What is ribociclib?

What is Ribociclib?

Ribociclib is an oral, selective cyclin-dependent kinase (CDK) 4/6 inhibitor used in combination with endocrine therapy for treating hormone receptor-positive, HER2-negative breast cancer in both early and advanced/metastatic settings. 1

Mechanism of Action

Ribociclib works by inhibiting CDK4 and CDK6, which are kinases activated upon binding to D-cyclins that drive cell cycle progression and cellular proliferation. 1 The drug specifically:

• Blocks phosphorylation of the retinoblastoma protein (pRb), resulting in G1 phase cell cycle arrest and reduced proliferation in breast cancer cells 1
• Restores Rb-mediated cell cycle control, preventing uncontrolled tumor cell division 2
• Demonstrates synergistic effects when combined with antiestrogen therapies (letrozole, fulvestrant) in preclinical models, showing greater tumor growth inhibition than either agent alone 1

Clinical Indications

Advanced/Metastatic Breast Cancer

Ribociclib is approved at 600 mg once daily (3 weeks on/1 week off) in combination with aromatase inhibitors or fulvestrant for HR-positive, HER2-negative advanced or metastatic breast cancer. 3

• In postmenopausal women receiving ribociclib plus letrozole as first-line therapy, median progression-free survival improved to 25.3 months versus 16.0 months with letrozole alone (HR 0.56) 3
• In premenopausal women (MONALEESA-7 trial), ribociclib plus goserelin and either an aromatase inhibitor or tamoxifen improved median PFS to 24 months versus 13 months (HR 0.55), with 3.5-year overall survival of 70% versus 46% (HR 0.71) 3

Early Breast Cancer (Adjuvant Setting)

Ribociclib 400 mg once daily (3 weeks on/1 week off) for 3 years plus endocrine therapy may be offered to patients with stage II-III HR-positive, HER2-negative early breast cancer at high risk of recurrence. 3

• The NATALEE trial demonstrated 3-year invasive disease-free survival rates of 90.4% with ribociclib versus 87.1% with endocrine therapy alone (HR 0.75), representing a 3.3% absolute benefit 3
• ASCO guidelines characterize this recommendation as conditional (not strong), pending longer-term follow-up data and regulatory updates 3
• For patients meeting criteria for both monarchE (abemaciclib) and NATALEE trials, ASCO favors abemaciclib due to longer follow-up, deepening benefit over time, shorter treatment duration (2 versus 3 years), and FDA approval in the adjuvant setting 3

Pharmacokinetics

• Oral bioavailability: 65.8% at 600 mg dose 1, 2
• Time to peak concentration: 1-4 hours (median 2.4 hours) 1, 2
• Half-life: Approximately 32 hours 1, 2
• Steady-state: Achieved after 8 days with mean accumulation ratio of 2.5 1
• Metabolism: Primarily hepatic via CYP3A4 (~84% of elimination) 2
• Protein binding: Approximately 70% 1

Key Adverse Events

Most Common Toxicities

Grade 3/4 neutropenia is the most frequent serious adverse event, occurring in 43.8% to 62% of patients depending on the regimen. 3

• Neutropenia (grade 3/4): 43.8% to 62% 3
• Leukopenia (grade 3/4): 14% to 21.3% 3
• Hepatotoxicity (grade 3/4): 8.3% to 10.2%, the most common cause of drug discontinuation 3
• QT prolongation: Concentration-dependent increases in QTcF interval; any-grade QT prolongation in 5.2% of patients 3, 1
• Common any-grade events: Nausea (23%), headache (22%), fatigue (21.9%) 3

Important Safety Monitoring

• QTcF interval monitoring is required due to dose-dependent QT prolongation (mean increase of 10.0 ms at 400 mg dose, 22-23.7 ms at 600 mg dose) 1
• Avoid concurrent use with strong CYP3A inhibitors/inducers due to significant drug-drug interactions 4

Dosing Considerations

• Standard dose for advanced disease: 600 mg once daily, 3 weeks on/1 week off 3
• Adjuvant dose for early disease: 400 mg once daily, 3 weeks on/1 week off 3
• Dose reductions available: 400 mg and 200 mg for toxicity management 1, 2
• Hepatic impairment: 400 mg starting dose for moderate/severe impairment in advanced disease 1
• Severe renal impairment: 200 mg starting dose 1