On February 3, 2015, the U. S. Food and Drug Administration granted accelerated approval to palbociclib (IBRANCE, Pfizer, Inc.) for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.  
Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. In vitro palbociclib reduced cellular proliferation of ER-positive breast cancer cell lines by blocking progression of cells from G1 into S phase of the cell cycle.

The approval of palbociclib is based on a randomized, multicenter, open-label trial in postmenopausal women with ER-positive, HER2-negative, advanced (locally advanced or metastatic) breast cancer who had not received previous systemic treatment for advanced disease. The trial enrolled 165 patients randomly allocated to receive either palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg daily continuously throughout the 28-day cycle) or letrozole alone.
Among the 165 patients, 43% had received chemotherapy and 33% had received anti-hormonal therapy as a neoadjuvant or adjuvant treatment. Forty- nine percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had metastatic disease; 48% had visceral disease, 75% had bone disease and 19% had bone only disease.
The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST). Median investigator-assessed PFS was 20.2 months (95% CI 13.8, 27.5) in the palbociclib plus letrozole arm and 10.2 months (95% CI 5.7, 12.6) in the letrozole alone arm [Hazard Ratio (HR) 0.488 (95% CI 0.319, 0.748)]. The treatment effect of the combination on PFS was also supported by a retrospective radiographic independent review [HR 0.621 (95% CI: 0.378, 1.019).]  Overall response rate in patients with measurable disease (investigator assessment) was higher in the palbociclib plus letrozole compared to the letrozole alone arm (55.4% versus 39.4%).
Most common adverse reactions (greater than or equal to 10%) were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse reactions in patients receiving palbociclib plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%).
The recommended dose and schedule of palbociclib is 125 mg daily for 21 consecutive days followed by 7 days off treatment with letrozole 2.5 mg daily continuously throughout the 28-day cycle.
FDA granted palbociclib breakthrough therapy designation in April, 2013 based on preliminary evidence of clinical activity in this patient population. This accelerated approval is based on demonstration of an improvement in PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in an on-going confirmatory trial.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Page Last Updated: 02/04/2015
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