Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial

Abstract

Purpose: To report population pharmacokinetic (PK) analysis of the phase 1 study (FPA144-001, NCT02318329) and to select a clinical dose and schedule that will achieve an empirical target trough concentration (Ctrough) for an anti-fibroblast growth factor receptor 2b antibody, bemarituzumab.

Methods: Nonlinear mixed-effect modeling was used to analyse PK data. In vitro binding affinity and receptor occupancy of bemarituzumab were determined. Simulation was conducted to estimate dose and schedule to achieve an empirical target Ctrough in a phase 2 trial (FIGHT, NCT03694522) for patients receiving first-line treatment combined with modified 5-fluourouracil, oxaliplatin and leucovorin (mFOLFOX6) for gastric and gastroesophageal junction adenocarcinoma.

Results: Bemarituzumab PK is best described by a two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment. Albumin, gender, and body weight were identified as the covariates on the linear clearance and/or volume of distribution in the central compartment, and no dose adjustment was warranted. An empirical target of bemarituzumab Ctrough of ≥ 60 µg/mL was projected to achieve > 95% receptor occupancy based on in vitro data. Fifteen mg/kg every 2 weeks, with a single dose of 7.5 mg/kg on Cycle 1 Day 8, was projected to achieve the target Ctrough on Day 15 in 98% of patients with 96% maintaining the target at steady state, which was confirmed in the FIGHT trial.

Conclusion: A projected dose and schedule to achieve the target Ctrough was validated in phase 1 of the FIGHT trial which supported selection of the phase 2 dose and schedule for bemarituzumab.

Keywords: Anti-fibroblast growth factor receptor 2b; Bemarituzumab; Dose selection; Gastric and gastroesophageal junction adenocarcinoma; Population PK analysis; Target-mediated clearance.

Conflict of interest statement

H. Xiang, A. Ahene, L. Dreiling, and H. Collins are employed with Five Prime Therapeutics, Inc. and M. Macal and AW Hsu are former Five Prime employees. They have ownership interest in the Five Prime stock. L. Liu and Y. Gao declare no potential conflicts of interest.

Figures

Fig. 1

Prediction-corrected VPC of bemarituzumab serum concentration–time profile across dose groups. Black open circles are observed serum concentrations, solid red line represents the median observed value, and dashed red lines represent 2.5th and 97.5th percentile of the observed values, respectively. Pink shaded areas represent the spread of the median predicted values (5th to 95th percentile), and blue shaded areas represent the spread (5th and 95th percentile) of the 2.5th and 97.5th predicted percentile concentrations

Fig. 2

Sensitivity plot comparing the effect of covariates on Ctrough ss of bemarituzumab. Base, as represented by the black vertical line and value, refers to the predicted typical Ctrough ss of bemarituzumab in a 61 kg male patient with an albumin of 3.7 g/dL kg after continuous Q2W dosing of 15 mg/kg bemarituzumab for 6 months. The black horizontal bar with values at each end shows the 5th to 95th percentile Ctrough ss range across the entire population. Each blue bar represents the influence of a single covariate on the Ctrough ss. The label at the left end of the bar represents the covariate being evaluated. The upper and lower values for each covariate capture 90% of the plausible range in the population. The length of each bar describes the potential impact of that particular covariate on bemarituzumab Ctrough ss with the percentage value in the parentheses at each end representing the percent change of Ctrough ss from the base. The most influential covariate is at the top of the tornado plot

Fig. 3

In vitro cell-based binding for bemarituzumab using gastric cell lines. Mean fluorescence intensity (ABC) versus bemarituzumab concentration profile from receptor occupancy study in vitro are presented for FGFR2b-amplified cell lines OCUM-2 M, HSC-39, and SNU-16 in Figs. 3A, 3B, and 3C, respectively. NCI-N87 is presented in 3D as a negative control. Symbols represent observed data (n = 3 per time point). L.D. limit of detection, which is at 62 for ABC

Fig. 4

Simulation results using PK parameters obtained from PopPK analysis versus observed Ctrough from phase 1 of the FIGHT trial. Simulated serum concentration versus time profiles of bemarituzumab after continuous Q2W dosing of bemarituzumab at 6 mg/kg (a) or 15 mg/kg Q2W with a single dose of 7.5 mg/kg on Cycle 1 Day 8 (b) for 6 months based on the final PopPK model. For each dose regimen, 1000 simulated model parameters constructed the distribution of model predictions for a typical population (61 kg male patients with albumin of 3.7 g/dL). In each figure, solid black line represents the median predicted value and dashed blue lines represent the 5th and 95th percentile of the predicted concentrations and dashed red line is for Ctrough of 60 µg/mL. Each symbol represents the individual bemarituzumab Ctrough (µg/mL) in the presence of mFOLFOX6 at 6 mg/kg (a, n = 3) and 15 mg/kg Q2W with a single dose of 7.5 mg/kg on Cycle 1 Day 8 (b, n = 7), respectively