Presentation Abstract

Abstract Number: CT101
Presentation Title: 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)
Presentation Time: Sunday, Apr 06, 2014, 10:15 AM -10:35 AM
Location: Hall F-G, San Diego Convention Center
Author Block: 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. UCLA, Los Angeles, CA, Irish Cooperative Oncology Research Group, Dublin, Ireland, Orszagos Onkologiai Intezet, Budapest, Hungary, Onkologia, Szent Margit Korhaz, Budapest, Hungary, Dnipropetrovsk City Multiple-Discipline Clinical Hospital, Dnipropetrovsk, Ukraine, Donetsk City Oncology Dispensary, Donetsk, Ukraine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany, Comprehensive Blood and Cancer Center, Bakersfield, CA, Petz Aladar Teaching Hospital Győr, Győr, Hungary, Department of Obstetrics and Gynecology, University Mainz, Mainz, Germany, Lviv State Oncologic Regional Treatment and Diagnostic Center, Ukraine, Lviv, Ukraine, Comprehensive Cancer Centers of Nevada, Henderson, NV, Kyiv City Clinical Oncology Center, Kyiv, Ukraine, Pfizer Oncology, San Diego, CA, University of California, Los Angeles, CA
Abstract Body: 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.