On September 17, the U.S. Food and Drug Administration (FDA) approved cabozantinib (Cabometyx) for the treatment of adult and pediatric patients aged 12 years and older with locally advanced or metastatic differentiated thyroid cancer that has progressed following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine–refractory or ineligible. The FDA granted Breakthrough Therapy designation and Priority Review to cabozantinib, and its approval is more than 2 months ahead of the Prescription Drug User Fee Act target action date of December 4, 2021.
Cabozantinib is a tyrosine kinase inhibitor that inhibits the activity of the RET, MET, VEGFR2, and other receptor tyrosine kinases.
Marcia S. Brose, MD, PhD
“Before today, patients with radioactive iodine–refractory differentiated thyroid cancer who have progressed following prior VEGFR-targeted therapy were facing aggressive disease and no standard treatment option,” said Marcia S. Brose, MD, PhD, of Sidney Kimmel Cancer Center at Jefferson Torresdale Hospital and Sidney Kimmel Cancer Center at Thomas Jefferson University, as well as principal investigator of COSMIC-311. “In the COSMIC-311 pivotal phase III trial, cabozantinib extended the time patients live without progression of their cancer. The FDA approval of cabozantinib is an important advancement for these patients who are badly in need of new treatment options.”
The approval is based on results from COSMIC-311 (ClinicalTrials.gov identifier NCT03690388), which evaluated cabozantinib vs placebo in patients with radioactive iodine–refractory differentiated thyroid cancer who experienced disease progression after up to two prior VEGFR-targeted therapies. COSMIC-311 was a multicenter, randomized, double-blind, placebo-controlled phase III pivotal trial that enrolled 258 patients at 164 sites globally. Patients were randomly assigned in a 2:1 ratio to receive either cabozantinib at 60 mg or placebo once daily. The primary endpoints were progression-free survival and objective response rate.
At a planned interim analysis, cabozantinib significantly reduced the risk of disease progression or death vs placebo (P < .0001) in the intent-to-treat population. At a follow-up analysis with a median follow-up of 10.1 months, the median progression-free survival as assessed by blinded independent radiology committee was 11.0 months for patients treated with cabozantinib compared with 1.9 months for patients treated with placebo (hazard ratio = 0.22, 95% confidence interval = 0.15–0.31).
The most common adverse events reported in at least 25% of patients treated with cabozantinib were diarrhea, palmar-plantar erythrodysesthesia, fatigue, hypertension, and stomatitis. Grade 3 or 4 adverse events that occurred in at least 5% of patients were palmar-plantar erythrodysesthesia, hypertension, fatigue, diarrhea, and stomatitis. Serious adverse events occurred in 34% of patients who received cabozantinib, and the most common serious events reported in at least 2% of patients included diarrhea, pleural effusion, pulmonary embolism, and dyspnea. Fatal adverse events occurred in 1.6% of patients treated with cabozantinib, including arterial hemorrhage (0.8%) and pulmonary embolism (0.8%). Dose reductions were required in 56% of patients treated with the agent, and 22% of patients required a second dose reduction. Adverse events leading to discontinuation of cabozantinib occurred in 5% of patients.