Palbociclib (PAL) is approved for the treatment of HR+, HER2- ABC in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women or with fulvestrant in women with disease progression following endocrine therapy based on major progression-free survival (PFS) improvement in phase III studies. An exposure response analysis was conducted to evaluate how the changes in PAL exposure (PAL-E), e.g. due to the dose modifications, would affect the PFS.

Data from PALOMA 2, a phase 3 study comparing the efficacy and safety of letrozole plus PAL (PAL+L) to letrozole plus placebo (L) in ABC patients (PTs), were used. The apparent PAL clearance (CL/F) for each PT was obtained from a population pharmacokinetic analysis. The individual PAL-E over the entire treatment (Cavg) was calculated using average daily dose intensity (ADI) and CL/F. PTs in the PAL+L group were divided into 4 quantiles (Q1, Q2, Q3, and Q4) based on their Cavg, and the median PFS in each quantile was compared to that of L using Kaplan-Meier plot. To account for the changes in PAL-E over time due to dose modifications during treatment, a time-varying PAL-E (Cavgt) was calculated using ADI and CL/F at each PFS time. The relationship between PFS and Cavgt was evaluated using Cox proportional hazard model. Univariate analyses were first conducted to identify any significant prognostic factors and the effect of Cavgt on PFS. Multivariate analysis was conducted to evaluate relationship between PFS and Cavgt when all significant prognostic factors identified from the univariate analysis were included in the model to account for their potential confounding effects.

The median PFS were 14.5, 24.9, 27.7, 25.7, and 24.0 months for patients in the L, Q1, Q2, Q3, and Q4, respectively, indicating similar PFS across all exposure quartiles. The identified significant prognostic factors from univariate analysis were Ki67 score, age, baseline AST, baseline tumor size, baseline alkaline phosphatase, and baseline albumin levels. The estimated coefficients for Cavgt were -0.00377 and -0.00224 in univariate and multivariate analysis, respectively. The effect of PAL-E on PFS was not statistically significant (p <0.05).

PFS was not found to be associated with Cavgt, suggesting that PTs with different PAL-E in P+L benefited similarly and the changes in PAL-E resulted from dose modifications in the trial would not significantly affect the efficacy. However, the impacts on efficacy are unknown for any other unstudied dose modifications algorithm.

Citation Format: Zheng J, Yu Y, Durairaj C, Amantea M, Dieras V, Finn R, Wang D. Palbociclib exposure-response analyses in the treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-21.