What is cabozantinib?
Cabozantinib is an oral, multi-kinase inhibitor that inhibits the activity of MET, VEGFR-1, 2, and 3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. Cabometyx® is the (S)-malate salt of cabozantinib.
How does cabozantinib work?
Cabozantinib inhibits multiple kinases involved in cellular processes such as oncogenesis, metastasis, tumor angiogenesis, and tumor microenvironment. It is thought that the inhibition of VEGFR is particularly useful for the treatment of renal cell carcinoma.
What is this approved for?
Cabozantinib (Cabometyx®) is approved for the treatment of patients with advanced renal cell carcinoma who have received previous anti-angiogenic therapy.
What is the basis for this approval?
The FDA approval for cabozantinib (Cabometyx®) was based on the results of the METEOR trial. This phase III, open-labeled, randomized trial compared patients with advanced renal cell carcinoma receiving cabozantinib 60 mg orally daily or everolimus 10 mg orally daily after progression with one or more VEGFR tyrosine kinase inhibitors. The primary endpoint was progression-free survival (PFS) with 658 patients randomized. Cabozantinib was associated with a 7.4 month median PFS compared to 3.9 months with everolimus (HR 0.51; p < 0.0001) and a statistically significant improvement in median overall survival (21.4 months vs. 16.5 months, HR 0.66; p=0.00026) (Lancet Oncol 2016;17:917-927).
How do you administer this drug?
Cabozantinib (Cabometyx®) is administered as a 60 mg oral dose per day. It is available as 20, 40, and 60 mg tablets. It should be given on an empty stomach with patients avoiding food for 2 hours prior or 1 hour after administration. Dosing should continue until disease progression or unacceptable toxicities.
Are there any premedications needed for cabozantinib?
No routine premedications are needed with cabozantinib. If patients experience nausea/vomiting, antiemetics can be given prior to administration.
What are common side effects associated with cabozantinib (> or =10%)?
- General: fatigue, headache, mouth pain, dizziness
- Dermatologic: palmar-plantar erythrodysesthesia, hair discoloration, skin rash
- Endocrine: increased triglycerides, hypokalemia, hypophosphatemia, hyperglycemia, hypomagnesemia
- GI: diarrhea, stomatitis, dysgeusia, abdominal pain, vomiting
- Hematologic: neutropenia, thrombocytopenia, anemia
- Hepatic: increased AST, ALT
What are uncommon side effects associated with cabozantinib (less than 10%)?
Pulmonary embolism, venous thromboembolism, arterial thromboembolism, peripheral neuropathy, gastrointestinal perforation, and proteinuria.
Are there any important drug interactions I should be aware of?
Cabozantinib is hepatically metabolized by both CYP2C9 and CYP3A4; therefore, evaluation for drug interactions is prudent. If a patient has to receive a strong inhibitor of CYP3A4, the daily dose of cabozantinib should be reduced by 20 mg. For strong inducers of CYP3A4, the daily dose should be increased by 20 mg.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
While ~27 percent of cabozantinib is excreted via the urine, there are no dose adjustments for patients with renal dysfunction. Patients with a creatinine clearance < 30 mL/min were not included in the clinical trials. Patients with mild to moderate hepatic impairment should start with 40 mg daily. Patients with severe hepatic impairment should not receive cabozantinib.
Cabozantinib tablets should be taken at the same time each day on an empty stomach. It should be stopped at least 28 days prior to scheduled surgery, including dental surgery. Blood pressure should be monitored regularly during treatment with cabozantinib. If medical management of blood pressure is not achieved, a dose reduction may be necessary.
What should my patients know about cabozantinib?
All patients should be educated on the side effects of cabozantinib as well the importance of compliance. Patients should contact their health care provider if they experience any of the following:
- Shortness of breath
- Elevated blood pressure
- Hand-foot skin redness
- Unexplained bleeding
What else should I know about cabozantinib?
- There are two formulations of cabozantinib approved by the FDA that are not interchangeable.
- Cabozantinib (Cometriq®) capsules are approved for the treatment of thyroid cancer, while cabozantinib (Cabometyx®) tablets are approved for the treatment of renal cell carcinoma. Special care should be taken when prescribing these medications to ensure proper dosing for the indication. Cabozantinib (Cometriq®) for the treatment of thyroid cancer is dosed at 140 mg oral capsule daily and cabozantinib (Cabometyx®) for renal cell carcinoma is dosed at 60 mg oral tablet daily.
- When prescribing cabozantinib, both the brand name and indication should be written to prevent prescribing errors.
What useful links are available regarding cabozantinib?
Any ongoing clinical trials related to cabozantinib?
Clinical trials with cabozantinib are being conducted in multiple disease states such as prostate cancer, cholangiocarcinoma, and hepatocellular carcinoma. Additionally, cabozantinib is being studied in the first-line setting against sunitinib for renal cell carcinoma. More information is available about the clinical trials at https://clinicaltrials.gov.
SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor. Oncology Times Clinical Advisory Editor RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor.
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