On April 25, 2016, the U. S. Food and Drug Administration approved cabozantinib (CABOMETYX, Exelixis, Inc.) for the treatment of advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy.
CABOMETYX is the (S)-malate salt of cabozantinib, a kinase inhibitor.
Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular Reference ID: 3921772 12 formula is C28H24FN3O5·C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:
Mechanism of Action
In vitro biochemical and/or 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.
INDICATIONS AND USAGE
CABOMETYX is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.
DOSAGE AND ADMINISTRATION
- Do not substitute CABOMETYX tablets with cabozantinib capsules.
- The recommended daily dose of CABOMETYX is 60 mg.
- Do not administer CABOMETYX with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking CABOMETYX.
- Continue treatment until patient no longer experiences clinical benefit or experiences unacceptable toxicity.
- Swallow CABOMETYX tablets whole.
- Do not crush CABOMETYX tablets.
- Do not take a missed dose within 12 hours of the next dose.
- Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during CABOMETYX treatment.
SAFETY & EFFICACY
- The approval was based on a randomized study in which patients with advanced renal cell carcinoma who had received prior anti-angiogenic therapy received either cabozantinib 60 mg orally once daily (N=330) or everolimus 10 mg orally once daily (N=328).
- The primary endpoint was progression-free survival among the first 375 randomized subjects. Median progression-free survival in this group was 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [HR 0.58 (95% CI: 0.45, 0.74); p<0.0001].
- Median overall survival in the intent-to-treat population was 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively [HR 0.66 (95% CI: 0.53, 0.83); p=0.0003]. Confirmed response rate was 17% (95% CI: 13, 22) in the cabozantinib arm and 3% (95% CI: 2, 6) in the everolimus arm.
- Safety was evaluated in 331 patients treated with cabozantinib.
WARNINGS AND PRECAUTIONS
• Hemorrhage: Do not administer CABOMETYX if recent history of severe hemorrhage.
• GI Perforations and Fistulas: Monitor for symptoms. Discontinue CABOMETYX for fistulas that cannot be adequately managed or perforations.
• Thrombotic Events: Discontinue CABOMETYX for myocardial infarction, cerebral infarction, or other serious arterial thromboembolic events.
• Hypertension and Hypertensive Crisis: Monitor blood pressure regularly. Discontinue CABOMETYX for hypertensive crisis or severe hypertension that cannot be controlled with antihypertensive therapy.
• Diarrhea: May be severe. Interrupt CABOMETYX treatment immediately until diarrhea resolves or decreases to Grade 1. Recommend standard antidiarrheal treatments.
• Palmar-plantar erythrodysesthesia syndrome (PPES): Interrupt CABOMETYX treatment until PPES resolves or decreases to Grade 1.
• Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue CABOMETYX.
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.
The most commonly reported (≥ 25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (PPES), hypertension, vomiting, weight decreased, and constipation.
This application was granted Breakthrough Therapy Designation, Fast Track, and Priority Review.