Cabozantinib is an oral tyrosine kinase inhibitor (TKI) used in the treatment of several advanced and metastatic cancers. It inhibits multiple pathways involved in tumor growth, angiogenesis, and metastasis, making it an important agent in targeted cancer therapy.
Mechanism of Action
Cabozantinib is a multi-kinase inhibitor that targets and inhibits several receptor tyrosine kinases implicated in tumor pathogenesis:
- VEGFR-1, VEGFR-2, VEGFR-3: Inhibit angiogenesis
- MET, RET, AXL, FLT3, KIT: Block tumor cell proliferation, survival, invasion, and metastasis
- TIE2, TRKB: Additional roles in vascular stability and neurotrophic signaling
By simultaneously targeting these pathways, cabozantinib reduces tumor growth, disrupts the tumor vasculature, and inhibits metastatic progression.
Indications (FDA-Approved Uses as of 2025)
✅ Cabometyx® (tablets)
- Advanced Renal Cell Carcinoma (RCC)
- First-line: In combination with nivolumab
- Subsequent-line: As monotherapy after prior anti-angiogenic therapy
- Hepatocellular Carcinoma (HCC)
- After prior treatment with sorafenib
- Differentiated Thyroid Cancer (DTC)
- In patients who are radioiodine-refractory and have progressed on prior VEGFR-targeted therapy (approved in 2021)
✅ Cometriq® (capsules)
- Progressive, metastatic Medullary Thyroid Carcinoma (MTC)
- Used in adults and pediatric patients ≥12 years
🔄 Note: Cometriq and Cabometyx are not interchangeable due to differences in formulation and pharmacokinetics.
Dosage and Administration
Cabometyx® Tablets (RCC, HCC, DTC)
- Monotherapy: 60 mg orally once daily
- With Nivolumab (RCC): 40 mg orally once daily
- Nivolumab: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks
- Continue until disease progression or unacceptable toxicity
- Nivolumab limited to 24 months
Cometriq® Capsules (MTC)
- Adults: 140 mg orally once daily (as 100 mg + 40 mg)
- Pediatrics (≥12 years): Based on body surface area (BSA)
📌 Continue until disease progression or intolerable toxicity.
Administration Guidelines
- Take on an empty stomach:
- No food ≥2 hours before and 1 hour after administration
- Swallow whole with water
- Avoid grapefruit juice: Can alter cabozantinib blood levels
- Do not crush, chew, or open capsules or tablets
Adverse Effects
Common Side Effects (≥25% incidence):
- Diarrhea
- Fatigue
- Decreased appetite
- Nausea and vomiting
- Weight loss
- Hypertension
- Hair color changes or hair loss
- Hand-foot skin reaction (palmar-plantar erythrodysesthesia)
Serious/Immune-Related Adverse Events:
| Category | Effects |
|---|---|
| Hemorrhage | Grade ≥3 bleeding in ~5% of patients (life-threatening) |
| GI perforation/fistula | Occur in ~1%; may be fatal |
| Hypertension crisis | Risk of hypertensive emergency |
| Hepatotoxicity | Elevated transaminases |
| Proteinuria | Monitor renal function |
| Thromboembolism | Increased arterial and venous risk |
| Osteonecrosis of the jaw | Especially with bisphosphonates |
⚠️ Cabozantinib should be discontinued in patients with Grade 4 adverse events (e.g., GI perforation, life-threatening hemorrhage).
Drug Interactions
Avoid with strong CYP3A4 modifiers:
- CYP3A4 Inhibitors (↑ Cabozantinib levels):
- Clarithromycin, itraconazole, ketoconazole, grapefruit juice
- CYP3A4 Inducers (↓ Cabozantinib levels):
- Rifampin, phenytoin, carbamazepine, St. John’s Wort
Other Notable Interactions:
- Antiepileptics, antiretrovirals, antifungals
- Anticoagulants (↑ bleeding risk)
- QT-prolonging drugs
- Contraceptives (↓ efficacy possible)
🧪 Monitor ECG and electrolytes if co-administered with QT-prolonging agents.
Warnings and Precautions
| Risk | Recommendation |
|---|---|
| Hemorrhage | Discontinue for Grade 3–4 bleeding |
| GI perforation/fistula | Discontinue if suspected |
| Hypertension | Monitor BP and manage before initiating |
| Wound healing complications | Hold for ≥28 days before and after major surgery |
| Osteonecrosis of the jaw | Dental evaluation prior to treatment recommended |
| Thromboembolism | Monitor for symptoms; discontinue if life-threatening |
Contraindications
- Recent hemorrhage (e.g., hemoptysis, hematemesis, GI bleeding)
- Uncontrolled hypertension
- Known hypersensitivity to cabozantinib
- Pregnancy or breastfeeding (Category D – Risk to fetus)
Use in Pregnancy and Lactation
- Pregnancy: Teratogenic and embryotoxic in animal models
- Effective contraception required during and for 4 months post-treatment
- Lactation: Unknown if excreted in breastmilk – avoid breastfeeding
Storage
- Store at 20–25°C (68–77°F)
- Excursions allowed from 15–30°C (59–86°F)
- Keep in original container, protected from moisture and light
Summary and Clinical Highlights (2025)
- Cabozantinib is a broad-spectrum tyrosine kinase inhibitor with indications across kidney, thyroid, and liver cancers
- Used both as monotherapy and in combination with immune checkpoint inhibitors (e.g., nivolumab)
- Associated with high rates of disease control and progression-free survival in treatment-resistant cancers
- Requires vigilant monitoring for vascular, gastrointestinal, and metabolic complications
- Not interchangeable between Cometriq (capsule) and Cabometyx (tablet) formulations
Key Clinical Trials (2025 Updates)
- CheckMate-9ER: Cabozantinib + Nivolumab in RCC
- CELESTIAL Trial: Cabozantinib in HCC post-sorafenib
- COSMIC-311: Cabozantinib in radioactive iodine-refractory DTC
- EXAM Trial: Cometriq in MTC