What is the recommended use and dosage of Ribociclib (ribociclib) for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer?

Ribociclib for Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer

Ribociclib should be administered at 600 mg orally once daily for 21 consecutive days followed by 7 days off treatment, in combination with an aromatase inhibitor or fulvestrant, for patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. 1, 2

Indications and Patient Selection

Ribociclib is indicated for:

• First-line therapy:

  • In combination with an aromatase inhibitor (letrozole or anastrozole) for postmenopausal women 1
  • In premenopausal women with ovarian ablation/suppression (using goserelin or other LHRH agonist) 1, 3

• Second-line therapy:

  • In combination with fulvestrant for patients who have progressed on prior endocrine therapy 1, 2

Dosing and Administration

• Standard dosing: 600 mg (three 200 mg tablets) orally once daily for 21 consecutive days followed by 7 days off treatment (28-day cycle) 2
• Administration: Can be taken with or without food 2
• For premenopausal women: Must be combined with ovarian suppression/ablation (goserelin 3.6 mg subcutaneously every 28 days) 1, 3
• Monitoring requirements:
  • Complete blood count: Every 2 weeks for first 2 cycles, then at beginning of each subsequent 4 cycles 3, 2
  • Liver function tests: Every 2 weeks for first 2 cycles, then at beginning of each subsequent 4 cycles 3, 2
  • ECG: At baseline, day 14 of first cycle, and as clinically indicated (due to QT prolongation risk) 2

Efficacy

Ribociclib has demonstrated significant improvements in both progression-free survival (PFS) and overall survival (OS):

• With letrozole (MONALEESA-2 trial):

  • PFS: 25.3 months vs 16.0 months with letrozole alone (HR 0.56) 1
  • Objective response rate: 43% vs 29% 1

• With fulvestrant (MONALEESA-3 trial):

  • PFS: 20.5 months vs 12.8 months with fulvestrant alone 2
  • Improved overall survival (HR 0.724) 2

• In premenopausal women (MONALEESA-7 trial):

  • PFS: 24 months vs 13 months with endocrine therapy alone 1
  • OS improvement: 70% vs 46% at 3.5 years (HR 0.71) 1

Adverse Effects and Management

Common grade 3/4 adverse events include:

1. Neutropenia (62%): Most common serious adverse effect 1

   • Manage with dose interruptions and reductions
   • Monitor CBC every 2 weeks for first 2 cycles

2. Leukopenia (21.3%) 1

3. Abnormal liver function tests (10.2%) 1

   • Monitor LFTs regularly
   • Dose reduction may be required

4. QT interval prolongation 2

   • Avoid concomitant use with drugs known to prolong QT interval
   • Monitor ECG and electrolytes

Dose Modifications

Dose reductions may be required based on tolerability:

• First reduction: 400 mg daily
• Second reduction: 200 mg daily
• Discontinue if unable to tolerate 200 mg daily 2

Special Considerations

• Premenopausal patients: Must receive ovarian suppression with goserelin or another LHRH agonist 1, 3

• Elderly patients: No dose adjustment required based on age alone, but may experience more toxicity 3

• After progression: Consider testing for PIK3CA mutations to guide next-line therapy 3

• Contraindications: Not indicated for concomitant use with tamoxifen due to increased QT prolongation risk 2

Clinical Pearls and Pitfalls

1. Do not continue ribociclib after progression: If disease progresses while on ribociclib, there are no data to support using another CDK4/6 inhibitor-containing regimen 1

2. Manage neutropenia proactively: The high rate of neutropenia (62%) requires close monitoring, but febrile neutropenia is rare 1

3. ECG monitoring is essential: Due to risk of QT prolongation, baseline and follow-up ECGs are required 2

4. Avoid strong CYP3A inhibitors: These can increase ribociclib exposure and toxicity 2

5. Real-world outcomes match clinical trials: Real-world studies show comparable or better PFS than in clinical trials 4

Ribociclib in combination with endocrine therapy represents a significant advance in the treatment of HR-positive, HER2-negative advanced breast cancer, with consistent benefits across different patient subgroups and treatment settings.