FDA Approves Cabozantinib for Medullary Thyroid Cancer

Richard Pazdur, MD

The FDA approved cabozantinib (Cometriq), a multi-targeted tyrosine kinase inhibitor, for the treatment of metastatic medullary thyroid cancer (MTC) after a pivotal clinical trial showed that the drug more than doubled progression-free survival (PFS) when compared with a placebo.

Cabozantinib, previously known as XL-184, is an oral therapy that inhibits mutations in MET, VEGFR2, and RET. Early clinical studies showed that by targeting these mutations, cabozantinib was able to kill tumor cells, reduce metastases, and inhibit angiogenesis.

Medullary thyroid cancer develops in cells in the thyroid responsible for the production of calcitonin, a hormone that regulates the level of calcium in the blood. A relatively rare cancer, medullary thyroid cancer accounts for about 4% of the 56,460 thyroid cancer cases expected to be diagnosed in the United States in 2012 and the 1780 patients expected to die from the disease, according to the National Cancer Institute.

“Cometriq is the second drug approved to treat medullary thyroid cancer in the past two years and reflects FDA’s commitment to the development and approval of drugs for treating rare diseases,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement. “Prior to today’s approval and the approval of Caprelsa (vandetanib) in April 2011, patients with this rare and difficult to treat disease had limited therapeutic treatment options.”

Cabozantinib was approved based on the results of the phase III EXAM trial, updated results of which were presented at key meetings such as the American Society of Clinical Oncology (ASCO) meeting and the European Society of Medical Oncology (ESMO) congress earlier this year.

In the EXAM trial, 330 patients with MTC were randomized in a 2:1 ratio to receive either cabozantinib 140 mg daily (n = 219) or a placebo (n = 111). The study found that cabozantinib significantly increased PFS, with patients in the cabozantinib arm of the study experiencing a median PFS of 11.2 months compared with 4.0 months in the placebo arm (HR=0.28; 95% confidence interval [CI], 0.19—0.40; P < .0001). A PFS period of 12 months was achieved by 47.3% of patients in the cabozantinib arm compared with 7.2% of patients in the placebo arm.

Additionally, patients benefitted from cabozantinib regardless of RET mutation status. The respective hazard ratios for subpopulations in the study were 0.24 for RET-positive patients, 0.47 for RET-negative patients, and 0.30 for RET-unknown patients. However, the study was unable to show any difference in overall survival between the cabozantinib arm and the placebo arm.

Steven I. Sherman, MD

"There has been little clinical progress in treating advanced MTC until the introduction of targeted therapies, and it is gratifying to give these patients a new treatment option that has been shown in clinical trials to improve progression-free survival remarkably by nearly three-fold," said Steven I. Sherman, MD, Naguib Samaan Distinguished Professor in Endocrinology at MD Anderson Cancer Center and a senior investigator in the phase III EXAM study, in a statement. "The availability of a new therapeutic approach that has the potential to improve patient care and outcomes changes the MTC treatment landscape and provides patients and physicians with a new way to manage the disease."

The approval for cabozantinib comes with a boxed warning, alerting patients and health care professionals that severe and fatal bleeding and holes (perforations and fistula) in the colon occurred in some patients during clinical trials. Additionally, the FDA warned that the most common side effects observed in clinical trials were diarrhea, inflammation or sores of the mouth, hand-foot syndrome, weight loss, loss of appetite, nausea, fatigue, oral pain, graying or loss of hair color, bad taste, new or worsening high blood pressure, abdominal pain, and constipation.

Cabozantinib was approved under the FDA’s priority review program. This is the first approval for cabozantinib. The drug is being explored as a therapy for numerous tumor types, including prostate, ovarian, brain, melanoma, breast, and non-small cell lung cancers.

Cometriq is marketed by California—based Exelixis.

Cohen E, Elisei R, Schlumberger MJ, et al. Clinical activity and pharmacokinetics (PK) of cabozantinib (XL184) in patients with progressive medullary thyroid carcinoma (MTC). Presented at: 37th European Society of Medical Oncology 2012 Congress; September 28—October 2, 2012; Vienna, Austria. Abstract 445.