What is Ribociclib (cyclin-dependent kinase 4/6 inhibitor)?

What is Ribociclib?

Ribociclib (marketed as KISQALI) is an orally bioavailable, highly specific cyclin-dependent kinase (CDK) 4/6 inhibitor approved for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer in combination with endocrine therapy. 1

Mechanism of Action

Ribociclib works by inhibiting CDK4 and CDK6, which are activated upon binding to D-cyclins and regulate cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). 1 By decreasing pRb phosphorylation, ribociclib arrests cells in the G1 phase of the cell cycle and reduces proliferation in breast cancer models. 1 In preclinical studies, combination therapy with ribociclib and antiestrogens (such as letrozole or fulvestrant) resulted in increased tumor growth inhibition compared to each drug alone. 1

Chemical Properties

The chemical name is 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate, with a molecular weight of 552.64 g/mol (434.55 g/mol free base). 1 Ribociclib succinate appears as a light yellow to yellowish brown crystalline powder. 1

Clinical Indications and Evidence

Advanced/Metastatic Breast Cancer

The NCCN panel has designated aromatase inhibitor (AI) in combination with CDK 4/6 inhibitors as a category 1 first-line option for postmenopausal women and premenopausal women with ovarian ablation/suppression with HR+/HER2- recurrent/stage IV breast cancer. 2

• In the MONALEESA-2 trial (postmenopausal women, n=668), ribociclib plus letrozole improved progression-free survival (PFS) to 25.3 months versus 16.0 months with letrozole alone (HR 0.56; 95% CI, 0.45-0.70), with an objective response rate (ORR) of 43% versus 29%. 2

• In the MONALEESA-7 trial (premenopausal/perimenopausal women, n=672), ribociclib with goserelin plus either a nonsteroidal AI or tamoxifen improved median PFS to 24 months versus 13 months (HR 0.55; 95% CI, 0.4-0.69). 2 At 3.5 years, overall survival improved to 70% versus 46% (HR 0.71; 95% CI, 0.54-0.95). 2

Early Breast Cancer (Adjuvant Setting)

• The NATALEE trial evaluated 3 years of ribociclib 400 mg once daily (3 weeks on/1 week off) plus endocrine therapy versus endocrine therapy alone in stage II-III HR+/HER2- early breast cancer. 2 At median follow-up of 27.7 months, ribociclib plus endocrine therapy improved invasive disease-free survival (HR 0.75; 95% CI, 0.62-0.91), with 3-year rates of 90.4% versus 87.1%. 2

Dosing and Administration

• Advanced/metastatic breast cancer: 600 mg once daily for 21 consecutive days followed by 7 days off (28-day cycle). 1
• Early breast cancer (adjuvant): 400 mg once daily for 21 consecutive days followed by 7 days off. 2
• Hepatic impairment: No adjustment needed for mild impairment (Child-Pugh A); reduce to 400 mg for moderate/severe impairment (Child-Pugh B/C) in advanced disease. 1
• Severe renal impairment: Reduce starting dose to 200 mg. 1

Safety Profile and Adverse Events

Common Adverse Events

• Neutropenia is the most frequent grade 3/4 adverse event, occurring in 62% of patients receiving ribociclib plus letrozole versus 1.2% with letrozole alone in MONALEESA-2. 2 In NATALEE, grade 3+ neutropenia occurred in 43.8% versus 0.8%. 2

• Leukopenia occurred in 21.3% (grade 3/4) with ribociclib plus letrozole versus 0.9% with letrozole alone. 2

• Hepatotoxicity: Abnormal liver function tests occurred in 10.2% (grade 3/4) versus 2.4% with letrozole alone. 2 Liver-related adverse events were the most frequent cause of ribociclib discontinuation (8.9%) in NATALEE. 2

• QT prolongation: In early breast cancer patients, the estimated mean QTcF interval change from baseline was 10.0 ms (90% CI: 8.0,11.9) at steady-state with ribociclib 400 mg. 1 In advanced breast cancer, QTcF changes ranged from 22.0-34.7 ms depending on combination therapy. 1 Any-grade QT prolongation occurred in 5.2% of NATALEE patients. 2

• Other common adverse events include nausea (23% vs 7.5%), headache (22% vs 16.5%), and fatigue (21.9% vs 12.7%) compared to endocrine therapy alone. 2

Important Drug Interactions

Ribociclib is a potent CYP3A4 inhibitor, creating significant risk when combined with CYP3A4-metabolized drugs like alprazolam (Xanax). 3 The combination poses serious risks including increased sedation, respiratory depression, and CNS toxicity. 3 Alprazolam should be discontinued before initiating ribociclib, with gradual tapering over 2-4 weeks. 3 If concurrent use is unavoidable, reduce alprazolam dose by at least 75% and monitor intensively. 3

Pharmacokinetics

• Ribociclib exhibits over-proportional increases in exposure across dose ranges. 1
• Time to maximum concentration (Tmax) is 1-4 hours. 1
• Mean absolute bioavailability is 65.8% after a single 600 mg dose. 1
• Steady-state is achieved after 8 days with mean accumulation ratio of 2.5. 1
• Mean half-life at the recommended dose is 32.6 hours. 4
• Protein binding is approximately 70%. 1

Clinical Pearls

• Treatment with ribociclib maintains health-related quality of life and significantly reduces pain scores in patients with advanced breast cancer. 2
• The safety profile is consistent across age groups, with no overall differences observed between older (≥65 years) and younger adults. 1
• Ribociclib demonstrated complete clinical response in case reports of locally advanced, pulmonary metastatic HR+/HER2- breast cancer with Ki67 expression of 90%. 5