PII-066 - POPULATION PHARMACOKINETICS AND EXPOSURE-RESPONSE ANALYSES OF ZOLBETUXIMAB IN PATIENTS WITH LOCALLY ADVANCED UNRESECTABLE OR METASTATIC GASTRIC OR GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA

A. Yamada¹, M. Takeuchi², K. Komatsu², P. Bonate², S. Poondru², J. Yang²; ¹Astellas Pharma, Inc, ²Astellas Pharma, Inc..

Background: Zolbetuximab is a first-in-class investigational chimeric (mouse/human) monoclonal antibody directed against the tight junction protein claudin 18.2, which is highly expressed in gastric (G), gastroesophageal junction (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.

Methods: A population PK model for intravenous zolbetuximab was developed based on data from 8 clinical studies and used to generate individual exposure metrics for safety/efficacy E-R analyses of 3 trials (phase 2 FAST; phase 3 SPOTLIGHT, GLOW).

Results: A 2-compartment model with zero-order input and first-order elimination adequately characterized zolbetuximab serum concentration–time data. Estimated mean systemic clearance, steady-state volume of distribution, and elimination half-life were 0.0150 L/h, 16.4 L, and 43.6 days, respectively. There were no clinically meaningful differences in zolbetuximab exposures by ethnicity (White, Asian, Chinese, Japanese, Korean). Mild hepatic or mild/moderate renal impairment did not alter zolbetuximab PK. Gastrectomy increased average zolbetuximab concentration by 36% vs no gastrectomy. Statistically significant relationships were noted between average zolbetuximab concentration and survival/response outcomes after controlling for other relevant covariates. Participants with higher zolbetuximab exposures tended to have longer progression-free survival and overall survival than those with lower exposures. Maximum concentration after first dose was significantly associated with gastrointestinal adverse events and infusion-related reactions. The phase 3 dose regimen of 800/600 mg/m2 every 3 weeks (Q3W) was supported by efficacy and safety data; an alternate regimen of 800/400 mg/m2 every 2 weeks (Q2W) was predicted to have similar efficacy and safety regardless of body size. Variability in drug exposure and efficacy/safety of fixed dosing regimens (Q3W or Q2W) was expected to be larger than that for body surface area–normalized dosing.

Conclusion: The population PK of zolbetuximab has been well characterized. E-R analyses support 800/600 mg/m2 Q3W or 800/400 mg/m2 Q2W regimens.