Cabozantinib Approved for Rare Thyroid Cancer

November has been a month of thanksgiving for South San Francisco's Exelixis. On the 29^th, the U.S. Food and Drug Administration (FDA) okayed cabozantinib (Cometriq) for the treatment of progressive, metastatic medullary thyroid cancer (MTC). The European Medicines Agency also announced that it would review the company's application to market the drug for MTC in the European Union.

Earlier in the month, a phase II study published in the Journal of Clinical Oncology reported that cabozantinib showed antitumor activity in men with metastatic, castration-resistant prostate cancer.

Cabozantinib is a small molecule that inhibits the activity of multiple tyrosine kinases, including MET, VEGF receptor 2, and RET, which are involved in oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

FDA approval of cabozantinib to treat MTC was based on a phase III trial involving 330 patients who were randomly assigned to take either 140 mg of the drug or a placebo daily. The median progression-free survival times were 11.2 months and 4 months for patients in the cabozantinib and placebo arms, respectively. The median duration of response was 14.7 months.

At the planned interim analysis, researchers observed no significant difference in overall survival between the cabozantinib and placebo arms. Gisela Schwab, MD, chief medical officer at Exelixis, anticipates that final data on overall survival will be submitted to the FDA in late 2013 or 2014.

The FDA has also required Exelixis to include a boxed warning on cabozantinib's package stating that serious and fatal gastrointestinal perforations and fistulas, as well as hemorrhaging, may occur. To see if lower doses of the drug might reduce toxicity, Schwab said Exelixis will conduct a phase II study in patients with MTC that will compare the safety and effectiveness of the approved 140-mg dose with a 60-mg dose that is being tested in the treatment of other cancers.

The company is also moving ahead with phase III trials of cabozantinib in patients with metastatic prostate cancer that no longer responds to androgen deprivation, based on positive results in a phase II randomized discontinuation trial. In that trial, 171 men took 100 mg of the drug for 12 weeks. After that initial period, those with stable disease were randomly assigned to continue taking cabozantinib or to take a placebo. Random assignment was stopped early, however, because the drug demonstrated activity.

All of the men reported side effects, and most reported more than one. The most common side effects included fatigue, decreased appetite, taste changes, nausea, diarrhea, weight loss, and hand–foot syndrome. Side effects led to dose reductions, usually to 60 mg, in 62% of the patients.

Researchers reported that 72% of patients had regression of tumors in soft tissue, and 68% of patients who had follow-up bone scans showed improvement, with complete resolution of bone metastases in 12% of patients, findings that the researchers called “unprecedented.”

“It's something you don't regularly see in men with prostate cancer,” says David C. Smith, MD, a professor of medicine and urology at the University of Michigan and lead author of the study. “We've seen dramatic improvement on bone scans in individual cases, but not the consistent effect that we see here.”

When he first heard about some of the results and saw a bone scan from Smith, “I was skeptical,” says Philip Kantoff, MD, chief clinical research officer and director of the Lank Center for Genitourinary Cancer at Dana-Farber Cancer Institute (DFCI) in Boston. “We'd never seen anything like it in a prostate cancer patient before.” Subsequently, the DFCI patients who were enrolled in the trial showed significant improvement on their bone scans. “Our hope is that cabozantinib will lead to prolonged survival in phase III trials,” Kantoff adds.

One possible mechanism of resistance to androgen-deprivation therapy, a mainstay of advanced prostate cancer treatment, is upregulation of MET, says Smith. As a result, combining cabozantinib, which targets the MET pathway, and agents that inhibit androgen signaling, such as abiraterone (Zytiga; Janssen Biotech), may restore responsiveness to therapy.

Cabozantinib may also prove effective in other cancers with high MET expression, such as hepatocellular carcinoma and renal cell carcinoma, researchers say.