Treatment Selection for Patients with HER2-Negative Metastatic Gastric Cancer Expressing Claudin 18.2 and PD-L1

Abstract

Combination therapy of chemotherapy and zolbetuximab demonstrated a significant survival benefit compared to chemotherapy alone in patients with human epidermal growth factor receptor 2 (HER2)-negative, claudin (CLDN) 18.2-positive metastatic gastric cancer (mGC). Consequently, it has been approved as a standard first-line therapy for these patients. Combination therapy of chemotherapy and immune checkpoint inhibitors (ICIs)-either nivolumab or pembrolizumab-is a standard first-line therapy for patients with HER2-negative mGCs that are positive for programmed death-ligand 1 (PD-L1) expression, as defined by a combined positive score (CPS). Although approximately 13-22% of CLDN-positive mGCs are also CPS-positive, optimal treatment for mGC patients expressing both CLDN and PD-L1 remains undetermined due to the absence of direct comparative studies between zolbetuximab and ICIs. Treatment selection under this condition has become a critical issue. In this review, we discuss the appropriate treatment selection for HER2-negative mGC patients who are double-positive for CLDN 18.2 and PD-L1 based on clinical data and differences in the mechanism of action and safety profile between zolbetuximab and ICI.

Keywords: claudin18.2; combined positive score (CPS); gastric cancer; immune checkpoint inhibitor; zolbetuximab.

Figure 1

Proposed treatment algorism in patients with HER2-negative CLDN-positive metastatic gastric cancer. CLDN 18.2: claudin 18.2, CPS: combined positivity score, HER2: human epidermal growth factor receptor 2, HRQoL: health-related quality of life, MMR: mismatch repair, dMMR: deficient MMR, pMMR: proficient MMR, and MSI-H: microsatellite instability-high.