What is the recommended use and dosage of Cabometyx (cabozantinib) 40 mg tablet in cancer treatment?

Cabozantinib (CABOMETYX) 40 mg Tablet: Recommended Use and Dosage in Cancer Treatment

Cabozantinib 40 mg once daily is the recommended dosage when used in combination with nivolumab for advanced renal cell carcinoma until disease progression or unacceptable toxicity. 1

Approved Indications and Dosing Recommendations

Renal Cell Carcinoma (RCC)

• As monotherapy: 60 mg once daily until disease progression or unacceptable toxicity 1
• In combination with nivolumab: 40 mg once daily until disease progression or unacceptable toxicity 1, 2
  • The CheckMate 9ER trial demonstrated significant benefits with this combination:
    • Improved median progression-free survival: 16.6 months vs 8.3 months with sunitinib
    • Higher 12-month overall survival: 85.7% vs 75.6%
    • Higher objective response rate: 55.7% vs 27.1% 2

Hepatocellular Carcinoma (HCC)

• Recommended dose: 60 mg once daily until disease progression or unacceptable toxicity 1
• Indication: Second-line treatment after sorafenib failure 2
• Clinical benefit: In the CELESTIAL trial, cabozantinib improved median overall survival to 10.2 months vs 8.0 months with placebo 2
• Patient selection: Appropriate for patients with:
  • Child-Pugh class A liver function
  • ECOG performance status 0-1
  • Progressive disease on one or two prior systemic therapies 2

Differentiated Thyroid Cancer

• For adults and pediatric patients ≥12 years with BSA ≥1.2 m²: 60 mg once daily
• For pediatric patients ≥12 years with BSA <1.2 m²: 40 mg once daily 1

Dose Modifications for Adverse Events

Recommended Dose Reductions

• First dose reduction: From 60 mg to 40 mg daily
• Second dose reduction: From 40 mg to 20 mg daily
• For 40 mg starting dose: First reduction to 20 mg daily, second to 20 mg every other day 1

Common Adverse Events Requiring Dose Modification

• Palmar-plantar erythrodysesthesia (17% grade 3/4 in HCC)
• Hypertension (16% grade 3/4 in HCC)
• Elevated liver enzymes (12% grade 3/4 AST in HCC)
• Fatigue (10% grade 3/4 in HCC)
• Diarrhea (10% grade 3/4 in HCC) 2

Management Strategy

• Withhold cabozantinib for intolerable Grade 2, or any Grade 3-4 adverse reactions
• Resume at reduced dose upon resolution to Grade 1 or baseline 1
• In real-world practice, 77.1% of RCC patients experience dose modifications due to adverse events 3

Important Considerations

Drug Interactions

• CYP3A4 inhibitors: Reduce cabozantinib dose by 20 mg when co-administered with strong CYP3A4 inhibitors 1, 2
• Primary metabolism: CYP3A4 is the main enzyme involved in cabozantinib metabolism 2

Pre-Surgery Considerations

• Stop treatment at least 3 weeks prior to scheduled surgery, including dental procedures 1

Exposure-Response Relationship

• Higher exposure (60 mg) provides greater anti-tumor activity but increased risk of adverse events 4, 5
• Dose reductions to manage adverse events are predicted to have minimal impact on efficacy in patients with lower drug clearance 5
• In HCC patients, 60 mg dosing showed greater benefit for overall survival and progression-free survival compared to lower doses 6

Clinical Pearls

1. Monitoring requirements: Regular assessment of blood pressure, liver function, urine protein, and skin toxicity
2. Adverse event management: Proactive dose modifications can maintain treatment continuity
3. Treatment duration: Median treatment duration in real-world setting is approximately 7.8 months 3
4. Common pitfall: Failure to recognize that dose reductions are often necessary (56.3% of patients in CheckMate 9ER required cabozantinib dose reduction) 2
5. Quality of life impact: Better health-related quality of life was observed with nivolumab plus cabozantinib compared to sunitinib in RCC 2

Remember that cabozantinib should not be substituted with cabozantinib capsules, as they are not bioequivalent 1.