Abstract CT101: Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18)
Authors: Finn Richard S. , Crown John P. , Lang Istvan , Boer Katalin , Bondarenko Igor M. , Kulyk Sergey O. , Ettl Johannes , Patel Ravindranath , Pinter Tamas , Schmidt Marcus , Shparyk Yaroslav V. , Thummala Anu R. , Voytko Nataliya L. , Huang Xin , Kim Sindy T. , Randolph Sophia S. , Slamon Dennis J. 
Published: May 2015

Abstract
Background: PD 0332991 (palbociclib), a selective inhibitor of CDK-4/6, prevents DNA synthesis by blocking cell cycle progression. Preclinical studies identified luminal ER+ breast cancer cell lines with elevated expression of cyclin-D1, Rb and reduced p16 expression as being associated with palbociclib sensitivity (Finn et al. 2009). In addition, synergistic activity was seen in vitro when combined with tamoxifen. As a result of these data Phase Ib safety testing was performed, and led to this randomized Phase II study using a recommended Phase II dose of palbociclib (P) 125 mg QD for 3 weeks followed by 1 week off plus letrozole (L) 2.5 mg QD continuously.
Methods: This Phase II trial was designed as a two-part study evaluating P+L in front-line ER+/HER2- metastatic breast cancer (MBC). Part 1 enrolled post-menopausal patients (pts) with this subtype using ER+/HER2- biomarkers while Part 2 enrolled pts with the same MBC subtype additionally screened for CCND1 amplification and/or loss of p16. The primary endpoint was investigator assessed progression-free survival (PFS) defined as time from randomization to objective progression or death. Secondary endpoints included objective response rate, overall survival, safety, and correlative biomarker studies. In both parts, post-menopausal women with ER+/HER2- MBC were randomized 1:1 to receive either P+L or L alone. Pts continued until disease progression, unacceptable toxicity, or consent withdrawal and were followed for tumor assessments every 2 months. The trial had 80% power to detect a 50% improvement in median PFS (hazard ratio 0.67 [P+L vs. L] with a 1-sided alpha=0.10).
Results: A total of 165 pts were randomized in this Phase II study; 66 pts in Part 1 and 99 pts in Part 2. Baseline characteristics were balanced between treatment arms. The final analysis of primary endpoint showed a statistically significant improvement in PFS for the P+L arm (20.2 months) vs. L arm (10.2 months) with hazard ratio (HR)=0.488 (95% CI: 0.319, 0.748) and 1-sided p=0.0004. The treatment effects were also demonstrated when Part 1 and Part 2 were analyzed separately (HR=0.299 [95% CI: 0.156, 0.572]; 1-sided p=0.0001 for Part 1 and HR=0.508 [95% CI: 0.303, 0.853]; 1-sided p=0.0046 for Part 2). The OS analysis with 61 events demonstrated a trend in favor of P+L vs. L (37.5 months vs. 33.3 months, respectively; HR=0.813; p=0.2105). The most common adverse events in the P+L arm were neutropenia, leukopenia, fatigue, and anemia.
Conclusions: P+L demonstrated a statistically significant improvement in PFS and showed significant clinical benefit as first-line treatment of ER+/HER2- advanced BC. A Phase III study of P+L in this same MBC population is ongoing.
Citation Format: Richard S. Finn, John P. Crown, Istvan Lang, Katalin Boer, Igor M. Bondarenko, Sergey O. Kulyk, Johannes Ettl, Ravindranath Patel, Tamas Pinter, Marcus Schmidt, Yaroslav V. Shparyk, Anu R. Thummala, Nataliya L. Voytko, Xin Huang, Sindy T. Kim, Sophia S. Randolph, Dennis J. Slamon. Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT101. doi:10.1158/1538-7445.AM2014-CT101