Human pharmacokinetic (PK) characterization of the novel dual-action anti-HER3/EGFR antibody MEHD7945A (MEHD) in patients with refractory/recurrent epithelial tumors.

Abstract

2567 Background: MEHD is a novel dual-action human IgG1 antibody that blocks ligand binding to HER3 and EGFR, and elicits antibody-dependent cell-mediated cytotoxicity (ADCC). MEHD demonstrates single-agent activity in a broad panel of tumor models, including models resistant to anti-HER3 or anti-EGFR treatment alone. The objective of this analysis was to characterize the PK of MEHD associated with body weight (BW)-based dosing used in a phase I study in patients with epithelial tumors and to evaluate the potential for using fixed dosing in future studies. Methods: Preliminary non-compartmental and population PK analyses were performed using patient data from the dose-escalation stage [1, 4, 10, 15, 22, and 30 mg/kg every two weeks (q2w)] and expansion stage (14 mg/kg q2w) of the phase I study. Patient demographic data and other relevant clinical covariates were evaluated in the population analysis. PK simulation of 1000 subjects with a log-normal BW distribution was performed to compare the inter-individual variability of MEHD exposure following fixed or BW-based dosing. Results: As expected,MEHD exhibited nonlinear PK. In the noncompartmenal analysis, the apparent clearance (CL) decreased in a dose-dependent fashion (about 40 to 9.9 mL/day/kg from 1 to 30 mg/kg) and approached linearity at doses >10 mg/kg (q2w). In the population analysis, the PK profile of MEHD was well described by a two compartment model with linear and nonlinear clearance. The target-mediated clearance was consistent with that of anti-EGFR antibodies. The nonspecific CL and central volume of distribution (V1) values were approximately 6 mL/day/kg and 52.4 mL/kg, respectively. BW had a moderate effect on V1, but not on CL. PK simulations suggest that, compared with BW-based dosing, fixed dosing would result in less inter-individual variability in MEHD exposure. Both 1100 mg q2w or 1650 mg q3w of MEHD achieve the targeted therapeutic exposure. Conclusions: The dual-action antibody MEHD demonstrated PK consistent with anti-EGFR antibodies. Fixed dosing of MEHD on an every 2 or 3 week schedule is supported.