Jeffrey R Proctor1, Elaina M Gartner1, Todd E Gray1,2, Rupert H Davies3,4. 1. Zymeworks Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, V5T 1G4, Canada. 2. Chinook Therapeutics, Inc., 400 Fairview Ave North, 9th floor, Seattle, WA, 98109, USA. 3. Zymeworks Inc., 114 East 4th Avenue, Suite 800, Vancouver, BC, V5T 1G4, Canada. rupert.davies@alpineimmunesciences.com. 4. Alpine Immune Sciences, 188 East Blaine Street, Suite 200, Seattle, WA, 98102, USA. rupert.davies@alpineimmunesciences.com.
Abstract
PURPOSE: To characterize the pharmacokinetics (PK) of zanidatamab including evaluation of the impact of intrinsic and extrinsic patient factors. To investigate alternative dosing regimens to improve caregiver convenience and reduce zanidatamab wastage. METHODS: Serum zanidatamab concentrations were obtained from 305 patients with advanced or metastatic breast cancer, gastroesophageal adenocarcinoma (GEA), biliary tract cancer, and other HER2-expressing cancers from four ongoing phase I and II clinical trials. Zanidatamab PK were described using population methods. The exposure of alternative dosing regimens and the impact of dose delay was estimated by model simulation. RESULTS: A two-compartment model with parallel linear and nonlinear clearance from the central compartment adequately described zanidatamab PK. At the recommended dose regimens of 20 mg/kg Q2W and 30 mg/kg Q3W, zanidatamab clearance was primarily linear at steady state. At steady state, 30 mg/kg Q3W zanidatamab returns within 10% of the steady state trough after 2 subsequent doses following either a 1-week or 2-week dose delay. Statistically significant covariates included in the final model were body weight, sex, albumin, GEA cancer type, baseline tumor size, and presence of post-baseline anti-drug antibodies, all of which resulted in less than 30% impact on exposure. Model simulation predicts weight-based and two-tiered flat dosing will result in similar exposure and variability. CONCLUSION: The identified significant covariates were not considered clinically meaningful. Both weight-based (30 mg/kg Q3W) and two-tiered flat dosing (1800/2400 mg Q3W, 70 kg threshold) strategies are expected to provide similar exposures of zanidatamab.
PURPOSE: To characterize the pharmacokinetics (PK) of zanidatamab including evaluation of the impact of intrinsic and extrinsic patient factors. To investigate alternative dosing regimens to improve caregiver convenience and reduce zanidatamab wastage. METHODS: Serum zanidatamab concentrations were obtained from 305 patients with advanced or metastatic breast cancer, gastroesophageal adenocarcinoma (GEA), biliary tract cancer, and other HER2-expressing cancers from four ongoing phase I and II clinical trials. Zanidatamab PK were described using population methods. The exposure of alternative dosing regimens and the impact of dose delay was estimated by model simulation. RESULTS: A two-compartment model with parallel linear and nonlinear clearance from the central compartment adequately described zanidatamab PK. At the recommended dose regimens of 20 mg/kg Q2W and 30 mg/kg Q3W, zanidatamab clearance was primarily linear at steady state. At steady state, 30 mg/kg Q3W zanidatamab returns within 10% of the steady state trough after 2 subsequent doses following either a 1-week or 2-week dose delay. Statistically significant covariates included in the final model were body weight, sex, albumin, GEA cancer type, baseline tumor size, and presence of post-baseline anti-drug antibodies, all of which resulted in less than 30% impact on exposure. Model simulation predicts weight-based and two-tiered flat dosing will result in similar exposure and variability. CONCLUSION: The identified significant covariates were not considered clinically meaningful. Both weight-based (30 mg/kg Q3W) and two-tiered flat dosing (1800/2400 mg Q3W, 70 kg threshold) strategies are expected to provide similar exposures of zanidatamab.
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