Pharmacokinetics of MEDI4736, an Anti-PD-L1 Monoclonal Antibody, in Advanced Solid Tumors
MEDI4736 is a human immunoglobulin G1 kappa (IgG1?) monoclonal antibody directed against human programmed death ligand 1 (PD-L1). MEDI4736 blocks inhibitory interaction of PD-L1 with the PD-1 (CD279) and B7-1 (CD80) molecules, and enhances T-cell activation.
The primary objectives of the analysis presented by Falman and colleagues (ASCO 2014; Abstract 2602) were to assess the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of MEDI4736 in patients with advanced solid tumors, including non-small-cell lung cancer, melanoma, head and neck, pancreatic, gastroesophageal, triple-negative breast cancer, and hepatocellular carcinoma. This phase 1 study is evaluating the safety, tolerability, and PK of MEDI4736 given at doses of 0.1, 0.3, 1.0, 3.0, and 10 mg/kg every 2 weeks, as well as 15 mg/kg every 3 weeks (Figure).
A total of 38 patients provided evaluable data for the PK assessment. PK parameters, including peak concentration (Cmax) and area under the concentration-time curve from 0 to 14 days (AUC [0-14]), were estimated after the first dose of MEDI4736. Cmax increased in an approximately dose-proportional manner over the dose range tested. In contrast, AUC [0-14] increased in a greater than dose-proportional manner that approached linearity at doses of 3 mg/kg every 2 weeks and higher, suggesting that MEDI4736 exhibits nonlinear PK. Researchers hypothesized that this may be due to saturable target-mediated clearance.
Figure: MEDI4736 Serum PK Profiles (Mean ± Standard Deviation)
Their analysis of the PD of MEDI4736 showed concentration-dependent target engagement as demonstrated by suppression of serum PD-L1. To date, no immunogenicity has been noted at the dose of 10 mg/kg every 2 weeks.
Falman and colleagues concluded that the 10-mg/kg dose of MED4736 is expected to yield concentrations that fully suppress PD-L1 throughout the dosing interval. It is this dose of MEDI4736 that is currently being evaluated in multiple trials of solid tumors.