PII-001 - POPULATION PHARMACOKINETICS OF TRASTUZUMAB REZETECAN IN PATIENTS WITH HER2 EXPRESSING OR MUTATED ADVANCED MALIGNANT SOLID TUMORS

X. Gao¹, K. Zhao¹, Y. Zhang², K. Shen¹, N. DJEBLI³; ¹Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals, Shanghai, China, ²Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals - Shanghai,, China, ³Luzsana / Hengrui, Luzsana Biotechnology (subsidiary of Jiangsu Hengrui Pharmaceutical), Basel, Switzerland.

Background: Trastuzumab rezetecan is an antibody-drug conjugate (ADC) targeting the human epidermal growth factor receptor 2 (HER2). It features a novel enzyme-cleavable linker and delivers the topoisomerase I inhibitor payload, rezetecan, with a drug-to-antibody ratio of approximately 6.0. Its efficacy and safety are under evaluation in three phase 1 trials (NCT04446260, NCT04513223, and NCT04818333). We have analyzed the population pharmacokinetics (PopPK) of trastuzumab rezetecan and the release of rezetecan, via Non-Linear Mixed Effect Modeling, in patients with HER2-expressing or mutated advanced malignant solid tumors and assessed any potential covariates significantly impacting the PK parameters and derived exposures.

Methods: The dataset was pooled using SAS (version9.4). A two-analyte PopPK model, with ADC and payload, was developed using PK data from 645 patients with 18671 samples across three clinical studies with NONMEM (version 7.4). The parameters-covariates’ relationships of patients’ characteristics such as demographics, liver and kidney functions, laboratory tests and tumor size were assessed via stepwise covariate modeling. The exploratory analysis, simulations and graphical analyses were performed using R (version 4.1.2).

Results: A two-compartment model with linear elimination best described the PK of the ADC, while a one-compartment model with release-rate constant and linear elimination best described the PK of released rezetecan. Significant parameters-covariates’ relationships were identified with baseline body weight, tumor size, albumin, aspartate aminotransferase, age and cancer type, resulting in < 20% change in AUC of both intact ADC and released rezetecan. No relationship was revealed between race, sex, formulation, renal or hepatic functions and exposures of intact ADC or of released rezetecan.

Conclusion: A PopPK model was built to describe the PK characteristics of the intact trastuzumab rezetecan and the released payload rezetecan. Overall, no dose adjustment is warranted based on the covariates’ assessment. This model is being used to support the dose selection considering exposure-response analysis.