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

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ABSTRACT 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/m 2 every 3 weeks was supported by efficacy/safety data; an alternative regimen of 800/400 mg/m 2 every 2 weeks was predicted to have similar efficacy/safety.

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