On September 17, 2021, cabozantinib was approved for adult and pediatric patients aged ≥ 12 years with locally advanced or metastatic differentiated thyroid cancer progressing after ­VEGFR-targeted therapy and who are ineligible or refractory to radioactive iodine.¹ Cabozantinib inhibits the activity of multiple tyrosine kinases, including RET, MET, and VEGF.

Supporting Efficacy Data

Approval was based on findings in the phase III, double-blind COSMIC-311 trial (ClinicalTrials.gov identifier NCT02632409), in which patients were randomly assigned 2:1 to receive oral cabozantinib at 60 mg once daily or placebo with best supportive care until disease progression or intolerable toxicity.¹

On blinded independent radiology review committee assessment, median progression-free survival was not reached in the primary analysis, which included 125 patients given cabozantinib vs 62 patients given placebo (95% confidence interval [CI] = 5.7 months to not evaluable) in the cabozantinib group vs 1.9 months (95% CI = 1.8–3.6 months) in the placebo group (hazard ratio [HR] = 0.22, 95% CI = 0.14–0.35, P < .0001). In an updated analysis including 170 vs 88 patients, median progression-free survival was 11.0 months vs 1.9 months (HR = 0.22, 95% CI = 0.15–0.31). Objective response rate among the first 100 randomly assigned patients was 15% vs 0% (P = 0.0281, not meeting the prespecified significance boundary of .01).

How It Is Used

The recommended dose of cabozantinib is 60 mg once daily in adults and pediatric patients with a body surface area (BSA) ≥ 1.2 m² and 40 mg once daily in pediatric patients with a BSA < 1.2 m² until disease progression or unacceptable toxicity.

Product labeling provides instructions on dosage modification, including dose reduction, for adverse reactions including hemorrhage, perforations and fistulas, thrombotic events, hypertension and hypertensive crisis, diarrhea, palmar-plantar erythrodysesthesia (PPE), proteinuria, osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome, and intolerable grade 2 reactions and grade 3 or 4 reactions. Product labeling provides instructions for concomitant use with strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, diltiazem) or inducers (phenobarbital, phenytoin, rifampicin) and in moderate and severe hepatic impairment.

Safety Profile

Among 125 patients receiving cabozantinib in the primary analysis in COSMIC-311, the most common adverse events of any grade (≥ 25%) were diarrhea (51%), PPE (46%), fatigue (42%), hypertension (30%), and stomatitis (26%). The most common grade 3 or 4 adverse events included PPE (10%), hypertension (10%), and fatigue (10%). The most common grade 3 or 4 laboratory abnormalities were increased lactate dehydrogenase (10%) and hypocalcemia (8%). Serious adverse events occurred in 34% of patients (diarrhea, pleural effusion, pulmonary embolism, and dyspnea in ≥ 2% each). Adverse events led to treatment discontinuation in 5%. Fatal adverse events occurred in 1.6% of patients, including arterial hemorrhage and pulmonary embolism.

Cabozantinib has warnings/precautions for hemorrhage, perforations and fistulas, thrombotic events, hypertension and hypertensive crisis, diarrhea, PPE, hepatotoxicity, adrenal insufficiency, proteinuria, osteonecrosis of the jaw, impaired wound healing, reversible posterior leukoencephalopathy syndrome, thyroid dysfunction, hypocalcemia, and embryofetal toxicity. Patients should be advised not to breastfeed while receiving cabozantinib. 

REFERENCE

1. Cabometyx (cabozantinib) tablets prescribing information, Exelixis, Inc, September 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s012lbl.pdf. Accessed September 30, 2021.