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Cancer Drug Information

  • Updated: 07/02/2013

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FDA Approval for Cabozantinib-S-Malate

Brand name: Cometriq™

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.

  • Approved for progressive metastatic medullary thyroid cancer

On November 29, 2012, the Food and Drug Administration (FDA) approved cabozantinib-s-malate (Cometriq™ capsules, made by Exelixis, Inc), for the treatment of patients with progressive metastatic medullary thyroid cancer (MTC). Cabozantinib-s-malate 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 randomly assigned to receive cabozantinib-s-malate 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-s-malate 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 percent were male, the median age was 55 years, 23 percent were 65 years or older, 54 percent had a baseline ECOG performance status of 0, and 92 percent had undergone thyroidectomy. Twenty-five percent received two or more prior systemic therapies and 21 percent had been previously treated with a TKI.

A statistically significant PFS prolongation was demonstrated in patients treated with cabozantinib-s-malate compared with patients treated with placebo [HR 0.28 (95 percent CI: 0.19, 0.40); p <0.0001]. The estimated median PFS was 11.2 months for patients treated with cabozantinib-s-malate and 4.0 months for patients treated with placebo.

The objective response rate was significantly higher in patients treated with cabozantinib-s-malate (27 percent versus 0 percent; p<0.0001) and all were partial responses. The median response duration was 14.7 months (95 percent 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 at least 25 percent of  patients treated with cabozantinib-s-malate and at a higher incidence than in patients receiving placebo (difference at least 5 percent), 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 (at least 25 percent) were increased aspartate aminotransferase (AST), increased alanine transaminase (ALT), lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions that occurred in at least 5 percent of patients tretaed with cabozantinib-s-malate and at a higher incidence than in patients receiving placebo (difference at least 2 percent), were diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite. Serious adverse reactions attributed to cabozantinib-s-malate included one patient with osteonecrosis of the jaw, one patient with reversible posterior leukoencephalopathy syndrome, one patient with nephrotic syndrome, and three patients with pancreatitis. Two patients treated with cabozantinib-s-malate suffered a fatal hemorrhage, and two patients had fatal perforation/fistula.

The recommended dose and schedule for cabozantinib-s-malate is 140 mg orally once daily; patients should not eat for at least 2 hours before and 1 hour after taking cabozantinib-s-malate. Dose reduction was required in 79 percent of patients.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products, or Patricia Keegan, M.D., director of the FDA's Division of Clinical Trials Design and Analysis.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

For further information related to oncology drug approvals, regulatory information and other oncology resources, please refer to the FDA's Oncology Tools Web site.

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