Modeling of Pharmacodynamic (PD) Biomarkers (BM) Related to CDK4/6 Inhibition and Exploratory BM-response (progression Free Survival [PFS]) Analyses in Patients with Advanced Breast Cancer.

e14528 Background: Palbociclib (PAL) is an oral inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6) approved for advanced breast cancer (ABC). In a clinical trial, the expression levels of PD BMs related to PAL effect, including thymidine kinase (TK) in serum and phosphor-Rb (pRb) and Ki67 in skin tissues, were measured at both baseline and post-treatment in patients with ABC treated with PAL plus letrozole (LET). Pharmacokinetic (PK)/PD modeling was conducted previously to characterize the longitudinal change of pRb and Ki67. The PK/PD was further evaluated for TK and exploratory analyses were conducted to evaluate the relationship between PFS and all three BMs. Methods: The present analyses used data from a Phase 1 study evaluating the PK, PD, safety and efficacy of PAL plus LET in 26 Chinese women with ABC. A 2 compartment model was used to describe the PK of PAL. A precursor-dependent indirect response model was developed to describe the TK time course after PAL treatment. PAL effect was modeled as Imax inhibitory model. Cox proportional hazard model was used to assess the correlation of PFS with three BM metrics (baseline BM, simulated lowest BM and maximum BM change in Cycle 1). Results: The BM data included 194 TK observations from 26 patients. The PK/PD models adequately described the longitudinal change of TK, and showed PAL caused TK reduction. The estimated IC50 value was 49.5 ng/mL, similar to those for pRb and Ki67. The BM-response analyses for PFS showed that correlation was found for TK. There was a significant correlation between PFS and baseline TK (BTK) and minimum TK (MTK) in Cycle 1. A longer PFS was associated with lower BTK and lower MTK. A trend for longer PFS with higher maximum TK change in Cycle 1 was observed although the relationship was not statistically significant. Conclusions: PAL exposure had significant correlation with the reduction of all three BMs. Longer PFS was associated with lower BTK and MTK. Due to the small sample size (N = 26), this analyses result need to be confirmed in a larger study.