Cancer Therapy: Preclinical Onartuzumab (MetMAb): Using Nonclinical Pharmacokinetic and Concentration–Effect Data to Support Clinical Development Hong Xiang 1 , Brendan C. Bender 1 , Arthur E. Reyes II 1 , Mark Merchant 2 , Nelson L. 'Shasha' Jumbe 6 , Mally Romero 8 , Teresa Davancaze 3 , Ihsan Nijem 3 , Elaine Mai 4 , Judy Young 4 , Amy Peterson 7 , and Lisa A. Damico-Beyer 5 Abstract Purpose: We characterized the pharmacokinetics of onartuzumab (MetMAb) in animals and determined a concentration–effect relationship in tumor-bearing mice to enable estimation of clinical pharmacoki- netics and target doses. Experimental Design: A tumor growth inhibition model was used to estimate tumoristatic concentra- tions (TSC) in mice. Human pharmacokinetic parameters were projected from pharmacokinetics in cynomolgus monkeys by the species-invariant time method. Monte Carlo simulations predicted the percentage of patients achieving steady-state trough serum concentrations (C trough ss ) TSC for every 3-week (Q3W) dosing. Results: Onartuzumab clearance (CL) in the linear dose range was 21.1 and 12.2 mL/d/kg in mice and cynomolgus monkeys with elimination half-life at 6.10 and 3.37 days, respectively. The estimated TSC in KP4 pancreatic xenograft tumor-bearing mice was 15 mg/mL. Projected CL for humans in the linear dose range was 5.74 to 9.36 mL/d/kg with scaling exponents of CL at 0.75 to 0.9. Monte Carlo simulations projected a Q3W dose of 10 to 30 mg/kg to achieve C trough ss of 15 mg/mL in 95% or more of patients. Conclusions: Onartuzumab pharmacokinetics differed from typical bivalent glycosylated mono- clonal antibodies with approximately 2-times faster CL in the linear dose range. Despite this higher CL, xenograft efficacy data supported dose flexibility with Q1W to Q3W dose regimens in the clinical setting with a TSC of 15 mg/mL as the C trough ss target. The projected human efficacious dose of 10 to 30 mg/kg Q3W should achieve the target TSC of 15 mg/mL. These data show effective phar- macokinetic/pharmacodynamic modeling to project doses to be tested in the clinic. Clin Cancer Res; 19(18); 5068–78. Ó2013 AACR. Introduction The importance of pharmacokinetic and pharmacody- namic modeling and simulation in all phases of drug development has been recognized (1, 2). In particular, target concentration approaches using nonclinical studies during drug development to support safe starting dose and therapeutically relevant dose escalation for human oncol- ogy studies, have been reported in the recent publications (3–5). However, limited work has been carried out for mAbs in the oncology field (6). Because inability to show efficacy is a leading reason for failure of phase III trials, exploration of the role of translational pharmacokinetics/pharmacody- namics to support dose and regimen selection in the clinic would improve risk management during drug development (7). This article describes how such an approach has been used in the development of onartuzumab (MetMAb). MET is a receptor tyrosine kinase with known specificity for a single ligand, the hepatocyte growth factor (HGF), also known as scatter factor (SF; ref. 8). HGF/SF binding to MET leads to receptor dimerization and autophosphoryla- tion of MET at multiple tyrosines on its intracellular kinase domain, and subsequent phosphorylation of its C-termi- nal docking site and juxtamembrane domain (9). These phosphorylation events enable activation of multiple Authors' Affiliations: Departments of 1 Pharmacokinetic and Pharmaco- dynamic Sciences, 2 Translational Oncology, 3 Bioanalytical Sciences, 4 Bio- chemical and Cellular Pharmacology, and 5 Portfolio Management and Operations, Genentech, Inc., South San Francisco; 6 Quantitative Solu- tions, Menlo Park; 7 Medivation, Inc., San Francisco; and 8 Celgene, San Diego, California Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). N. L. 'Shasha' Jumbe, M. Romero, and A. Peterson were employed by Genentech during their involvement in this study. Corresponding Author: Hong Xiang, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. Phone: 650-225-8854; Fax: 650-742-5234; E-mail: xiang.hong@gene.com doi: 10.1158/1078-0432.CCR-13-0260 Ó2013 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 19(18) September 15, 2013 5068 on February 1, 2016. © 2013 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst July 26, 2013; DOI: 10.1158/1078-0432.CCR-13-0260