Selection of a phase 3 dose regimen for denosumab based on pharmacokinetic (PK), pharmacodynamic (PD), and safety data from multiple subcutaneous (SC) dosing regimens in breast cancer patients (pts) with bone metastases (BM)

Abstract

3086 Background: Receptor activator of NF-κB ligand (RANKL) is essential for osteoclast formation, function, and survival. PK and PD of denosumab (AMG 162), a fully human monoclonal IgG2 antibody to RANKL, from a randomized, double-blind, active-controlled, multidose study in breast cancer pts with BM were evaluated and modeled to assist in dose selection for the pivotal phase 3 study. Methods: Five dosing cohorts (∼40/cohort) received 30-, 120-, or 180-mg denosumab SC Q4W; 60- or 180-mg denosumab SC Q12W. Data through 12 weeks were used for PK/PD modeling and dose decisions. Validated methods were used to quantify all serum and urine analytes. The bone resorption marker uNTx (reported as uNTx/Cr ratio) was used as the PD endpoint, and population PK/PD model parameters were estimated using nonlinear mixed effects modeling methods (NONMEM). A combination of PK/PD trial simulation (TS), clinical chemistries, and safety profiles was utilized for phase 3 dose selection. Results: Exposure to denosumab increased approximately dose-proportionally for both the Q4W and Q12W schedules, and accumulation (3rd vs 1st Q4W dose) ranged from 2.37- to 2.56-fold. The population typical half-maximal inhibitory concentration (IC50) for denosumab to affect uNTx and the typical maximum suppression were estimated to be 12.2 ng/mL and 77.8%, respectively. While denosumab in all cohorts caused rapid and sustained suppression of uNTx from baseline (>60%), TS showed that for a dose of 120 mg Q4W, 97% of subjects would be expected to attain denosumab serum concentrations above their individual IC90 at steady state. TS did not suggest that higher doses (180 mg Q4W) would result in further uNTx suppression, and more asymptomatic decreases in calcium were noted in pts dosed above 120 mg Q4W. Conclusions: The PK and PD of denosumab in pts with BM are consistent with those in other pt populations and demonstrate rapid and substantial suppression of uNTx. Population PK/PD analysis and TS suggests a dose of 120mg Q4W is appropriate for use in a phase 3 program in this study population. [Table: see text]