The Food and Drug Administration (FDA) has approved Kisqali (ribociclib; Novartis) 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.

Kisqali was reviewed and approved under the FDA Breakthrough Therapy designation and Priority Review programs.The approval was based on results from the Phase 3 MONALEESA-2 clinical trial which included 668 patients randomized to receive either ribociclib plus letrozole (n=334) or placebo plus letrozole (n=334); these patients received no prior systemic therapy for their advanced breast cancer. Treatment continued until disease progression or unacceptable toxicity.

Compared to letrozole alone, ribociclib plus letrozole reduced the risk of progression or death by 44% (hazard ratio [HR] 0.556 (95% CI: 0.429, 0.720; P<0.0001) at the first pre-planned interim analysis. The estimated median progression-free survival (PFS) had not been reached in the ribociclib-containing arm (95% CI: 19.3 months-not reached) and was 14.7 months in the placebo-containing arm (95% CI: 13.0–16.5 months). In the ribociclib plus letrozole group, objective response rate (ORR) in patients with measurable disease was 52.7% (95% CI: 46.6, 58.9); ORR in the letrozole only group was 37.1% (95% CI: 31.1, 43.2). 

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At a subsequent analysis with additional 11-month follow-up and progression events, a median PFS of 25.3 months for ribociclib plus letrozole and 16 months for letrozole alone was observed. Overall survival data was not yet mature and will be available at a later date.

The most common adverse reactions associated with treatment included neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain.  In addition, the prescribing information states that Kisqali has been show to prolong the QT interval in a concentration-dependent manner.

Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vitro, ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle and reduced cell proliferation in breast cancer cell lines. In studies using patient-derived estrogen receptor positive breast cancer xenograft models, the combination of ribociclib and antiestrogen (eg, letrozole) resulted in increased tumor growth inhibition compared to each drug alone. 

Kisqali is will be available in a 200mg tablet formulation in 14- and 21-count blister packs.

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