Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer

Abstract

Background: The iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study.

Methods: Patients aged < 18 years (n = 69) received a weight-adjusted dose of atezolizumab (15 mg/kg every 3 weeks [q3w]; maximum 1200 mg); those aged ≥ 18 years (n = 18) received a flat dose (1200 mg q3w). A prior two-compartment intravenous infusion input adult population-PK (popPK) model of atezolizumab was used as a basis to model pediatric data.

Results: A total of 431 atezolizumab serum concentrations from 87 relapse-refractory pediatric and young adult patients enrolled in the iMATRIX-atezolizumab study were used for the popPK analysis. The dataset comprised predominantly patients aged < 18 years, including two infants aged < 2 years, with a wide body weight and age range. The clearance and volume of distribution estimates of atezolizumab were 0.217 L/day and 3.01 L, respectively. Atezolizumab geometric mean trough exposures were ~ 20% lower in pediatric patients versus young adults; this was not clinically meaningful as both groups achieved the target concentration (6 μg/mL). Safety was similar between pediatric and young adult patients with no exposure-safety relationship observed. Limited responses (4/87) precluded an exposure-response assessment on outcomes. A comparable rate (13% vs 11%) of atezolizumab anti-drug antibodies was seen in pediatric and young adult patients.

Conclusions: These findings demonstrate a similar exposure-safety profile of atezolizumab in pediatric and young adult patients, supportive of weight-based dosing in pediatric patients.

Trial registration: NCT02541604.

Keywords: Atezolizumab; Cancer immunotherapy; Clinical pharmacology; Exposure-safety; Immune checkpoint inhibitor; Pediatric oncology; Population pharmacokinetics.

Fig. 1

(a) Prediction-corrected visual predictive check, (b) goodness of fit diagnostic plots, (c) Eta distributions, and (d) random effect correlations to covariates. Prediction-corrected visual predictive check (a): the gray solid and dashed lines represent the observed median and the 10th and 90th percentiles, respectively, while the two shades of blue represent overlap between the empirical 95% prediction intervals. Goodness of fit diagnostic plots (b): the gray solid line indicates fitted values from a nonparametric smoother. Dashed lines indicate the line of unity (top plots), or zero lines and boundary lines for conditional weighted residuals (bottom). Eta distributions (c): the blue solid line represents a density curve. Random effect correlations to covariates (d): for continuous covariates, the blue solid line represents fitted values from a nonparametric smoother. The dashed line indicates the zero line, the box-plot indicates the median and interquartile range (25th to 75th percentile), the whiskers indicate 1.5 times the interquartile range. Abbreviations: ADA anti-drug antibody, CL clearance, V1 volume of the central compartment, V2 volume of the peripheral compartment

Fig. 2

Cycle 1 and steady-state (cycle 10) exposure metrics by age group: (a) C_max, (b) C_min, and (c) AUC. Expected interquartile range (IQR) from simulated distributions (n = 1000) based on reported geometric means and %CVs. The box-plots indicate the median and IQR (25th to 75th percentile). The whiskers indicate 1.5 times the IQR. Abbreviations: AUC area under the curve, C_min minimum concentration, C_max maximum concentration

Fig. 3

Post-hoc exposures at cycle 1 (a) and steady-state (cycle 10) (b). Exposures across 69 patients aged < 18 years (including two infants < 2 years, 29 children 2 to < 12 years, and 38 adolescents 12 to < 18 years) and 18 young adults aged 18 to < 29 years. The dotted line indicates the therapeutic target exposure of 6 μg/mL. The height of the bar represents the number of patients within that concentration range. A cumulative distribution trend (red line) is superimposed over the frequency distribution histogram. Abbreviation: C_min minimum concentration

Fig. 4

Incidence of grade ≥ 3 AEs (a) and any-grade AESI (b). AEs and AESI are displayed by open blue circles. Solid black circles with standard error bars (y-value: binned probability of having an event from observations; x-value: median exposure value within the bin). Red line: mean model fitted curve (obtained from averaging the fitted curve for each exposure record in the data set). Dashed green lines: binning boundaries. Exposure levels are binned based on the quantiles of the log transformed exposure variable levels. Blue shaded area: based on 100 bootstrap replicates, depicting the 90% confidence band for the mean model fitted curve. Plot is based on 69 patients. Abbreviations: AE adverse event, AESI adverse event of special interest, AUC area under the curve