Cabozantinib

Cabozantinib is a tyrosine kinase inhibitor used for advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). In vitro biochemical and cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2.

These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

• Advanced Renal Cell Carcinoma (RCC)
• Hepatocellular Carcinoma (HCC) - in patients previously treated with sorafenib

Adults (RCC and HCC): 60 mg once daily without food until clinical benefit is no longer observed or unacceptable toxicity occurs.

Administration instructions: Take at least 1 hour before or at least 2 hours after eating. Swallow tablets whole; do not crush.

Dose modification: Dose adjustments may be needed for patients with hepatic impairment and those taking CYP450 inhibitors/inducers.

Prior to surgery: Stop cabozantinib at least 28 days prior to scheduled surgery (including dental surgery).

Pediatric: Safety and effectiveness have not been established.

Common side effects: Diarrhea (63%), Palmar-plantar erythrodysesthesia (44%), Hypertension, Proteinuria (7%), Fatigue, Decreased appetite, Nausea, Vomiting, Weight loss, Abdominal pain.

Serious side effects: Hemorrhage (Grade 3 or 4 - discontinue); Perforations and fistulas (GI - 1%); Thrombotic events (Venous 7%, Arterial 2%); Hypertensive crisis; Osteonecrosis of the jaw (ONJ - <1%); Reversible Posterior Leukoencephalopathy Syndrome (RPLS); Wound complications.

• Hemorrhage: Severe and fatal hemorrhages may occur; do not administer to patients with recent history of hemorrhage (hemoptysis, hematemesis, melena); discontinue for Grade 3 or 4 hemorrhage.
• Perforations and Fistulas: GI perforations and fistulas (including fatal) may occur; monitor; discontinue if fistula cannot be appropriately managed or GI perforation occurs.
• Thrombotic Events: Discontinue in patients who develop acute myocardial infarction or serious arterial/venous thromboembolic events.
• Hypertension: Do not initiate in patients with uncontrolled hypertension; monitor blood pressure regularly; withhold until controlled and resume at reduced dose; discontinue for severe hypertension/hypertensive crisis.
• Diarrhea: Withhold until improvement to Grade 1 and resume at reduced dose for intolerable Grade 2, Grade 3 (unmanageable with standard treatment), or Grade 4 diarrhea.
• Palmar-Plantar Erythrodysesthesia (PPE): Withhold until improvement to Grade 1 and resume at reduced dose for intolerable Grade 2 or Grade 3 PPE.
• Proteinuria: Monitor urine protein regularly; discontinue for nephrotic syndrome.
• Osteonecrosis of the Jaw (ONJ): Perform oral examination before and periodically during treatment; withhold for at least 28 days prior to dental surgery.
• Wound Complications: Stop at least 28 days prior to scheduled surgery; resume after adequate wound healing.
• RPLS: Evaluate if seizures, headache, visual disturbances, or confusion occur; discontinue if RPLS develops.
• Contraception: Females of reproductive potential should use effective contraception during treatment and for 4 months after the final dose.

• Hypersensitivity to cabozantinib or any components

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice): May increase cabozantinib exposure; avoid coadministration (reduce dose if unavoidable).
• Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's Wort): May decrease cabozantinib exposure (reducing efficacy); avoid coadministration (increase dose if unavoidable).