Abstract CT048: Biomarker analysis from a phase 1 study of palbociclib (PAL) plus letrozole (L) as first-line treatment for ER+/HER2– advanced breast cancer (ABC) in Chinese women
Authors: Xu* Binghe , Zhang* Qingyuan , Li* Huiping , Sun Wan , Li Wei , Wang Shusen , Liao Ning , Shen Peng , Shao Bin , Zhao Wenhui , Liu Yuan , Li Vincent (Bai) , Linn Carlos , Yan Ping , Plotka Anna , Jiang John , Wang Diane D. 
Published: August 2018

Abstract
Background
The cyclin-dependent kinase (CDK) 4/6 inhibitor PAL is approved for treatment of estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2–) ABC in combination with endocrine therapy. This ongoing, phase 1, open-label, single-arm study (NCT02499146) is evaluating the pharmacokinetics, safety, and efficacy of PAL+L as first-line treatment for ER+/HER2– ABC in Chinese women. The longitudinal alterations of multiple pharmacodynamic biomarkers related to PAL mechanism of action and cell cycle modulation were also characterized in this study.
Methods
From Cycle (C) 1, Day (D) 1, patients received PAL 125 mg/d 3 wk on followed by 1 wk off plus L 2.5 mg/d continuously. Skin biopsies (SBs) and blood samples for biomarker evaluation were collected after a single dose (SD) of PAL in a lead-in phase and after PAL dose on C1D21 (at steady state). SB as a tumor tissue surrogate for Ki67 and pRb expression were collected predose and on 2 randomly assigned schedules: (1) 24 h after SD and on days 22, 24 and 26 of C1; (2) 10 h after SD and on days 21, 23 and 25 of C1. Serum samples for thymidine kinase (TK) evaluation as a marker for cell cycle modulation were collected predose and up to 120 h after SD, on D 21–26 of C1, and D1 of C2.
Results
Out of 26 patients, 25 had an evaluable baseline and ≥1 postdose pRb and Ki67 value; 26 blood samples from baseline, 156 from the lead-in phase, and 222 after multiple-doses were analyzed for TK activity, including 4, 54, and 153 samples, respectively, below the limit of quantification. Skin expression levels of pRb were reduced instantly from baseline after a SD of PAL+L and remained low at steady-state levels of PAL following multiple doses, then rebounded back to or higher than baseline level during the off treatment period. A similar pattern was observed for skin Ki67 levels and serum TK activity, but both had a delayed reduction and rebounding during treatment and the off treatment period, respectively.
Conclusions
The on-target effect of PAL measured by longitudinal alterations of Ki67, pRb, and TK activity consistently demonstrated CDK4/6 inhibition and subsequent prohibition of cell cycle progression by PAL. TK activity measured in blood could potentially be used to assess cell cycle modulation by PAL.*equal contributor
Citation Format: Binghe Xu*, Qingyuan Zhang*, Huiping Li*, Wan Sun, Wei Li, Shusen Wang, Ning Liao, Peng Shen, Bin Shao, Wenhui Zhao, Yuan Liu, Vincent (Bai) Li, Carlos Linn, Ping Yan, Anna Plotka, John Jiang, Diane D. Wang. Biomarker analysis from a phase 1 study of palbociclib (PAL) plus letrozole (L) as first-line treatment for ER+/HER2– advanced breast cancer (ABC) in Chinese women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT048.