Cabometyx - Drug Monograph

Introduction

Cabometyx (cabozantinib) is an oral, small-molecule tyrosine kinase inhibitor developed by Exelixis, Inc. It received initial FDA approval in 2016 for the treatment of advanced renal cell carcinoma (RCC). Cabometyx represents a significant advancement in targeted cancer therapy, offering improved outcomes for patients with various solid tumors through its multi-targeted mechanism of action.

Mechanism of Action

Cabozantinib inhibits multiple receptor tyrosine kinases involved in tumor pathogenesis and angiogenesis, including:

• MET
• VEGFR-1, -2, and -3
• RET
• KIT
• AXL
• FLT-3
• TIE-2
• TRKB

This multi-targeted approach simultaneously disrupts tumor cell proliferation, metastasis, and angiogenesis while modifying the tumor microenvironment. The inhibition of MET and AXL receptors is particularly significant as these pathways are involved in resistance development to anti-VEGF therapies.

Indications

FDA-approved indications: 1. Advanced renal cell carcinoma (RCC) following prior anti-angiogenic therapy 2. First-line treatment of advanced RCC in combination with nivolumab 3. Hepatocellular carcinoma (HCC) previously treated with sorafenib 4. Differentiated thyroid cancer (DTC) that is radioactive iodine-refractory or ineligible

Dosage and Administration

• RCC (monotherapy): 60 mg orally once daily
• RCC (combination with nivolumab): 40 mg orally once daily
• HCC: 60 mg orally once daily
• DTC: 60 mg orally once daily

• Take on an empty stomach (at least 1 hour before or 2 hours after eating)
• Swallow tablets whole with water
• Do not crush or break tablets

• First dose reduction: 40 mg daily
• Second dose reduction: 20 mg daily
• Subsequent modifications based on tolerability

• Hepatic impairment: Reduce dose in severe impairment
• Renal impairment: No initial adjustment needed for mild-moderate impairment; use caution in severe impairment
• Elderly: No specific dose adjustment required

Pharmacokinetics

• Peak plasma concentration: 2-5 hours post-dose
• Food effect: High-fat meal increases AUC by 57% and Cmax by 121%
• Absolute bioavailability: Not fully characterized

• Protein binding: >99.7%
• Volume of distribution: 319 L
• Extensive tissue distribution

• Primarily metabolized by CYP3A4
• N-demethylation and hydrolysis are major metabolic pathways

• Half-life: Approximately 55 hours
• Excretion: Feces (54%) and urine (27%)
• Clearance: 4.5 L/hour

Contraindications

1. Hypersensitivity to cabozantinib or any component of the formulation 2. Concomitant use with strong CYP3A4 inducers 3. Recent history of hemoptysis or serious bleeding 4. Perforation or fistula formation

Warnings and Precautions

• Severe hemorrhagic events: Fatal hemorrhages have occurred. Discontinue in patients with severe hemorrhage.

• Gastrointestinal perforations and fistulas: Monitor symptoms and discontinue if occurs
• Thrombotic events: Increased risk of myocardial infarction, cerebral infarction, and other arterial thrombotic events
• Hypertension and hypertensive crisis: Monitor blood pressure regularly
• Diarrhea: May be severe and require dose interruption/reduction
• Palmar-plantar erythrodysesthesia syndrome: Manage with dose modifications
• Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue if diagnosed
• Thyroid dysfunction: Monitor thyroid function tests regularly
• Hepatotoxicity: Monitor liver function tests
• Proteinuria: Monitor urine protein regularly
• Osteonecrosis of the jaw: Perform dental exam before initiation
• Wound healing complications: Withhold at least 3 weeks before elective surgery

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): Increase cabozantinib exposure; reduce dose
• Strong CYP3A4 inducers (rifampin, carbamazepine): Decrease cabozantinib exposure; avoid concomitant use
• Proton pump inhibitors: May decrease solubility and absorption

• Drugs that prolong QT interval: Potential additive effects
• Anticoagulants and antiplatelets: Increased bleeding risk

Adverse Effects

• Diarrhea (74%)
• Fatigue (56%)
• Nausea (50%)
• Decreased appetite (46%)
• Palmar-plantar erythrodysesthesia (44%)
• Hypertension (40%)
• Vomiting (31%)
• Weight decreased (30%)
• Constipation (27%)
• Dysgeusia (26%)

• Hemorrhage (3% severe, 1% fatal)
• Gastrointestinal perforation (1%)
• Arterial thromboembolism (1%)
• Hepatotoxicity (≤1%)
• RPLS (<1%)

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel (including liver function tests)
• Urinalysis with protein quantification
• Thyroid function tests
• Blood pressure
• ECG (if risk factors for QT prolongation)
• Dental examination

• Blood pressure: Weekly for first 6 weeks, then monthly
• Urine protein: Regularly (at least every 3 months)
• Liver function tests: Monthly for first 3 months, then as clinically indicated
• Thyroid function: Every 2 months for first 6 months, then as needed
• Symptoms of bleeding, GI perforation, fistula formation
• Signs of hand-foot skin reaction
• Diarrhea assessment and management

Patient Education

• Take medication on an empty stomach as directed
• Do not crush or break tablets
• Report any signs of bleeding (unusual bruising, blood in urine/stool)
• Monitor blood pressure regularly as instructed
• Report severe diarrhea, nausea, or vomiting
• Be aware of hand-foot skin reactions and report redness, swelling, or pain
• Maintain good oral hygiene and inform dentist about cabozantinib therapy
• Use effective contraception during treatment and for 4 months after
• Avoid grapefruit and grapefruit juice during treatment
• Report any new or worsening symptoms immediately
• Keep all follow-up appointments for monitoring

References

1. Choueiri TK, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1814-1823. 2. Abou-Alfa GK, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018;379(1):54-63. 3. Brose MS, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8):1126-1138. 4. Cabometyx® (cabozantinib) prescribing information. Exelixis, Inc. 2023. 5. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. Version 4.2023. 6. FDA Approval: Cabozantinib for Advanced Renal Cell Carcinoma. FDA.gov. 7. Lenvima® (lenvatinib) plus Keytruda® (pembrolizumab) prescribing information. Merck & Co., Inc. 2023.