In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On January 14, 2019, cabozantinib was approved for the treatment of patients with hepatocellular carcinoma previously treated with sorafenib.^1,2

Supporting Efficacy Data

APPROVAL WAS based on the phase III double-blind CELESTIAL trial (ClinicalTrials.gov identifier NCT01908426). A total of 707 patients who had previously received sorafenib and had Child-Pugh class A liver impairment were randomly assigned 2:1 to receive cabozantinib at 60 mg orally once daily (n = 470) or placebo (n = 237) until disease progression or unacceptable toxicity.^2,3 The primary efficacy measure was overall survival.

The median age of patients was 64 years, 82% were male, 56% were white, and 34% were Asian. In all patients, the Eastern Cooperative Oncology Group performance status was 0 or 1. The etiology of hepatocellular carcinoma was attributed to hepatitis B virus in 38% of patients, hepatitis C virus in 21%, and other causes in 40%. Macroscopic vascular invasion or extrahepatic tumor spread was present in 78% of patients, and 41% had alpha-fetoprotein levels of at least 400 ng/L. Two prior systemic therapy regimens had been received by 27% of patients.

The median overall survival was 10.2 months in the cabozantinib group vs 8 months in the placebo group (hazard ratio [HR] = 0.76, P = .0049). The median progression-free survival was 5.2 months vs 1.9 months (HR = 0.44, P < .001). Overall response rates on Response Evaluation Criteria in Solid Tumors version 1.1 were 4% vs 0.4%.

How It Works

CABOZANTINIB INHIBITS the tyrosine kinase activity of MET; VEGFR-1, -2, and -3; AXL; RET; ROS1; TYRO3; MER; KIT; TRKB; FLT3; and TIE-2 in in vitro studies. 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 dosage of cabozantinib is 60 mg once daily without food until disease progression or unacceptable toxicity. The starting dose should be reduced to 40 mg once daily in patients with moderate hepatic impairment; cabozantinib should be avoided in those with severe hepatic impairment.

Treatment with cabozantinib should be stopped at least 28 days prior to scheduled surgery, including dental surgery.

Treatment should be withheld for grade 3 or 4 adverse reactions, intolerable grade 2 adverse reactions, and osteonecrosis of the jaw. Upon return to baseline or resolution to grade 1 of an adverse reaction, treatment can be resumed at lower doses as follows: from 60 mg to 40 mg, from 40 mg to 20 mg; in patients receiving 20 mg, treatment can be resumed at 20 mg if tolerated, or otherwise discontinued.

Treatment should be permanently discontinued for severe hemorrhage, unmanageable fistula or gastrointestinal perforation, serious thromboembolic events (eg, myocardial infarction, cerebral infarction), hypertensive crisis or severe hypertension despite optimal medical management, nephrotic syndrome, and 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, with resumption of the former dose 2 to 3 days after discontinuing the strong inducer. A daily dose of 80 mg should not be exceeded.

Safety Profile

THE MOST COMMON adverse events reported (≥ 25%) in patients who received cabozantinib in clinical trials were diarrhea, fatigue, decreased appetite, palmar-plantar erythrodysesthesia, nausea, hypertension, and vomiting.

In the CELESTIAL trial, the most common adverse events of any grade in the cabozantinib group were diarrhea (54% vs 19% in placebo group), decreased appetite (48% vs 18%), palmar-plantar erythrodysesthesia (46% vs 5%), fatigue (45% vs 30%), nausea (31% vs 18%), hypertension (30% vs 6%), and vomiting (26% vs 12%). The most common grade 3 or 4 adverse events included palmar-plantar erythrodysesthesia, hypertension, fatigue, and diarrhea. The most common grade 3 or 4 laboratory abnormalities in the cabozantinib group were increased aspartate transaminase (AST), increased alanine transaminase, and decreased platelet levels.

The cabozantinib dose was reduced in 62% of patients, with 33% requiring a reduction to 20 mg/d; the most frequent adverse events or laboratory abnormalities leading to dose reduction were palmar-plantar erythrodysesthesia, diarrhea, fatigue, hypertension, and increased levels of AST. Adverse events led to dose interruption in 84% of patients and to permanent treatment discontinuation in 16%; the most common causes of treatment discontinuation were palmar-plantar erythrodysesthesia, fatigue, decreased appetite, diarrhea, and nausea. Adverse events led to death in six patients receiving cabozantinib (hepatic failure, hepatorenal syndrome, esophagobronchial fistula, portal vein thrombosis, pulmonary embolism, and upper gastrointestinal hemorrhage).

Cabozantinib carries warnings/precautions for hemorrhage, perforations and fistulas, thrombotic events, hypertension and hypertensive crisis, diarrhea, palmar-plantar erythrodysesthesia, proteinuria, osteonecrosis of the jaw, wound complications, reversible posterior leukoencephalopathy syndrome, and embryofetal toxicity. Blood pressure and urine protein must be monitored. Patients should be advised not to breastfeed while receiving cabozantinib. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves cabozantinib for hepatocellular carcinoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm629512.htm. Accessed February 21, 2019.

2. Cabometyx (cabozantinib) tablets prescribing information, Exelixis, Inc, January 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/208692s003lbl.pdf. Accessed February 21, 2019.

3. Abou-Alfa GK, Meyer T, Cheng AL, et al: Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 379:54-63, 2018.