ON DECEMBER 19, 2017, cabozantinib (Cabometyx) was granted regular approval for the treatment of advanced renal cell carcinoma.^1,2 Cabozantinib was initially granted approval in 2016 for the treatment of patients with advanced renal cell carcinoma who had received prior antiangiogenic therapy. The current approval provides for treatment in the first-line setting.

Supporting Efficacy Data

APPROVAL IN the first-line setting is based on findings from the multicenter open-label phase II CABOSUN study, in which 157 patients with intermediate- or poor-risk previously untreated renal cell carcinoma were randomized to receive oral cabozantinib at 60 mg daily (n = 79) or oral sunitinib (Sutent) at 50 mg daily (n = 78) for 4 weeks on treatment followed by 2 weeks off until disease progression or unacceptable toxicity.² Patients had a median age of 63 years, 78% were male, 81% had intermediate-risk disease, and 36% had bone metastases. Overall, 87% had an Eastern Cooperative Oncology Group performance status of 0 or 1 and 13% had a performance status of 2.

The estimated median progression-free survival on blinded independent radiology review committee assessment was 8.6 months in the cabozantinib group vs 5.3 months in the sunitinib group (hazard ratio = 0.48, P = .0008). The objective response rate was 20% vs 9%. The hazard ratio for overall survival was 0.80 (95% confidence interval = 0.53–1.21).

How It Works

IN VITRO STUDIES have shown that cabozantinib inhibits the tyrosine kinase activity of MET; vascular endothelial growth factor receptor 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 in such pathologic processes as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

How It Is Used

THE RECOMMENDED DAILY dose of cabozantinib is 60 mg without food until the patient no longer experiences clinical benefit or experiences unacceptable toxicity. The starting dose should be reduced to 40 mg once daily in patients with mild or moderate hepatic impairment; cabozantinib is not recommended for use in patients with severe hepatic impairment.

Treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery. Treatment should be withheld for grade 4 adverse reactions and for grade 3 or intolerable grade 2 adverse reactions that cannot be managed with dose reduction or supportive care. With a return to baseline or resolution to grade 1, treatment should be resumed at a lower dose as follows: from 60 to 40 mg and from 40 to 20 mg; in patients receiving 20 mg, treatment can be resumed at 20 mg if tolerated and otherwise discontinued.

Treatment should be permanently discontinued in cases of unmanageable fistulae or gastrointestinal (GI) perforation, severe hemorrhage, arterial thromboembolic event (eg, myocardial or cerebral infarction), hypertensive crisis or severe hypertension despite optimal medical management, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome.

In patients taking a strong CYP3A4 inhibitor (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole), the cabozantinib daily dose should be reduced by 20 mg; the dose used prior to initiating the strong inhibitor can be resumed 2 to 3 days after discontinuation of the inhibitor. In patients taking a strong CYP3A4 inducer (eg, rifampin, phenytoin, carbamazepine, St John’s wort), the cabozantinib daily dose should be increased by 20 mg (eg, from 60 to 80 mg or 40 to 60 mg), with resumption of the former dose 2 to 3 days after discontinuing the strong inducer. Patients should not ingest foods (eg, grapefruit or grapefruit juice) or nutritional supplements known to inhibit cytochrome P450 during cabozantinib treatment.

Safety Profile

THE MOST commonly reported (≥ 25%) adverse events in patients receiving cabozantinib are diarrhea, fatigue, nausea, decreased appetite, hypertension, palmar-plantar erythrodysesthesia, decreased weight, vomiting, dysgeusia, and stomatitis.

In the CABOSUN trial, grade 3 or 4 adverse events occurred in 68% of the cabozantinib group vs 65% of the sunitinib group; the most common adverse events in the cabozantinib group were hypertension (28% vs 21%), diarrhea (10% vs 11%), hyponatremia (9% vs 8%), hypophosphatemia (9% vs 7%), and palmar-plantar erythrodysesthesia (8% vs 4%). Adverse events led to dose reduction in 46% vs 35% of patients, withholding of dose in 73% vs 71%, and drug discontinuation in 21% vs 22%.

Cabozantinib carries warnings/precautions for hemorrhage, GI perforation and fistula, thrombotic events, hypertension and hypertensive crisis, diarrhea, palmar-plantar erythrodysesthesia, reversible posterior leukoencephalopathy syndrome, and embryofetal toxicity. Blood pressure must be monitored regularly during cabozantinib therapy.

REPORT ADVERSE EVENTS

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 www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088). ■

REFERENCES

1. U.S. Food and Drug Administration: FDA grants regular approval to Cabometyx for first-line treatment of advanced renal cell carcinoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm589842.htm. Accessed February 21, 2018.

2. Cabometyx (cabozantinib) tablets prescribing information, Exelixis, Inc, December 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/208692s002lbl.pdf. Accessed February 21, 2018.