Introduction
Kisqali (ribociclib) is an oral targeted therapy approved by the FDA for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. It belongs to the class of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and is used in combination with aromatase inhibitors or fulvestrant. Kisqali represents a significant advancement in the management of advanced breast cancer, demonstrating improved progression-free survival and overall survival in clinical trials.
Mechanism of Action
Ribociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). These kinases, when activated by cyclin D, phosphorylate and inactivate the retinoblastoma (Rb) protein, promoting cell cycle progression from G1 to S phase. By inhibiting CDK4/6, ribociclib prevents Rb phosphorylation, thereby maintaining Rb in its active, growth-suppressive state. This results in G1 phase arrest and ultimately inhibits cellular proliferation in Rb-positive cancer cells. The drug specifically targets the dysregulated cell cycle progression that characterizes many cancer cells, particularly in HR+ breast cancer.
Indications
Kisqali is indicated in combination with:
- An aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with HR+/HER2- advanced or metastatic breast cancer
- Fulvestrant for postmenopausal women with HR+/HER2- advanced or metastatic breast cancer as initial endocrine-based therapy or following disease progression on endocrine therapy
Dosage and Administration
Standard dosing: 600 mg orally once daily for 21 consecutive days followed by 7 days off treatment (28-day cycle) Administration:- Taken with or without food
- Tablets should be swallowed whole with water
- If a dose is missed or vomited, do not make up the dose; resume with the next scheduled dose
- Based on hematologic and non-hematologic toxicities
- First dose reduction: 400 mg daily
- Second dose reduction: 200 mg daily
- Discontinue if unable to tolerate 200 mg daily
- Hepatic impairment: Reduce dose in patients with severe impairment (Child-Pugh C)
- Renal impairment: No dose adjustment required for mild to moderate impairment; use caution in severe impairment
- Geriatric patients: No specific dose adjustment required
Pharmacokinetics
Absorption: Median Tmax is approximately 1-4 hours post-dose. Administration with food does not significantly affect exposure. Distribution: Mean apparent volume of distribution is 1090 L. Protein binding is approximately 70%. Metabolism: Primarily metabolized via CYP3A4-mediated oxidation. Major metabolites include LEQ803 and CCI284. Elimination: Mean elimination half-life is 32.6 hours. Approximately 69% of the dose is excreted in feces (17% as unchanged drug) and 23% in urine (<1% as unchanged drug).Contraindications
- Hypersensitivity to ribociclib or any component of the formulation
- Concomitant use with strong CYP3A inhibitors
- Patients with QT interval >450 msec or certain cardiac conditions
- Severe hepatic impairment when combined with certain aromatase inhibitors
Warnings and Precautions
QT interval prolongation: Kisqali can prolong the QT interval in a dose-dependent manner. Obtain ECG and electrolytes prior to initiation, during dose escalation, and as clinically indicated. Hepatotoxicity: Elevations in transaminases and bilirubin have been observed. Monitor liver function tests prior to initiation and every 2 weeks for the first two cycles, then as clinically indicated. Neutropenia: Severe neutropenia may occur. Monitor complete blood counts prior to initiation, every 2 weeks for the first two cycles, and as clinically indicated. Embryo-fetal toxicity: Can cause fetal harm. Advise patients of reproductive potential to use effective contraception during treatment and for at least 3 weeks after the last dose. Interstitial lung disease/pneumonitis: Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis.Drug Interactions
Strong CYP3A inhibitors: Contraindicated (e.g., ketoconazole, itraconazole, clarithromycin) Moderate CYP3A inhibitors: Avoid concomitant use or reduce Kisqali dose (e.g., erythromycin, diltiazem, fluconazole) CYP3A inducers: Avoid concomitant use (e.g., rifampin, carbamazepine, St. John's wort) Drugs that prolong QT interval: Use with caution and monitor ECG Acid-reducing agents: No significant interaction expectedAdverse Effects
Very common (≥10%):- Neutropenia (75%)
- Nausea (52%)
- Infections (50%)
- Fatigue (37%)
- Diarrhea (35%)
- Alopecia (33%)
- Vomiting (29%)
- Constipation (25%)
- Headache (22%)
- Back pain (21%)
- Rash (17%)
- Anemia (16%)
- Leukopenia (16%)
- Increased ALT (13%)
- Increased AST (12%)
- Thrombocytopenia (10%)
- Severe neutropenia (6%)
- QT prolongation (3%)
- Hepatotoxicity (10%)
- Pneumonitis (<1%)
- Venous thromboembolism (2%)
Monitoring Parameters
- ECG and electrolytes at baseline, during dose escalation, and as clinically indicated
- Complete blood counts every 2 weeks for the first two cycles, then at the beginning of each subsequent cycle
- Liver function tests at baseline, every 2 weeks for the first two cycles, then as clinically indicated
- Renal function at baseline and periodically
- Signs and symptoms of infection
- Pulmonary symptoms
- Response to therapy (imaging, tumor markers)
Patient Education
- Take Kisqali at approximately the same time each day
- Do not crush, break, or chew tablets
- Report any signs of infection (fever, chills)
- Immediately report palpitations, dizziness, or fainting
- Report yellowing of skin or eyes, dark urine, or abdominal pain
- Use effective contraception during treatment and for at least 3 weeks after last dose
- Inform all healthcare providers about Kisqali use
- Do not start new medications without discussing with oncology team
- Adhere to scheduled laboratory monitoring appointments
References
1. US Food and Drug Administration. Kisqali prescribing information. 2023. 2. Hortobagyi GN, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016;375(18):1738-1748. 3. Slamon DJ, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2020;382(6):514-524. 4. Tripathy D, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7). Lancet Oncol. 2018;19(7):904-915. 5. National Comprehensive Cancer Network. Breast Cancer Guidelines Version 3.2023. 6. Novartis Pharmaceuticals. Kisqali clinical trial data on file.