Claudin 18.2 Targeting: A Pan-Cancer Perspective.

Claudin 18.2 (CLDN18.2) is exclusively expressed on gastric mucosal cell tight junctions, with minimal expression in other healthy adult tissues. Prior studies assessed expression by immunohistochemistry, mainly membrane staining. The FDA CLDN18.2 threshold for zolbetuximab approval is ≥ 75% moderate-to-strong staining. Higher-level expression has been seen in a number of cancers, including (but not limited to) gastric, gastroesophageal junction (GEJ), pancreatic, and ovarian cancers. CLDN18.2 expression can change with treatment and can exhibit heterogeneity between tumor sites. Zolbetuximab is a recently FDA-approved anti-CLDN18.2 mAb for first-line therapy of gastric/GEJ cancers in combination with chemotherapy, based on the improvement in outcomes demonstrated in the biomarker-selected populations of the SPOTLIGHT and GLOW trials. Given limited single-agent response rates to zolbetuximab, a number of other CLDN18.2-directed therapies, including antibody-drug conjugates, chimeric antigen receptor T cells, and bispecific antibodies, are under exploration in clinical trials. Despite the expression of CLDN18.2 on the gastric mucosa, these therapies have overall been tolerable in clinical trials, albeit with the use of aggressive antiemetic regimens. Herein, we summarize CLDN18.2 expression in cancer along with clinical trials of zolbetuximab and other CLDN18.2-directed therapies. Given the variability in CLDN18.2 expression within and between tumor types, biomarker-driven approaches will be critical for patient selection in clinical trials and therapeutic approaches.