General Information

Ibrance (palbociclib) is an orally available pyridopyrimidine-derived cyclin-dependent kinase (CDK) inhibitor with antineoplastic activity.

Ibrance is specifically indicated for use in combination with letrozole for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with 1) an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men; or 2) fulvestrant in patients with disease progression following endocrine therapy

Ibrance is supplied as a capsule for oral administration. The recommended dose of Ibrance is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Ibrance should be taken with food in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle. The dose should be taken at approximately the same time each day.

If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. Ibrance capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.

Please see the drug label for recommended dose modifications based on adverse events.

Clinical Results

FDA Approval

The FDA approval of Ibrance was based on the following trials:

PALOMA 2: a randomized, open-label, multicenter study of Ibrance plus letrozole versus letrozole alone conducted in 165 postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment for their advanced disease. Randomization was stratified by disease site (visceral versus bone only versus other) and by disease-free interval (>12 months from the end of adjuvant treatment to disease recurrence versus ≤12 months from the end of adjuvant treatment to disease recurrence or de novo advanced disease). Ibrance was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Subjects received study treatment until progressive disease, unmanageable toxicity, or consent withdrawal. For subjects treated with the combination of Ibrance plus letrozole, the median PFS was 24.8 months compared to the 14.5 months of PFS in subjects who received letrozole alone. Overall response rate in subjects with measurable disease as assessed by the investigator was higher in the Ibrance plus letrozole compared to the letrozole alone arm (55.4% versus 39.4%).

PALOMA-3 was an international, randomized, double-blind, parallel group, multicenter study of Ibrance plus fulvestrant versus placebo plus fulvestrant conducted in women with HR-positive, HER2-negative advanced breast cancer, regardless of their menopausal status, whose disease progressed on or after prior endocrine therapy. A total of 521 pre/postmenopausal women were randomized 2:1 to Ibrance plus fulvestrant or placebo plus fulvestrant and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri versus postmenopausal), and presence of visceral metastases. Ibrance was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. The median PFS in the Ibrance plus fulvestrant arm was 9.5 months versus 4.6 months in the placebo plus fulvestrant arm. The objective response rate was 24.6% versus 10.9% for each arm, respectively.

To obtain FDA approval of Ibrance in males with breast cancer, Pfizer provided the results of an analysis of real-world data (RWD) from electronic health records (EHRs) as additional supportive data to characterize the use of palbociclib in combination with endocrine therapy (aromatase inhibitor or fulvestrant) in male patients with breast cancer based on observed tumor responses in this rare subset of patients with breast cancer.

Mechanism of Action

Ibrance (palbociclib) is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma protein (Rb) phosphorylation resulting in reduced E2F expression and signaling and increased growth arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens leads to increased cell senescence, which was sustained for up to 6 days following drug removal. In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling and tumor growth compared to each drug alone.