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

Journal for ImmunoTherapy of Cancer

Jane Ruppel¹  Russ Wada²  Kris Jamsen²  Rene Bruno³  Pascal Chanu³  Gianluca Rossato⁴  Sandhya Girish⁵  Helen Winter⁵  Jin Jin⁵  Amit Garg⁵  Xin Wang⁵  Colby S. Shemesh⁵  Francis Donaldson⁶ 

[1] Bioanalytical Sciences, Genentech Inc.;Certara Strategic Consulting;Clinical Pharmacology, Modeling and Simulation, Genentech/Roche;Clinical Science, F. Hoffmann-La Roche Ltd;Department of Clinical Pharmacology Oncology, Genentech Inc.;Safety Science, Roche Products Ltd;

关键词: Atezolizumab;    Cancer immunotherapy;    Clinical pharmacology;    Exposure-safety;    Immune checkpoint inhibitor;    Pediatric oncology;   

DOI  :  10.1186/s40425-019-0791-x

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown