Population pharmacokinetic (PK) analysis from phase 1 and 2 studies of the HER3 inhibitor patritumab in patients with advanced non-small cell lung cancer (NSCLC) or solid tumors.

2587 Background: Patritumab is a fully human antibody specific to HER3, a HER family receptor implicated in tumor resistance to anticancer treatment. In order to support patritumab dose recommendations, a population PK model was developed for phase 1 and 2 patritumab studies to characterize its PK and identify influencing factors. Methods: Population PK analysis was performed using data from the international phase 1b/2 HERALD study of patritumab (18 mg/kg every three weeks [q3w] or 18 mg/kg loading dose followed by 9 mg/kg q3w maintenance dose) in combination with erlotinib in EGFR treatment-naïve patients with advanced NSCLC after failure of ≥1 prior chemotherapy. Data from an open-label, phase 1 study of patritumab (9 mg/kg q3w or 18 mg/kg q3w) in Japanese patients with advanced solid tumors were also included. The effects of gender, baseline body weight (BW), creatinine clearance, eGFR, and albumin as covariates for clearance (CL), and gender and baseline BW as covariates for volume of central compartment (Vc) were investigated. PK simulations were performed to compare interpatient variability of patritumab exposure following fixed or BW-based dosing. Results: In total, 833 serum concentrations from 145 patients (136 NSCLC, 9 solid tumor) were included in the analysis. Serum patritumab concentrations were described by a two-compartment intravenous model with first-order elimination. Linear PK were observed at doses of 9 mg/kg and 18 mg/kg. CL, Vc, and volume of peripheral compartment were estimated as 0.0238 L/h, 3.62 L, and 2.50 L, respectively. BW and baseline albumin were significant covariates of CL (p<.05) and BW was a significant covariate of Vc (p<.05). PK simulations showed that BW-based dosing reduces interpatient variability in exposure compared with fixed dosing. Conclusions: Results showed that Vc was approximately serum volume and that CL was relatively low, indicative of a long terminal half-life. BW and albumin were significant factors affecting PK. The analysis supports an 18 mg/kg loading dose and 9 mg/kg q3w maintenance dose, and suggests that BW-adjusted dosing reduces interpatient variability. Clinical trial information: NCT01211483.