Atezolizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting human programmed death‐ligand 1 (PD‐L1), is US Food and Drug Administration (FDA) approved in metastatic urothelial carcinoma (MUC) and is being investigated in various malignancies. This analysis based upon 906 patients from two phase I and one phase II MUC studies, is the first report of the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of atezolizumab. Atezolizumab exhibited linear PK over a dose range of 1–20 mg/kg, including the labeled 1,200 mg dose. The clearance, volume of distribution, and terminal half‐life estimates from population pharmacokinetic (PopPK) analysis of 0.200 L/day, 6.91 L, and 27 days, respectively, were as expected for an IgG1. Exposure‐response analyses did not identify statistically significant relationships with either objective response rate or adverse events of grades 3–5 or of special interest. None of the statistically significant covariates from PopPK (body weight, gender, antitherapeutic antibody, albumin, and tumor burden) would require dose adjustment.

Abstract Purpose: This first-in-human study evaluated the safety, immunogenicity, pharmacokinetics, and antitumor activity of onartuzumab, a monovalent antibody against the receptor tyrosine kinase MET. Experimental Design: This 3+3 dose-escalation study comprised three stages: (i) phase Ia dose escalation of onartuzumab at doses of 1, 4, 10, 20, and 30 mg/kg intravenously every 3 weeks; (ii) phase Ia cohort expansion at the recommended phase II dose (RP2D) of 15 mg/kg; and (iii) phase Ib dose escalation of onartuzumab at 10 and 15 mg/kg in combination with bevacizumab (15 mg/kg intravenously every 3 weeks). Serum samples were collected for evaluation of pharmacokinetics, potential pharmacodynamic markers, and antitherapeutic antibodies. Results: Thirty-four patients with solid tumors were treated in phase Ia and 9 in phase Ib. Onartuzumab was generally well tolerated at all dose levels evaluated; the maximum tolerated dose was not reached. The most frequent drug-related adverse events included fatigue, peripheral edema, nausea, and hypoalbuminemia. In the phase Ib cohort, onartuzumab at the RP2D was combined with bevacizumab and no dose-limiting toxicities were seen. Onartuzumab showed linear pharmacokinetics in the dose range from 4 to 30 mg/kg. The half-life was approximately 8 to 12 days. There were no apparent pharmacokinetic interactions between onartuzumab and bevacizumab, and antitherapeutic antibodies did not seem to affect the safety or pharmacokinetics of onartuzumab. A patient with gastric carcinoma in the 20-mg/kg dose cohort achieved a durable complete response for nearly 2 years. Conclusions: Onartuzumab was generally well tolerated as a single agent and in combination with bevacizumab in patients with solid tumors. Clin Cancer Res; 20(6); 1666–75. ©2014 AACR.

Onartuzumab is a unique, humanized, monovalent (one‐armed) monoclonal antibody (mAb) against the MET receptor. The intravenous (IV) pharmacokinetics (PK) of onartuzumab were investigated in a phase I study and a phase II study in recurrent non‐small cell lung cancer (NSCLC) patients. The potential for drug–drug interaction (DDI) was assessed during co‐administration of IV onartuzumab with oral erlotinib, by measuring the PK of both drugs. The concentration–time profiles of onartuzumab were adequately described using a two‐compartment model with linear clearance (CL) at doses between 4 and 30 mg/kg. The estimates for CL, central compartment volume (V1), and median terminal half‐life were 0.439 L/day, 2.77 L, and 13.4 days, respectively. Statistically significant covariates included creatinine clearance (CrCL) on clearance, weight and gender on V1, and weight on peripheral compartment volume (V2), but the clinical relevance of these covariates needs to be further evaluated. The current analysis did not indicate obvious DDI between onartuzumab and erlotinib. MET diagnostic status did not impact the exposure of either agent. Despite the slightly faster clearance compared with typical bivalent mAbs, the PK of onartuzumab support dosing regimens of 15 mg/kg every 3 weeks or doses equivalent to achieve the target minimum tumoristatic concentration in patients.

e13050 Background: Crosstalk between the Met and vascular endothelial growth factor (VEGF) pathways may be important during tumorigenesis. Aberrant activation of the HGF/Met pathway may promote angiogenesis via tumor cell secretion of angiogenic factors or directly activating endothelial cells. The combination of Met and VEGF inhibition resulted in enhanced antitumor activity in multiple preclinical models than either treatment alone. MetMAb is a recombinant, humanized, monovalent (one-armed) monoclonal antibody antagonist of HGF-induced Met signaling. In phase Ia, MetMAb was generally well tolerated up to 30 mg/kg IV Q3W. Herein, we describe results from a phase Ib study in which we tested MetMAb in combination with bevacizumab. Methods: The phase Ib trial tested the combination of MetMAb with bevacizumab in two cohorts: 3 patients in cohort 1 received MetMAb, 10 mg/kg, and bevacizumab, 15 mg/kg, IV Q3W; and 6 patients in cohort 2 received MetMAb,15 mg/kg, and bevacizumab,15 mg/kg IV Q3W. Pre- and post-dose sera were collected for evaluation of pharmacodynamic (PD) biomarkers that could be affected by inhibition of Met and/or VEGF signaling. Results: The combination of MetMAb with bevacizumab was generally well tolerated at all doses tested. No Gr3-5 drug- related toxicities were observed. One DLT of Gr1 hemoptysis in cohort 2 was observed in a patient who had central-necrosis of pulmonary metastases. Gr2 drug-related toxicities included peripheral edema and hypoalbuminemia. The most frequently observed toxicities (>30 %) included fatigue and increased weight. The best response was stable disease, with 3 patients receiving ≥ 6 cycles. PD biomarker data will be discussed. MetMAb PK was similar to that from phase Ia and no apparent interaction with bevacizumab was observed. Conclusions: This phase Ib trial demonstrated that the combination of MetMAb and bevacizumab is generally safe and well tolerated at the recommended dose of 15mg/kg Q3W for each agent. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech

2010 Background: E is an orally active, highly potent and selective inhibitor of the epidermal growth factor receptor (EGFR). Preliminary results from both Phase I and Phase II trials of E in GBM patients have been reported (ASCO 2003, Abs#394 and ASCO 2004, Abs#1555). The purpose of this analysis is to characterize E PK in this patient population when administered with or without CYP3A4 enzyme inducing anti-epileptic drugs (EIAEDs) and to identify a dose to provide equivalent exposure during concomitant therapy in GBM patients. Methods: Intensive PK data were collected in the Phase I study and plasma trough concentration data were collected in the Phase II study at steady-state. A total of 775 E concentrations from 107 patients were available for the analysis. A population PK approach (NONMEM) was used to characterize the clinical PK in this patient population and the effect of EIAEDs on the PK of E. Results: Co-administration of EIAEDs was shown to increase the E clearance (CL/F) by 230% in GBM patients. This effect is similar to that seen in a previous drug-drug interaction study with a CYP3A4 enzyme inducer (rifampicin) in healthy volunteers. For patients with no EIAEDs, population estimates and the %CV of inter-individual variance for CL/F and Vc/F of erlotinib were 5.63 L/hr (44%) and 388 L (40%), respectively. Conclusions: Based on the modeling results, for GBM patients with EIAEDs, an estimate of erlotinib dose of 500 mg/d is needed to achieve an equivalent exposure as patients who receive the dose of 150 mg/d with no EIAEDs. The new population PK model provides an operational tool to predict E exposure during treatment, and simulate alternative dosing regimens for GBM patients. [Table: see text]

A randomized, open‐label, 2‐period crossover study was conducted to evaluate the bioequivalence of 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg (arm A, n = 42) and the oral bioavailability of the 150‐mg tablet versus a 25‐mg intravenous infusion (arm B, n = 20) in healthy subjects. The washout period was 2 weeks between treatments. Plasma concentrations of erlotinib and its active metabolite, OSI‐420, were measured after each dose. The ratios of geometric means for AUC 0‐∞ and C max of erlotinib following 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg were (1 and 0.95) within the predefined bioequivalence range of 0.80 to 1.25. The mean absolute oral bioavailability, using compartmental analysis, was estimated as 59% (95% confidence interval, 55%–63%). Overall, 6 tablets of erlotinib 25 mg are bioequivalent to a single 150‐mg tablet. Both intravenous and oral erlotinib were generally well tolerated with an estimated bioavailability of 59% following oral administration.

Background Erlotinib hydrochloride (E) as a single agent has been demonstrated to prolong survival in patients with advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. An absolute oral bioavailability (F) study of the 150 mg tablet was performed in healthy volunteers. A relatively conservative dose of 25 mg IV was selected for this study to assure safety. Using the non-compartmental approach, the absolute F was estimated to be >100%. The different half-lives (21 h oral vs. 13h i.v.) suggested possible differences in CL in the two dose groups. Objective To determine if a compartmental approach that considered the CL difference in the two dose groups would provide a more reliable estimate of F. Methods Data included 18 subjects receiving erlotinib 25 mg as a 30-minute infusion and 150 mg tablet in a 2-way randomized cross over study. Four different models were evaluated to determine the most appropriate model to fit the data. Individual F and other PK parameters were estimated by fitting oral and i.v. data simultaneously using the POSTHOC option in NONMEM. Results A two-compartment model with nonlinear elimination provided the best fit of the data and was able to account for the differences in elimination of erlotinib, presumably due to the 6-fold difference in dose. The model-based analysis provided an estimate of F of 59%, which was consistent with observed preclinical data. Conclusion The results indicate that the compartmental model provided a reasonable estimate of F of E. Clinical Pharmacology & Therapeutics (2005) 77, P37–P37; doi: 10.1016/j.clpt.2004.12.035