Palbociclib Plus Letrozole Achieves Impressive Results in Metastatic Breast Cancer
First-line treatment with the combination of palbociclib plus letrozole extended progression-free survival by approximately 50% in patients with metastatic estrogen receptor–positive, HER2-negative breast cancer, according to final results of a randomized phase II study presented at the American Association for Cancer Research (AACR) Annual Meeting 2014 in San Diego.
Palbociclib plus letrozole achieved progression-free survival of 20.2 months vs 10.2 months with letrozole alone (P = .0004). Overall survival was trending in favor of the combination but was not statistically significant at the time of the progression-free survival analysis.
“These data give us the confidence to move ahead with a phase III study. To put the data in perspective, no study of aromatase inhibitors alone in metastatic breast cancer showed as dramatic a progression-free survival improvement as this study,” said presenting author Richard S. Finn, MD, of the University of California, Los Angeles.
Palbociclib, being developed by Pfizer, Inc, is a first-in-class cyclin-dependent kinase (CDK) 4/6 inhibitor that inhibits cell proliferation and cellular DNA synthesis by preventing cell-cycle progression. Other companies are also pursuing CDK4 and CDK6 inhibitors in breast cancer, including Lilly (with LY2835219) and Novartis (with LEE011).
Phase II Study
The phase II study presented at the AACR Annual Meeting consisted of two parts. Part 1 randomly assigned 66 postmenopausal patients with estrogen receptor–positive, HER2-negative, locally recurrent or metastatic breast cancer to palbociclib plus letrozole or letrozole alone. Part 2 randomly assigned an additional 99 patients to the same treatment arms with the same tumor characteristics as well as two additional potential biomarkers: CCND1 amplification and/or loss of p16.
In part 1, progression-free survival was 26.1 months for the combination of palbociclib plus letrozole vs 5.7 months for letrozole alone (P < .0001). In part 2, progression-free survival was 18.1 vs 11 months, respectively (P = .0046).
Dr. Finn called attention to progression-free survival in the control arms of part 1 and 2, noting that the population enriched for CCND1 amplification and loss of p16 “behaved differently” with letrozole alone. Overall, he continued, the take-away message from this study is that estrogen receptor positivity is the most sensitive predictor of response to the novel agent in combination with letrozole.
Best overall response was 43% for the combination vs 33% for letrozole alone. Clinical benefit rate (complete and partial response plus stable disease) was 81% vs 58%, respectively.
Acceptable Toxicity
Toxicity of palbociclib in combination with letrozole was acceptable. Adverse events associated more frequently with the combination than with letrozole alone included neutropenia (grade 3 in 48%, grade 4 in 6%), leukopenia (grade 3 in 19%), fatigue, and anemia.
“These data with palbociclib plus letrozole are impressive; they are as impressive as the everolimus [Afinitor] data that led to FDA approval of that drug,” commented Patricia LoRusso, DO, Director of the Center for Experimental Therapeutics at the Barbara Ann Karmanos Cancer Institute in Detroit. Dr. LoRusso moderated the press conference where these results were presented.
Palbociclib plus letrozole will be compared with letrozole alone in a similar patient population in the phase III PALOMA-2 trial.
Dr. Finn reported no potential conflicts of interest. Study author Dennis Slamon, MD, PhD, has shares of common stocks in Pfizer.
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