In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On November 29, 2012, cabozantinib (Cometriq) was approved for the treatment of patients with progressive metastatic medullary thyroid cancer.1
Approval was based on results of an international trial in which 330 patients with metastatic medullary thyroid cancer were randomly assigned to receive oral cabozantinib at 140 mg (n = 219) or placebo (n = 111) daily until disease progression or intolerable toxicity.2 Patients were required to have progressive disease within 14 months prior to entry.
Overall, patients had a median age of 55 years (23% ≥ 65 years), 67% were male, 90% were white, 54% had ECOG performance status of 0, and 92% had undergone thyroidectomy; 25% had received two or more prior systemic therapies and 21% had prior tyrosine kinase inhibitor treatment. Placebo patients could not cross over to cabozantinib at progression.
Median progression-free survival was 11.2 months in the cabozantinib group and 4.0 months in the placebo group, representing a significant 72% reduction in risk of progression (hazard ratio [HR] = 0.28, P < .0001). The overall response rate was 27% (all partial responses) vs 0% (P < .0001), and median response duration was 14.7 months. No significant difference in overall survival was observed between the groups at a planned interim analysis or in an updated survival analysis requested by FDA.
How It Works
Cabozantinib is a small-molecule inhibitor of the activity of multiple tyrosine kinases—RET, MET, VEGFR-1, -2, and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. These kinases are involved in both normal cellular function and in oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.
How It Is Given
Cabozantinib is given at a dosage of 140 mg once daily. Patients should not eat for least 2 hours before and 1 hour after taking the medication. There are no specific contraindications to cabozantinib use.
Cabozantinib is a CYP3A4 substrate, and concomitant use of strong CYP3A4 inhibitors (eg, ritonavir, idinavir, clarithromycin, ketoconazole, itraconazole) or CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John’s wort) should be avoided. The cabozantinib daily dose should be reduced by 40 mg if concomitant use of strong inhibitors is required (or increased by 40 mg if concomitant use of strong inducers is required) and returned to the prior dose 2 to 3 days after stopping treatment with the inhibitor (or inducer). Patients with moderate or severe hepatic impairment should not receive cabozantinib.
Treatment should be withheld for grade 4 hematologic toxicity, grade 3 or higher nonhematologic adverse reactions, or intolerable grade 2 adverse reactions. Upon resolution/improvement of adverse reactions, the dose should be reduced by 40 mg; treatment should be stopped in patients unable to tolerate a retrial of a 60-mg daily dose. Overall, dose reduction was required in 79% of patients in the clinical trial.
Treatment should be permanently discontinued for any of the following: visceral perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic event (eg, myocardial infarction, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, osteonecrosis of the jaw, and reversible posterior leukoencephalopathy syndrome.
Patients should have blood pressure and urine protein monitored regularly and should be monitored for signs and symptoms of bleeding.
Adverse events occurring in at least 30% of cabozantinib patients and at an incidence at least 5% greater than in placebo patients included diarrhea (63% vs 33%), stomatitis (51% vs 6%), palmar-plantar erythrodysesthesia syndrome (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), and hypertension (33% vs 4%).
Grade 3 or 4 adverse events that occurred in at least 8% of cabozantinib patients and at an incidence at least 2% greater than that in patients receiving placebo were diarrhea (16% vs 2%), palmar-plantar erythrodysesthesia syndrome (13% vs 0%), fatigue (9% vs 3%), and hypertension (8% vs 0%). Nearly all cabozantinib patients experienced elevated blood pressure, and 61% vs 30% of placebo patients had overt hypertension (based on Joint National Committee staging criteria). No patients developed malignant hypertension.
The most common laboratory abnormalities of any grade (≥ 35%) in cabozantinib patients were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%), increased alkaline phosphatase (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), and thrombocytopenia (35% vs 4%). The most common grade 3 or 4 abnormalities were lymphopenia (16% vs 11%), hypocalcemia (12% vs 3%), increased ALT (6% vs 2%), and hypokalemia (4% vs 3%).
Serious adverse events attributed to cabozantinib included pancreatitis in 3 patients, fatal hemorrhage in 2, fatal perforation/fistula in 2, osteonecrosis of the jaw in 1, reversible posterior leukoencephalopathy syndrome in 1, and nephrotic syndrome in 1.
Cabozantinib carries a boxed warning for perforations and fistulas. Gastrointestinal perforations occurred in 3% of patients receiving cabozantinib and fistula formation occurred in 1%. Severe and sometimes fatal hemorrhage, including hemoptysis and gastrointestinal hemorrhage, occurred in 3%. Cabozantinib has warnings/precautions for thrombotic events, wound complications, hypertension, osteonecrosis of the jaw, palmar-plantar erythrodysesthesia syndrome, proteinuria, reversible posterior leukoencephalopathy syndrome, and embryofetal toxicity. ■
1. U.S. Food and Drug Administration: Cabozantinib. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm330213.htm. Accessed January 9, 2013.
2. COMETRIQTM (cabozantinib capsules) prescribing information. Exelixis, Inc, November 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf. Accessed January 9, 2013.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid...