Population PK and Exposure-Response Analyses of Zolbetuximab in Patients With Locally Advanced Unresectable or Metastatic G/GEJ Adenocarcinoma.

Zolbetuximab is a chimeric (mouse/human) monoclonal antibody directed against the tight junction protein claudin 18.2, which is highly expressed in gastric/gastroesophageal junction (G/GEJ) and pancreatic adenocarcinoma. We report a population pharmacokinetic (PK) and exposure-response (E-R) analysis of zolbetuximab in patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma. A population PK model for zolbetuximab was developed using data from eight clinical studies to generate exposure metrics for safety/efficacy E-R analyses of three trials. A two-compartment model with zero-order input and time-dependent clearance adequately characterized zolbetuximab serum concentration-time data. Estimated mean clearance at baseline, steady-state clearance, steady-state volume of distribution, and elimination half-life were 0.0276 L/h, 0.0117 L/h, 5.53 L, and 7.56-15.2 days, respectively. Time required for trough concentration to reach steady state was 24 weeks. Mild hepatic or mild/moderate renal impairment did not alter zolbetuximab PK. Gastrectomy increased average zolbetuximab concentration (30%), trough concentration (first dose, 114%; steady state, 50%), and area under the concentration-time curve (26%-34%), but maximum concentrations were similar (gastrectomy vs. no gastrectomy) and no clinical relevance is anticipated. Multivariable Cox proportional hazard modeling indicated statistically significant relationships between average zolbetuximab concentration and progression-free survival and overall survival (both p < 0.0001) after controlling for other relevant covariates. Maximum concentration after the first dose was significantly associated with gastrointestinal adverse events and infusion-related reactions. The phase 3 zolbetuximab regimen of 800/600 mg/m2 every 3 weeks was supported by efficacy/safety data; an alternative regimen of 800/400 mg/m2 every 2 weeks was predicted to have similar efficacy/safety.