Covariate effects and population pharmacokinetic analysis of the anti-FGFR2b antibody bemarituzumab in patients from phase 1 to phase 2 trials

Hong Xiang,Ago Ahene,Helen Collins,Lucy Liu,Yuying Gao

doi:10.1007/s00280-021-04333-y

Hong Xiang, Ago Ahene + Show 3 more

Open Access

https://doi.org/10.1007/s00280-021-04333-y

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Abstract

PurposeA population pharmacokinetic (PK) analysis of the anti-fibroblast growth factor receptor 2b antibody, bemarituzumab, was performed to evaluate the impact of covariates on the PK and assess whether dose adjustment is necessary for a future phase 3 trial.MethodsSerum concentration data were obtained from three clinical trials, with 1552 bemarituzumab serum samples from 173 patients, and were analyzed using nonlinear mixed-effects modeling.ResultsA two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment best described the bemarituzumab serum concentration data. The final model estimated a typical linear clearance (CL) of 0.311 L/day, volume of distribution in the central compartment (Vc) of 3.58 L, distribution clearance (Q) of 0.952 L/day, volume of distribution in the peripheral compartment (Vp) of 2.71 L, maximum drug elimination by nonlinear clearance (Vmax) of 2.80 μg/day, and Michaelis–Menten constant (Km) of 4.45 μg/mL. Baseline body weight, baseline albumin, gender, and chemotherapy were identified as statistically significant covariates on the PK of bemarituzumab. Given the low interindividual variability of bemarituzumab key PK parameters (CL and Vc) and the small or modest effect of all statistically significant covariates on bemarituzumab exposure at steady-state, no covariate is expected to have clinically meaningful effects on bemarituzumab exposure.ConclusionNo covariate had a clinically meaningful impact on bemarituzumab exposure. These results indicate that dose adjustment of bemarituzumab is not necessary, based on the aforementioned covariates, for a future phase 3 trial in gastric and gastroesophageal junction adenocarcinoma population with FGFR2b overexpression in combination with mFOLFOX6.

Highlights

Bemarituzumab (FPA144) is a first-in-class, recombinant, humanized, afucosylated immunoglobulin G1 (IgG1) kappa monoclonal antibody directed against fibroblastBemarituzumab has been evaluated in three clinical trials {FPA144-001, FPA144-002, and FPA144-004 [FIGHT]}
Based on an examination of PK parameter–covariate relationships, gender, combotherapy/study, aspartate aminotransferase, albumin, a single dose of mFOLFOX6 prior to randomization, hepatic function based on NCI-ODWG, Eastern cooperative oncology group (ECOG) performance status, lactate dehydrogenase, total bilirubin on CL, gender, and combotherapy/study on Vc had a statistical significance of p < 0.05 and were carried forward to the forward covariate search in NONMEM
The sensitivity analysis and population simulations support the decision to test the same dose and regimen used in the phase 2 FIGHT trial for a future phase 3 trial in the gastroesophageal junction adenocarcinoma (GEA) population with FGFR2b over expression in combination with mFOLFOX6 without any dose adjustment

Summary

Introduction

Bemarituzumab (FPA144) is a first-in-class, recombinant, humanized, afucosylated immunoglobulin G1 (IgG1) kappa monoclonal antibody (mAb) directed against fibroblastBemarituzumab has been evaluated in three clinical trials {FPA144-001, FPA144-002, and FPA144-004 [FIGHT]}. FPA144-001 (NCT02318329), a phase 1, open-label, dosefinding trial evaluating the safety and pharmacokinetics (PK) of FPA144 in patients with advanced solid tumors including gastric and gastroesophageal junction adenocarcinoma (GEA) at six dose levels ranging from 0.3 to 15 mg/kg once every 2 weeks (Q2W), demonstrated evidence of monotherapy activity and acceptable tolerability of bemarituzumab in patients. FPA144-002, a phase 1, open-label, dose-finding trial evaluating the safety and PK of bemarituzumab in Japanese patients with advanced GEA at two dose levels, demonstrated that bemarituzumab can be administered safely to Japanese patients in doses up to 15 mg/kg Q2W. The FIGHT trial using bemarituzumab at 15 mg/kg Q2W with 1 additional dose of 7.5 mg/kg on Cycle 1 Day 8 achieved clinically meaningful and statistically significant improvements across all three of its prespecified efficacy endpoints including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with FGFR2b-positive, non-HER2 positive frontline advanced GEA [4]

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