Clinical Pharmacology Profile of the Claudin 18.2 Antibody Zolbetuximab.

Zolbetuximab is a first-in-class chimeric (mouse/human) monoclonal antibody targeted to the tight junction protein claudin 18.2 (CLDN18.2), an emerging biomarker in gastric/gastroesophageal junction (G/GEJ) cancer. This review summarizes the clinical pharmacology of zolbetuximab on the basis of available clinical trial data. Population pharmacokinetics (PK) were evaluated using data from eight clinical studies (n = 714). Zolbetuximab PK following intravenous administration was described by a two-compartment model with linear and time-dependent clearance components. On the basis of simulations using the 800/600 mg/m² every 3 weeks (Q3W) dosing regimen from phase 3 trials, gastrectomy (versus no gastrectomy) was predicted to increase zolbetuximab C_trough by ≥ 50%, but without apparent effects on the benefit-risk profile of zolbetuximab. No dose adjustments are necessary for individuals with mild/moderate renal impairment or mild hepatic impairment. Zolbetuximab PK was not different among the ethnicities evaluated (White, Asian, Chinese, Japanese, Korean). There were no apparent safety or PK ramifications of zolbetuximab coadministration with oxaliplatin or 5-fluorouracil. The incidence of antidrug antibodies to zolbetuximab was low, with no apparent clinical consequence. Exposure-response analysis suggested that higher zolbetuximab exposures may prolong survival outcomes but may also increase the probability of experiencing gastrointestinal events and infusion-related reactions. A proposed alternative 800/400 mg/m² every 2 weeks (Q2W) regimen for use in combination with Q2W chemotherapy was shown to have comparable safety and efficacy to the 800/600 mg/m² Q3W regimen. Zolbetuximab, the first and only approved therapy targeted to CLDN18.2, is a valuable new treatment option for patients with CLDN18.2-positive, locally advanced unresectable or metastatic G/GEJ cancer.