New drug development

ABSTRACT Background PD 0332991, a selective inhibitor of CDK 4/6, prevents cellular DNA synthesis by blocking cell cycle progression. Preclinical studies in a BC cell line panel identified the luminal ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to PD 0332991 (Finn et al. 2009). Synergistic activity was also observed in vitro when combined with tamoxifen. Based on these observations, a phase 1/2 study in combination with letrozole was initiated. We present results from the randomized phase 2 portion. Methods The phase 2 portion is a two-part study; Part 1, ER + /HER2- selected; Part 2, further biomarkers. We present results from Part 1. The primary endpoint is progression-free survival (PFS); secondary endpoints include response rate, overall survival, safety, and correlative biomarker studies. Post-menopausal women with ER + /HER2- advanced BC were randomized 1:1 to receive either letrozole 2.5 mg QD plus PD 0332991 125 mg QD on Schedule 3/1 (L + P) or letrozole 2.5 mg QD alone (L). Pts continue on assigned study treatment until disease progression, unacceptable toxicity, or consent withdrawal, and are followed for tumor assessments every 2 months. Results 66 pts were randomized. Baseline characteristics were balanced between the two arms. As of the data cut-off, median duration of treatment was 47 wks for the L + P arm and 24 wks for the L arm. The most commonly reported treatment-related AEs in the combination arm were neutropenia, leukopenia, and fatigue. The response rate was 27% vs. 23% (out of 26 and 22 pts with measurable disease, L + P vs. L, respectively), clinical benefit rate (PR + SD ≥24 weeks) was 59% vs. 44%, respectively. Two vs. 7 pts had best response of progressive disease for L + P vs. L, respectively. PFS was significantly greater in the L + P arm vs. L (HR = 0.38; 95% CI, 0.17 to 0.86; p = 0.015). There were 20 vs. 8 pts ongoing on assigned treatment. Conclusions The combination of PD 0332991 and letrozole is well tolerated with encouraging clinical benefit, confirming the preferential sensitivity of ER+ BC observed in preclinical models. Disclosure R.S. Finn: Research funding from Pfizer. A. Breazna: Pfizer employee. Spouse Pfizer employee. 401k plans, restricted stock options and stock options. S.N. Ho: Employee of Pfizer, Inc.S.T. Kim: Employee of Pfizer Inc. with stock ownership. S. Randolph: Employee of Pfizer with some stock options. D.J. Slamon: Research funding from Novartis and Genetech. All other authors have declared no conflicts of interest.