Indications for Cabozantinib Dose Reduction
Dose reduction of cabozantinib is indicated for Grade 3 or higher adverse events, with the most common triggers being hypertension, diarrhea, fatigue, hand-foot syndrome, and thromboembolic events—85% of patients require dose reduction during treatment. 1, 2
FDA-Approved Dose Reduction Strategy
The standard starting dose is 60 mg daily, with dose reductions following a stepwise approach 1:
- First reduction: 40 mg daily
- Second reduction: 20 mg daily
- Discontinuation: If unable to tolerate 20 mg daily
When used in combination with nivolumab, start at 40 mg daily 1.
Specific Adverse Events Requiring Dose Modification
Hypertension
- Interrupt cabozantinib for hypertension not adequately controlled with antihypertensive therapy 1
- Permanently discontinue for hypertensive crisis or severe hypertension that cannot be controlled with medical management 1
- Grade 3 hypertension occurred in 12-19% of patients in clinical trials 3, 4
Diarrhea
- Interrupt treatment until diarrhea resolves or decreases to Grade 1 or less 1
- Resume at reduced dose after resolution 1
- Implement standard antidiarrheal treatments during interruption 1
- Grade 3 diarrhea occurred in 6-7% of patients 5, 3
Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome)
- Interrupt treatment until PPE resolves or decreases to Grade 1 1
- Resume at reduced dose after improvement 1
- Grade 3 hand-foot syndrome occurred in 8% of patients 3, 4
Hemorrhage
- Do not administer if recent history of hemorrhage 1
- Permanently discontinue for Grade 3 or 4 hemorrhagic events 1
Thromboembolic Events
- Permanently discontinue for myocardial infarction or serious arterial or venous thromboembolic events 1
- Grade 3-4 pulmonary embolism occurred in 8% of patients in combination therapy 5
Hepatotoxicity (Particularly with Nivolumab Combination)
- Withhold cabozantinib and/or nivolumab for Grade 3 or 4 ALT/AST elevation 1
- Consider initiating corticosteroid therapy 1
- Permanently discontinue for severe or life-threatening hepatotoxicity 1
Proteinuria
- Interrupt treatment until proteinuria resolves to Grade 1 or less 1
- Resume at reduced dose after improvement 1
- Permanently discontinue for nephrotic syndrome 1
Fatigue
- Grade 3 fatigue occurred in 7-16% of patients 5, 3, 4
- Interrupt and reduce dose for Grade 3 fatigue that impacts daily activities 1
Special Considerations for Atrial Fibrillation
In patients with stable atrial fibrillation, cabozantinib can be administered with appropriate monitoring 6:
- Monitor cardiovascular status closely, as thromboembolic events are a known risk requiring permanent discontinuation 1
- Avoid drug interactions with rate-control agents: cabozantinib does not have significant interactions with beta-blockers, calcium channel blockers, or digoxin 7
- Maintain anticoagulation as indicated for atrial fibrillation, recognizing that cabozantinib increases bleeding risk 7
Surgical Considerations
- Stop cabozantinib at least 3 weeks before scheduled surgery, including dental procedures 1
- Do not administer for at least 2 weeks following major surgery until adequate wound healing 1
- Withhold for development of osteonecrosis of the jaw 1
Clinical Context for Prostate Cancer
In the hormone-naïve metastatic prostate cancer setting, dose reductions occurred in 85% of patients, with median treatment duration of 16.1 months demonstrating that dose reduction does not necessarily require treatment discontinuation 2. The high rate of dose reduction reflects the need for individualized dosing to balance efficacy with tolerability, particularly given the prolonged treatment duration required in prostate cancer 2, 5.