On April 25, 2016, a tablet formulation of cabozantinib (Cabometyx) was approved for treatment of advanced renal cell carcinoma in patients who have received prior antiangiogenic therapy.^1,2 The capsule formulation of cabozantinib (Cometriq) was previously approved for the treatment of metastatic medullary thyroid carcinoma.

Supporting Efficacy Data

The current approval was based on a phase III trial in which 653 patients with advanced renal cell carcinoma received cabozantinib at 60 mg daily (n = 331) or everolimus (Afinitor) at 10 mg daily (n = 322) until disease progression or unacceptable toxicity.^2,3 Patients in both groups who had disease progression could continue treatment at an investigator’s discretion. The primary endpoint was progression-free survival on independent review among the first 375 randomly assigned patients.

Overall, patients had a median age of 62 years; 75% were male; 69% had received one prior antiangiogenic therapy; Memorial Sloan Kettering Cancer Center risk group was favorable for 46%, intermediate for 42%, and poor for 13%; and 54% had at least three organs with metastatic disease, including lungs (63%), lymph nodes (62%), liver (29%), and bone (22%).

Median progression-free survival among the first 187 cabozantinib (Cometriq) recipients was 7.4 vs 3.8 months among the first 188 everolimus recipients (hazard ratio [HR] = 0.58, P < .0001). Median overall survival in the intent-to-treat population was 21.4 vs 16.5 months (HR = 0.66, P = .0003). The confirmed response rate was 17% vs 3%. 

How It Works

Cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, VEGFR-2, VEGFR-3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2 in in vitro studies. These receptor tyrosine kinases are involved in both normal cellular function and 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. 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 return to baseline or resolution to grade 1, treatment should be resumed at a lower dose as follows: from 60 mg to 40 mg, and from 40 mg 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 for unmanageable fistula or gastrointestinal perforation, severe hemorrhage, arterial thromboembolic event (eg, myocardial infarction, 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 [Victrelis], clarithromycin, conivaptan [Vaprisol], grapefruit juice, indinavir [Crixivan], itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir [Viracept], posaconazole [Noxafil], saquinavir [Fortovase], telithromycin [Ketek], voriconazole), the daily dose of cabozantinib 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, phenobarbital, rifabutin, rifapentine [Priftin], St John’s wort), the daily dose of cabozantinib should be increased by 20 mg (eg, from 60 mg to 80 mg or 40 mg 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

In the total population of the phase III trial, the most common adverse events of any grade in the cabozantinib group were diarrhea (74% vs 28%), fatigue (56% vs 47%), nausea (50% vs 28%), decreased appetite (46% vs 34%), palmar-plantar erythrodysesthesia syndrome (42% vs 6%), hypertension (39% vs 8%), vomiting (32% vs 14%), and decreased weight (31% vs 12%).

The most common grade 3 or 4 adverse events were hypertension (16% vs 3%), diarrhea (11% vs 2%) , fatigue (9% vs 7%), and palmar-plantar erythrodysesthesia syndrome (8% vs < 1%). The most common grade 3 or 4 laboratory abnormalities in cabozantinib recipients were hypophosphatemia (8% vs 5%), hyponatremia (8% vs 6%), decreased lymphocytes (7% vs 12%), and hypomagnesemia (7% vs < 1%).

Serious adverse events were reported in 40% of cabozantinib-treated patients, with the most common (≥ 2%) being abdominal pain, pleural effusion, diarrhea, and nausea. Doses were reduced in 60% of the cabozantinib group and 24% of the everolimus group; 20% of cabozantinib-treated patients had 20 mg/d as their lowest dose. The most common adverse events leading to dose reduction in cabozantinib recipients were diarrhea, palmar-plantar erythrodysesthesia syndrome, fatigue, and hypertension. 

Adverse events led to treatment interruption in 70% vs 59% of the cabozantinib group and everolimus group, respectively, and to treatment discontinuation in 10% vs 10%. The most common causes in cabozantinib-treated patients were decreased appetite (2%) and fatigue (1%).

Cabozantinib carries warnings/precautions for hemorrhage, gastrointestinal perforation and fistula, thrombotic events, hypertension and hypertensive crisis, diarrhea, palmar-plantar erythrodysesthesia syndrome, reversible posterior leukoencephalopathy syndrome, and embryofetal toxicity. Blood pressure must be routinely monitored during cabozantinib therapy. Women of reproductive potential must be advised of potential risk to a fetus and to use effective contraception. ■

References

1. U.S. Food and Drug Administration: Cabozantinib (Cabometyx). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm497483.htm. Accessed May 6, 2016.

2. Cabometyx (cabozantinib) tablets prescribing information, Exelixis, Inc, April 2016. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2016/208692s000lbl.pdf. Accessed May 6, 2016.

3. Choueiri TK, Escudier B, Powles T, et al: Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1814-1823, 2015. 

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 http://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).