FDA Approves Cabozantinib for Medullary Thyroid Cancer

Roxanne Nelson

November 29, 2012

The US Food and Drug Administration (FDA) today approved cabozantinib (Cometriq, Exelixis), for the treatment of metastatic medullary thyroid cancer.

The review was completed in just 6 months under the FDA's priority review program. This program provides for an expedited review of pharmaceutical agents that may offer major advances in treatment or that provide therapy in cases where adequate treatment does not exist.

Cabozantinib has also been granted orphan-product designation by the FDA, as only about 4% percent of thyroid cancers are medullary, which makes it one of the rarer types of disease.

"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 in April 2011, patients with this rare and difficult to treat disease had limited therapeutic treatment options."

Cabozantinib is an oral inhibitor of multiple receptor tyrosine kinases, including RET, MET and vascular endothelial growth factor 2 (VEGFR2). These receptor kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

The agent's safety and efficacy was evaluated in an international, multicenter, randomized, controlled trial known as EXAM, which included 330 patients with progressive, metastatic medullary thyroid carcinoma. All study participants were required to have evidence of actively progressive disease within 14 months prior to study entry. Patients were randomized (2:1) to receive either cabozantinib 140 mg (n = 219) or placebo (n = 111) once daily until disease progression or intolerable toxicity.

The randomization was stratified by age (≤ 65 years vs > 65 years) and previous use of a tyrosine kinase inhibitor. No crossover was allowed at the time of progression. The main efficacy outcome measures were progression free survival, objective response, and response duration.

A statistically significant prolongation in progression-free survival was seen with cabozantinib compared with placebo (11.2 vs 4.0 months; P < .0001).

Partial responses were observed only among patients in the in the active treatment arm (27% vs 0%; P < .0001), and more patients in the cabozantinib group than in the placebo group were alive and free of disease progression at 1 year (47.3% vs 7.2%). Median duration of response was 14.7 months.

The most commonly reported adverse drug reactions (≥ 25%) were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, 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.

The prescribing information includes a boxed warning alerting patients and healthcare professionals that severe and fatal perforations and fistula in the colon have occurred in some patients.

Exelixis also announced today that the European Medicines Agency (EMA) has accepted for review the Marketing Authorization Application of cabozantinib for the proposed indication of treatment of progressive, unresectable, locally advanced, or metastatic medullary thyroid cancer. The completion of this validation process confirms that the submission is sufficient to permit a substantive review for marketing authorization in the European Union.