What is ribociclib (cyclin-dependent kinase 4/6 inhibitor) and its side effects?

What is Ribociclib and Its Side Effects

Ribociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor approved for treating hormone receptor-positive, HER2-negative breast cancer in combination with endocrine therapy, demonstrating significant survival benefits but requiring careful monitoring for neutropenia, hepatotoxicity, and QT interval prolongation. 1

Mechanism of Action

Ribociclib inhibits CDK4 and CDK6 kinases, which regulate cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). 1 By blocking these kinases, ribociclib arrests cancer cells in the G1 phase of the cell cycle, preventing proliferation in hormone receptor-positive breast cancer models. 1 The drug demonstrates enhanced tumor growth inhibition when combined with antiestrogen therapies like letrozole or fulvestrant compared to either agent alone. 1

Clinical Indications and Efficacy

Metastatic/Advanced Breast Cancer

Ribociclib combined with endocrine therapy is the preferred first-line treatment for most patients with HR-positive, HER2-negative metastatic breast cancer, including those with visceral disease and high-risk features. 2

• In premenopausal women (MONALEESA-7), ribociclib plus endocrine therapy with ovarian suppression achieved a median progression-free survival (PFS) of 23.8 months versus 13.0 months with placebo (HR 0.55, P<0.0001). 2
• Overall survival at 42 months was 70.2% with ribociclib versus 46.0% with placebo (HR 0.71, P=0.00973). 2
• In postmenopausal women (MONALEESA-2), ribociclib plus letrozole significantly improved PFS with an estimated 12-month PFS rate of 82% versus 66% with placebo. 2
• When combined with fulvestrant (MONALEESA-3), median PFS was 20.5 months versus 12.8 months with placebo (HR 0.593, P<0.001), with a 28% reduction in risk of death. 2

Early Breast Cancer

The NATALEE trial demonstrated improved invasive disease-free survival with ribociclib in high-risk early breast cancer, though overall survival data remain immature and the benefit-to-toxicity ratio in this curative setting requires careful consideration. 2, 1

Side Effects and Safety Profile

Most Common Adverse Events

Neutropenia is the most frequent and significant toxicity, occurring in 61-63.5% of patients as grade 3/4 events, requiring systematic blood count monitoring. 2

Hematologic Toxicities

• Neutropenia (grade 3/4): 61-63.5% of patients versus 4-4.5% with placebo 2
• Leukopenia (grade 3/4): 14% versus 1% with placebo 2
• Blood counts should be monitored on day 14 of the first two cycles and at the start of each 28-day cycle, with dose delays and reductions for management 2

Hepatobiliary Toxicity

• Elevated ALT (grade 3/4): 5% versus 1% with placebo 2
• Hepatobiliary toxic effects (grade 3/4): 11% versus 6.8% with placebo after median 2 years of treatment 2
• Ribociclib has a higher incidence of liver function test abnormalities compared to other CDK4/6 inhibitors and should be avoided in patients with significant hepatic impairment 3

Cardiac Toxicity

• QT interval prolongation (grade 3/4): 1.8% versus 1.2% with placebo 2
• Mean QTcF interval increase of 22-23.7 ms at steady-state with 600 mg dose in advanced breast cancer 1
• Mean QTcF interval increase of 10.0 ms with 400 mg dose in early breast cancer 1
• Ribociclib should be prudently avoided in patients with cardiac morbidities or risk factors for QTc prolongation, including drug interactions 3

Gastrointestinal and Other Common Effects

• Nausea, diarrhea, vomiting, and fatigue occur in more than 20% of patients 4
• Alopecia, constipation, headache, and back pain are also common 4
• Serious adverse events related to treatment occurred in 4-11.2% of patients depending on the combination used 2

Dosing and Administration

The standard starting dose is 600 mg once daily for 21 days followed by 7 days off in a 28-day cycle for advanced/metastatic disease, or 400 mg daily for 21 days on/7 days off for early breast cancer. 1

• Dose reductions to 400 mg and 200 mg are effective for managing toxicity while maintaining efficacy 5
• Patients with moderate to severe hepatic impairment should start at 400 mg 1
• Patients with severe renal impairment should start at 200 mg 1
• No dose adjustment needed for mild hepatic or mild-to-moderate renal impairment 1

Drug Interactions

Strong CYP3A4 inhibitors increase ribociclib exposure by 3.2-fold (AUC) and should be avoided; strong CYP3A4 inducers decrease exposure by 89% and should also be avoided. 1

• Moderate CYP3A4 inhibitors increase exposure by 1.1-1.2-fold 1
• Ribociclib increases midazolam (CYP3A4 substrate) exposure by 3.8-5.2-fold, indicating significant drug interaction potential 1
• No clinically relevant interactions with letrozole, anastrozole, exemestane, or fulvestrant 1
• Tamoxifen exposure increases approximately 2-fold when combined with ribociclib 600 mg, though ribociclib is not indicated for use with tamoxifen at this dose 1

Quality of Life Considerations

Health-related quality of life was maintained longer in patients receiving ribociclib compared to placebo, with longer time to definitive deterioration in overall quality of life (HR 0.67) and pain (HR 0.65). 2 Symptom scores were generally higher with ribociclib but remained below the minimally clinically important difference threshold, and the drug was associated with clinically meaningful pain reduction. 2

Special Populations

No overall differences in safety or effectiveness were observed between older (≥65 years) and younger adults, though toxicity may be increased in patients ≥75 years. 2, 1 The drug may impair fertility in males based on animal studies showing testicular atrophy and effects on sperm production. 1