Abstract
In a randomized phase III clinical trial, patients with metastatic differentiated cancer of the thyroid who were treated with sorafenib achieved median progression-free survival of 10.8 months, compared with 5.8 months among patients treated with placebo.
Patients with metastatic differentiated cancer of the thyroid don't have any effective treatment options if they develop resistance to standard radioactive iodine therapy. Doctors often perceive the only alternative—doxorubicin—as overly toxic, and it's not widely used, according to Ezra Cohen, MD, an associate professor of medicine and co-director of the Head and Neck Cancer Program at the University of Chicago Medicine in Illinois.
Now scientists are reporting positive results in metastatic thyroid cancer with sorafenib (Nexavar; Bayer and Onyx Pharmaceuticals), a multikinase inhibitor that blocks the activity of VEGF in addition to other targets. In the DECISION randomized phase III clinical trial, 417 patients received either sorafenib or a placebo. Those treated with sorafenib achieved median progression-free survival (PFS) of 10.8 months, compared with 5.8 months among patients treated with placebo, a statistically significant improvement.
“The DECISION trial shows that sorafenib is an active agent in refractory metastatic differentiated cancer of the thyroid,” said Marcia Brose, MD, PhD, an assistant professor at the University of Pennsylvania's Abramson Cancer Center and the trial's principal investigator. She presented the findings on June 2 at the American Society of Clinical Oncology 2013 Annual Meeting in Chicago, IL.
Conducted at 89 sites in the United States, Europe, and Asia, the DECISION trial included overall survival as a secondary endpoint, but those results have yet to mature and were not presented. Brose emphasized, however, that the PFS improvements produce meaningful clinical benefits, among them minimizing patient pain.
Sorafenib treatment could be most beneficial for patients with rapidly growing tumors, or tumors located near the spinal cord, major vessels in the chest, and other dangerous regions, Cohen added.
“These patients are likely to become symptomatic in the near term,” Cohen said. “If we can forestall symptoms with sorafenib, then that's what we should do.”
Brose pointed out that sorafenib was selected for the DECISION trial in part because thyroid cancer tends to be highly vascularized, as are the kidney and liver tumors that constitute the drug's currently approved indications.
However, the drug's mechanism of action in thyroid cancer remains unclear. Cohen said that drugs targeting the VEGF ligand, such as bevacizumab (Avastin; Genentech), apparently don't work against thyroid cancer, while small molecules targeting the VEGF receptor, such as sorafenib, do.
Analyses of sorafenib's activity in thyroid cancer may be further complicated because sorafenib inhibits not just VEGF but also RAF, PDGF, FLT3, Ret, and c-Kit, according to its manufacturers.
“We need to find out more about why sorafenib works against thyroid cancer,” Cohen said. “Then we need to investigate even more-effective therapies that might combine sorafenib with other inhibitors.”
If approved, sorafenib will be the first new treatment for metastatic differentiated cancer of the thyroid in 40 years.
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