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includes suggestions for Palbociclib
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Approval Status: FDA Approved February 2015
Specific Treatments: ER-positive, HER2-negative breast cancer
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 estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
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.
The FDA approval of Ibrance was based on 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 20.2 months compared to the 10.2 months of PFS in subjectswho 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%).
Adverse effects associated with the use if Ibrance may include, but are not limited to, the following:
- upper respiratory infection
- decreased appetite
- peripheral neuropathy
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.