On March 13, 2017, the U.S. Food and Drug Administration approved ribociclib (KISQALI®, Novartis Pharmaceuticals Corp.), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
Approval was based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2), in post-menopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer who received no prior therapy for advanced disease. A total of 668 patients were randomized to receive either ribociclib plus letrozole (n=334) or placebo plus letrozole (n=334). Ribociclib 600 mg or placebo was administered orally once daily for 21 consecutive days, followed by 7 days off, with letrozole 2.5 mg administered orally once daily for 28 days. Treatment continued until disease progression or unacceptable toxicity.
A pre-planned interim efficacy analysis demonstrated an improvement in PFS (investigator-assessed) with hazard ratio of 0.556 (95% CI: 0.429, 0.720; p<0.0001). The estimated median PFS had not been reached in the ribociclib-containing arm and was 14.7 months in the placebo-containing arm. Objective response rate (ORR) in patients with measurable disease was 52.7% (95% CI: 46.6, 58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI: 31.1, 43.2) in the placebo plus letrozole arm. Overall survival data are immature.
The most common adverse reactions (ARs) observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. The most common grade 3 or 4 ARs (reported in >2%) were neutropenia, leukopenia, abnormal liver function tests, lymphopenia, and vomiting. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner (refer to details in Warning and Precautions section of the label).
The recommended starting dose of ribociclib is 600 mg orally (three 200 mg tablets) taken once daily with or without food for 21 consecutive days followed by 7 days off treatment.
Full prescribing information for ribociclib is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209092s000lbl.pdf
FDA granted this application a priority review and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
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).