Cabozantinib — Drug Monograph
Brand names: Cabometyx, Cometriq
Drug class: Tyrosine Kinase Inhibitor
Mechanism of Action
Oral multi-kinase inhibitor targeting VEGFR1, VEGFR2, VEGFR3 (anti-angiogenic), MET (hepatocyte growth factor receptor — key mediator of tumor invasion, metastasis, and VEGFR inhibitor resistance), AXL (receptor tyrosine kinase implicated in epithelial-mesenchymal transition and immune evasion), RET, KIT, TRKB, FLT3, and TIE2. The combination of VEGFR2 + MET + AXL inhibition is particularly important: MET inhibition blocks a key escape pathway from VEGFR-targeted therapy, potentially explaining cabozantinib's activity in sorafenib/sunitinib-refractory RCC and HCC.
FDA Indications
- Renal cell carcinoma (RCC) — advanced, first-line (with nivolumab — CheckMate 9ER); second-line after prior anti-VEGF therapy (METEOR trial)
- Hepatocellular carcinoma (HCC) — second-line after sorafenib (CELESTIAL trial)
- Medullary thyroid carcinoma (MTC) — progressive, metastatic (Cometriq formulation — EXAM trial)
- Differentiated thyroid carcinoma (DTC) — RAI-refractory, after VEGFR-targeted therapy (Cabometyx)
Common Side Effects
- Diarrhea
- Fatigue
- Hypertension
- Hand-foot skin reaction (palmar-plantar erythrodysesthesia)
- Nausea
- Decreased appetite
- Vomiting
- Dysgeusia
- Mucositis/stomatitis
- Constipation
- Hypothyroidism
Clinical Pearl
Osteonecrosis of the jaw (ONJ) is an important but underrecognized risk with cabozantinib (anti-angiogenic effects impair jaw bone vascularization). Baseline dental exam and avoidance of invasive dental procedures during treatment are recommended. In RCC, the nivolumab + cabozantinib combination (CheckMate 9ER) is now a preferred first-line regimen — demonstrating OS benefit across IMDC risk groups. In MTC, cabozantinib (Cometriq) and vandetanib are both FDA-approved; for RET-mutant MTC,…
Related Therapies & Mechanisms
- Lenvatinib (Lenvima) — Tyrosine Kinase Inhibitor · HCC
- Sorafenib (Nexavar) — Tyrosine Kinase Inhibitor · HCC
- Axitinib (Inlyta) — Tyrosine Kinase Inhibitor · RCC
- Dabrafenib (Tafinlar) — Tyrosine Kinase Inhibitor · Thyroid