Abstract
PurposePF-05280014 is a biosimilar to trastuzumab (Herceptin®). Following demonstration of pharmacokinetic (PK) similarity in healthy volunteers, a comparative clinical study in patients with HER2-positive metastatic breast cancer (mBC) compared the efficacy, safety and immunogenicity of PF-05280014 and trastuzumab sourced from the EU (trastuzumab-EU), both with paclitaxel.MethodsPopulation PK of PF-05280014 and trastuzumab-EU was evaluated.ResultsOverall, 702 patients were treated: PF-05280014 (n = 349) and trastuzumab-EU (n = 353). Peak-and-trough serum drug concentration samples were collected (selected doses) following repeated intravenous administration of PF-05280014 or trastuzumab-EU. Population PK analysis was performed with drug concentration–time data to cycle 17 for each compound, using nonlinear mixed effect modeling. Potential baseline covariates (circulating HER2 concentrations, body weight, Japanese race, Eastern Cooperative Oncology Group status, number of metastatic sites and antidrug antibody status) were evaluated. Concentration–time data of PF-05280014 and trastuzumab-EU were adequately described by a two-compartment model with first-order elimination, with inter-individual variability (IIV) on clearance (CL), volumes of distribution in central compartment (V1) and peripheral compartments, and intercompartment clearance. Similar estimated PK parameters and IIV were obtained for both treatments. For PF-05280014 and trastuzumab-EU, baseline body weight was an influential covariate on CL and V1; the magnitude was comparable between treatments. PK was consistent between the limited number of Japanese and non-Japanese patients for both compounds.ConclusionsPF-05280014 and trastuzumab-EU had similar PK parameters and influential PK covariates in patients with HER2-positive mBC. These results provided further evidence in patients for PK similarity between PF-05280014 and trastuzumab-EU.Clinical trial registrationClinicalTrials.gov, NCT01989676.
Highlights
Trastuzumab (Herceptin®; Genentech, San Francisco, CA, USA) is a recombinant humanized IgG1 monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2) [1, 2]
A phase 1 study in healthy male subjects demonstrated that the pharmacokinetics (PK) of PF-05280014 were similar to both trastuzumab-US and trastuzumab-EU [6]
A total of 707 patients were enrolled in this multinational, double-blind, randomized, comparative clinical trial evaluating the efficacy, safety, PK and immunogenicity of PF-05280014 versus trastuzumab-EU in patients with HER2-positive metastatic breast cancer (mBC) in the first-line treatment setting [7]
Summary
Trastuzumab (Herceptin®; Genentech, San Francisco, CA, USA) is a recombinant humanized IgG1 monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2) [1, 2]. Biosimilars are biologic drugs that are highly similar to the corresponding approved originator (reference) biologic, with no clinically meaningful differences in quality, efficacy and safety between the two products [3]. PF-05280014 (TrazimeraTM) was recently approved by the European Medicines Agency as a biosimilar to trastuzumab sourced from the EU (trastuzumab-EU) for all. A phase 1 study in healthy male subjects demonstrated that the pharmacokinetics (PK) of PF-05280014 were similar to both trastuzumab-US and trastuzumab-EU [6]. Healthy subjects were randomized to receive a single 6 mg/kg intravenous (IV) dose of PF-05280014, trastuzumab-US or trastuzumab-EU. The 90% confidence intervals (CIs) for the ratios of exposure parameters, including maximum serum concentration (Cmax), area under the serum concentration–time profile (AUC) from time zero to the last time point with quantifiable concentration (AUCtlast) and extrapolated to infinite time (AUC0–∞), were within 80–125% for the pairwise comparisons among the three treatment groups
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