On November 29, 2012, the U. S. Food and Drug Administration approved cabozantinib (COMETRIQ capsules, Exelixis, Inc), for the treatment of patients with progressive metastatic medullary thyroid cancer (MTC). Cabozantinib is a small molecule that inhibits the activity of multiple tyrosine kinases, including RET, MET, and VEGF receptor 2.
The approval was based on the demonstration of improved progression-free survival (PFS) observed in an international, multi-center, randomized (2:1), placebo-controlled trial enrolling 330 patients with metastatic MTC. Patients were required to have progressive disease within 14 months prior to entry.
Patients were randomized to receive cabozantinib 140 mg (n = 219) or placebo (n = 111) orally once daily. Randomization was stratified by age and prior tyrosine kinase inhibitor (TKI) use. Patients were treated until disease progression or intolerable toxicity. At the time of disease progression, cross-over to cabozantinib was not permitted in patients receiving placebo. An independent radiology review committee (IRC), using the modified RECIST criteria, determined radiographic progression and tumor response.
Of 330 patients, 67% were male, the median age was 55 years, 23% were 65 years or older, 54% had a baseline ECOG performance status of 0, and 92% had undergone thyroidectomy. Twenty-five percent (25%) received two or more prior systemic therapies and 21% had been previously treated with a TKI.
A statistically significant PFS prolongation was demonstrated in the cabozantinib arm compared to the placebo arm [HR 0.28 (95% CI: 0.19, 0.40); p <0.0001]. The estimated median PFS was 11.2 and 4.0 months for the cabozantinib and placebo arms, respectively.
The ORR was significantly higher in the cabozantinib arm (27% versus 0%; p<0.0001) and all were partial responses. The median response duration was 14.7 months (95% CI: 11.1, 19.3). No statistically significant difference in overall survival was observed between the treatment arms at the planned interim analysis and in an updated survival analysis requested by FDA.
Selected adverse reactions observed in ≥ 25% of cabozantinib-treated patients and at a higher incidence than in patients receiving placebo (difference ≥ 5%), were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes (hypopigmentation/graying), dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions which occurred in ≥ 5% of cabozantinib-treated patients and at a higher incidence than in patients receiving placebo (difference ≥ 2%), were diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite. The following serious adverse reactions attributed to cabozantinib included osteonecrosis of the jaw (n=1), reversible posterior leukoencephalopathy syndrome (n=1), pancreatitis (n=3), nephrotic syndrome (n=1), fatal hemorrhage (n=2), and fatal perforation/fistula (n=2).
The recommended dose and schedule for cabozantinib is 140 mg orally once daily; patients should not eat for at least 2 hours before and 1 hour after taking COMETRIQ. Dose reduction was required in 79% of patients.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and 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) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).