+ ≥50%. ^bThe top 10 most frequent gene mutations, top 10 most frequent amplifications, and CLDN18-ARHGAP6/26 fusion.

Figure 2

Relationship between CLDN and other biomarkers (A) and PD-L1 CPS (B). All-negative: negative for neither MMR-D, EBV nor HER2. CLDN, claudin; CPS, combined positive score; EBV, Epstein–Barr virus; HER2, human epidermal growth factor receptor 2; MMR-D, mismatch repair deficient; MMR-P, mismatch repair proficient. ^aPatients with available CPS results.

Figure 3

Kaplan–Meier plots of progression-free survival (PFS) with each line treatment according to CLDN expression. (A) first-line chemotherapy (platinum + fluoropyrimidine, n = 226), (B) second-line chemotherapy (taxanes ± RAM, n = 275), (C) anti-PD-1 antibody (n = 164). CI, confidence interval; CLDN, claudin; FP, fluoropyrimidine; HR, hazard ratio; RAM, ramucirumab; ref, reference.

Figure 4

Kaplan–Meier plots of overall survival (OS) in patients who received standard first-line chemotherapy (platinum + fluoropyrimidine, n = 226). HR, hazard ratio; ref, reference.