The U.S. Food and Drug Administration has granted accelerated approval to palbociclib (Ibrance) in combination with letrozole for the treatment of postmenopausal women with estrogen receptor–positive, HER2-negative metastatic breast cancer who have not yet received an endocrine-based therapy.

Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. In vitro palbociclib reduced cellular proliferation of estrogen receptor–positive breast cancer cell lines by blocking progression of cells from the G1 into the S phase of the cell cycle.

“The addition of palbociclib to letrozole provides a novel treatment option to women diagnosed with metastatic breast cancer,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Clinical Trial Results

The approval was based on the results of a randomized, multicenter, open-label trial in 165 postmenopausal women with estrogen receptor–positive, HER2-negative, locally advanced or metastatic breast cancer who had not received previous systemic treatment for advanced disease. Patients were randomly assigned to receive either palbociclib (125 mg/d for 21 days, followed by 7 days off treatment) plus letrozole (2.5 mg/d continuously throughout the 28-day cycle) or letrozole alone.

Among the 165 patients, 43% had received chemotherapy and 33% had received antihormonal therapy as a neoadjuvant or adjuvant treatment; 49% of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had metastatic disease.

Participants treated with palbociclib plus letrozole had a median progression-free survival of 20.2 months (95% confidence interval [CI] = 13.8–27.5), compared to about 10.2 months (95% CI = 5.7–12.6) in patients receiving only letrozole (hazard ratio [HR] = 0.488, 95% CI = 0.319–0.748). The treatment effect of the combination on progression-free survival was also supported by a retrospective radiographic independent review (HR = 0.621, 95% CI = 0.378–1.109). The overall response rate in patients with measurable disease was higher in the palbociclib-plus-letrozole arm compared to the letrozole-alone arm (55.4% vs 39.4%). Information on overall survival is not available at this time.

The most common side effects of the drug 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 the combination were pulmonary embolism (4%) and diarrhea (2%). Health-care professionals should inform patients of these risks.

It is recommended that treatment begin with a 125-mg dose for 21 days, followed by 7 days without treatment. Health-care professionals are advised to monitor complete blood cell count prior to the start of therapy and at the beginning of each cycle, as well as on day 14 of the first two cycles, and as clinically indicated.

Approval History

The FDA granted palbociclib Breakthrough Therapy designation in April 2013 based on preliminary evidence of clinical activity in this patient population. It also received a priority review, which provides for an expedited review of drugs intended to provide a significant improvement in safety or effectiveness in the treatment of a serious condition or meet an unmet medical need. Palbociclib is being approved more than 2 months ahead of the prescription drug user fee goal date of April 13, 2015.

This accelerated approval is based on demonstration of an improvement in progression-free survival. See  this issue's In the Clinic for a comprehensive overview of palbociclib in combination with letrozole for advanced breast cancer. ■