Palbociclib exposure-response analyses in second-line treatment of hormone-receptor positive advanced breast cancer (ABC).

Abstract

1053 Background: Palbociclib (PAL) is an oral inhibitor of cyclin-dependent kinases 4 and 6 approved for ABC. Exposure-response analyses for efficacy and safety endpoints were performed to evaluate the current PAL clinical dosing regimen (125 mg daily, 3 weeks on and 1 week off) and dose modification strategy in 2nd-line ABC. Methods: The present analyses used data from PALOMA3, a phase 3 study comparing the safety and efficacy of fulvestrant plus either PAL or placebo in 2nd-line ABC patients (PTs). A Bayesian pharmacokinetic (PK) analysis was conducted to estimate PAL PK parameters for individual PTs. Average concentration of PAL over the entire treatment (Cavg) was derived from average daily dose intensity divided by post hoc estimates of clearance for each PT. Time varying Cavg (Cavgt) was also derived to account for dose modifications up to each observation point. Kaplan-Meier method and the Cox proportional hazards model were employed to explore relationship between progression-free survival (PFS) and Cavg, Cavgt, as well as other prognostic factors. A semi-mechanistic PK-pharmacodynamic (PD) model was built to quantify the relationship between PAL concentration and absolute neutrophil count (ANC). Results: The median PFS for low and high PAL exposure groups divided according to Cavg were similar (9.47 and 10.9 months, respectively) and significantly higher than that of the control arm (4.57 months). While Cavgtwas found to be a significant predictor for PFS in univariate analysis (P-value < 0.05), this relationship was not significant in the multivariate analysis where other significant prognostic factors were also included. The PK-PD analysis for safety endpoint indicated higher PAL concentrations were associated with lower ANC, which is consistent with the fact that ANC profiles were well managed by dose modification strategies, i.e., dose interruption, delay and reduction. Conclusions: The analysis results suggested PTs were benefited similarly from fulvestrant plus PAL treatment with manageable safety profile, supporting a favorable benefit-risk profile of PAL under the current dosing regimen and dose modification strategy in 2nd-line ABC. Funding: Pfizer Inc. Clinical trial information: NCT01942135.