SAN DIEGO – Palbociclib, a first-in-class cyclin-dependent kinase 4/6 inhibitor, in combination with letrozole, significantly improved median progression-free survival in patients with advanced estrogen receptor–positive, human epidermal growth factor receptor 2–negative breast cancer in the first-line setting.
In preclinical studies, palbociclib, previously known as PD 0332991, "has been shown to block the transition from G1 to S in the cell cycle," Dr. Richard S. Finn said during a press briefing at the annual meeting of the American Association for Cancer Research. "That’s a place where CDK 4 and 6 play a critical role in regulating cell metabolism. What is important to note is that palbociclib, unlike prior CDK inhibitors, is very specific for CDK 4 and 6. Earlier [nonspecific] CDK inhibitors had trouble in clinical development."
In a study supported by Pfizer Inc., which is developing palbociclib, Dr. Finn of the University of California, Los Angeles, and his associates conducted an open-label, randomized, phase II study of palbociclib in combination with letrozole vs. letrozole alone for first-line treatment of ER-positive, HER2-negative advanced breast cancer.
©2014 AACR/Todd Buchanan
Dr. Richard S. Finn
The study, known as PALOMA-1, included 165 patients and was conducted in two parts. Part one included 66 postmenopausal women with ER-positive/HER2-negative breast cancer, while part two included 99 postmenopausal women with the same cancer subtype who were additionally screened for CCND1 amplification and/or loss of p16. Women in both study arms were randomized 1:1 open label to letrozole vs. palbociclib 125 mg on a 3-week-on, 3-week-off course and were followed for tumor assessments every 2 months. The primary endpoint was investigator-assessed progression-free survival defined as the time from randomization to objective progression or death.
The median age of the patients was 64 years, and about one-third had received prior hormone replacement therapy in the adjuvant setting. The median progression-free survival was 10.2 months among patients who received letrozole alone, compared with 20.2 months among patients who received letrozole plus palbociclib. This difference reached statistical significance with a hazard ratio of 0.488, or a 51% decrease in the risk of progression with the addition of palbociclib (P = .0004), Dr. Finn reported.
In secondary measures, the researchers observed a benefit of letrozole plus palbociclib, compared with letrozole only, in terms of the objective response rate among all randomized patients (43% vs. 33%, respectively), the objective response rate among patients with measurable disease (55% vs. 39%), and in the clinical benefit rate (81% vs. 58%).
The median overall survival increased from 33.3 months among patients in the letrozole-only arm to 37.5 months among patients in the letrozole-plus-palbociclib arm. That translated into a hazard ratio of 0.813, "which at this time is not statistically significant," Dr. Finn noted.
The most common adverse events were neutropenia, leukopenia, and fatigue. "This neutropenia is not the type we see with chemotherapy," he said. "It is self limited and recovers quickly. We did not see neutropenic fever."
A randomized phase III study is under way to confirm these findings in a similar patient population.
In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, characterized the findings as impressive. "This is just as impressive as the everolimus data that led to a subsequent phase III [trial] that led to subsequent approval of that drug," she said.
The study was supported by Pfizer. Dr. Finn disclosed that he has received research support from the company. Dr. LoRusso disclosed that she has received research funding from Agios Pharmaceuticals.