What is Ribociclib (cyclin-dependent kinase 4/6 inhibitor) used for in the treatment of breast cancer?

Ribociclib: CDK4/6 Inhibitor for Hormone Receptor-Positive Breast Cancer

What is Ribociclib?

Ribociclib is a selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that blocks cell cycle progression by preventing phosphorylation of the retinoblastoma protein, thereby arresting cancer cells in the G1 phase and inhibiting tumor proliferation. 1

• Ribociclib works by inhibiting CDK4/6 kinases, which are activated by D-cyclins and drive cell cycle progression through phosphorylation of retinoblastoma protein (pRb) 1
• When combined with endocrine therapy, ribociclib demonstrates enhanced tumor growth inhibition compared to either agent alone in preclinical models 1

Clinical Indications for Breast Cancer

Metastatic/Advanced Disease (First-Line Setting)

Ribociclib combined with an aromatase inhibitor (letrozole or anastrozole) is a Category 1 preferred first-line treatment for postmenopausal women with HR-positive, HER2-negative advanced breast cancer. 2

• In the MONALEESA-2 trial, ribociclib plus letrozole achieved a median progression-free survival (PFS) of 25.3 months versus 16.0 months with letrozole alone (HR 0.56, p<0.001) 2
• The combination demonstrated an objective response rate of 43% versus 29% with letrozole monotherapy 2
• Overall survival data show sustained benefit with ribociclib-based therapy 2

Premenopausal Women

For premenopausal or perimenopausal women, ribociclib combined with endocrine therapy (aromatase inhibitor or tamoxifen) plus ovarian suppression with goserelin is the standard first-line treatment. 2

• The MONALEESA-7 trial demonstrated median PFS of 23.8 months with ribociclib versus 13.0 months with placebo (HR 0.55, p<0.0001) 2
• At 42 months, overall survival was 70.2% in the ribociclib group versus 46.0% in the placebo group (HR 0.71, p=0.00973) 2
• This represents a doubling of PFS regardless of whether patients received an aromatase inhibitor or tamoxifen as the endocrine backbone 2

Second-Line Setting (After Aromatase Inhibitor Failure)

Ribociclib plus fulvestrant should be offered to patients who progress on aromatase inhibitors or develop recurrence within 1 year of completing adjuvant aromatase inhibitor therapy. 2

• In the MONALEESA-3 trial, ribociclib-fulvestrant achieved median PFS of 20.5 months versus 12.8 months with placebo-fulvestrant (HR 0.593, p<0.001) 2
• Overall survival at 42 months was 57.8% with ribociclib-fulvestrant versus 45.9% with placebo-fulvestrant, representing a 28% reduction in risk of death (HR 0.72, p=0.00455) 2
• The objective response rate was 40.9% versus 28.7% with fulvestrant alone 2

Early Breast Cancer (Adjuvant Setting)

Ribociclib 400 mg daily (3 weeks on, 1 week off) for 3 years combined with endocrine therapy is approved for stage II-III HR-positive, HER2-negative early breast cancer at high risk of recurrence. 2

• The NATALEE trial showed a 3-year invasive disease-free survival rate of 90.4% with ribociclib versus 87.1% with endocrine therapy alone (HR 0.75, p=0.003) 2
• Distant disease-free survival was also significantly improved (HR 0.74,3-year rates 90.8% vs 88.6%) 2
• This indication uses a lower dose (400 mg) compared to the metastatic setting (600 mg) 2

Dosing and Administration

The standard dose is 600 mg orally once daily for 21 consecutive days followed by 7 days off in a 28-day cycle for metastatic disease, or 400 mg daily (3 weeks on, 1 week off) for adjuvant treatment. 2, 1

• Ribociclib reaches steady-state after approximately 8 days with a mean accumulation ratio of 2.5 1
• Time to maximum concentration (Tmax) is 1-4 hours after administration 1
• Food has no clinically meaningful effect on absorption and can be taken with or without meals 1

Safety Profile and Monitoring

Common Adverse Events

The most frequent grade 3-4 adverse events are neutropenia (62-66%), leukopenia (13-21%), and elevated liver enzymes (5-10%). 2

• Neutropenia occurred in 62% (grade 3) and 6.8% (grade 4) of patients in MONALEESA-3 2
• In MONALEESA-7, neutropenia was reported in 61% (grade 3-4) of ribociclib-treated patients versus 4% with placebo 2
• Hepatobiliary toxicity (grade 3-4) occurred in 11% versus 6.8% with placebo 2

Cardiac Monitoring Requirements

Ribociclib causes concentration-dependent QTc prolongation requiring baseline and periodic ECG monitoring. 1

• At the 600 mg dose in metastatic disease, mean QTcF increase from baseline is 22-24 ms with aromatase inhibitors/fulvestrant, and 34.7 ms with tamoxifen 1
• At the 400 mg dose in early breast cancer, mean QTcF increase is 10.0 ms 1
• QT prolongation (grade 3-4) occurred in 1.8% of patients in MONALEESA-7 2

Management of Toxicity

Dose reductions and treatment interruptions effectively manage toxicity while maintaining efficacy. 3

• Exposure-efficacy analyses demonstrate no apparent relationship between ribociclib exposure and progression-free or overall survival, supporting dose reductions when needed 3
• Patients continue to benefit from treatment following dose reduction to 400 mg or 200 mg 3
• Serious adverse events related to study medication occurred in 11.2% of ribociclib-treated patients versus 2.5% with placebo 2

Quality of Life Considerations

Ribociclib maintains or improves health-related quality of life and provides clinically meaningful pain reduction compared to endocrine therapy alone. 2

• Time to definitive deterioration in overall quality of life was longer with ribociclib-endocrine therapy (HR 0.67) in MONALEESA-7 2
• Pain scores showed clinically meaningful reduction (>5 points) in 26% of ribociclib-letrozole patients versus 15% with placebo-letrozole in MONALEESA-2 2
• Global health status and quality of life were maintained from baseline and similar across treatment arms 2

Clinical Positioning

Ribociclib-based combinations represent the preferred first-line treatment for the majority of patients with HR-positive, HER2-negative metastatic breast cancer, with survival benefits that have solidified the role of CDK4/6 inhibitors in this setting. 2

• The survival benefits with CDK4/6 inhibitors plus endocrine therapy are impressive and consistent across all three approved agents (ribociclib, palbociclib, abemaciclib) 2
• Sequential endocrine therapy before chemotherapy is emphasized, except in cases of primary endocrine resistance or immediately life-threatening visceral disease 2
• Prior chemotherapy negatively impacts PFS and OS in response to subsequent endocrine therapy, further supporting early use of CDK4/6 inhibitor combinations 2