Kinase inhibitors and antiangiogenic drugs may offer the first real hope of treating differentiated metastatic thyroid cancer, and seem to be especially effective in tumors exhibiting the B-type Raf kinase mutation.
Although such tumors are uncommon, there are no effective therapies for patients who develop them, Dr. Steven I. Sherman said at a thyroid cancer meeting sponsored by the American Thyroid Association.
“The standard treatment for thyroid cancer—radioactive iodine—is only effective as long as the cancer retains its ability to absorb and retain iodine,” said Dr. Sherman, medical director of the Endocrine Center at the M.D. Anderson Cancer Center, Houston. “At least half the time these metastatic tumors have lost that ability, and radioactive iodine won't work.”
For patients who have slow-growing, asymptomatic metastatic thyroid tumors, the adverse effects of treatment might be worse than the disease itself, Dr. Sherman said in an interview. “But for those whose cancer is progressing, affecting lung function, or causing bone problems, there is really no good option.”
The low incidence of these tumors has stymied many clinical trials: From 1975 to 1999, 15 trials were initiated and only 5 ended with published results, Dr. Sherman said.
However, recent discoveries of mutations that cause aggressive thyroid tumors have inspired new hope. The B-type Raf kinase (BRAF) mutation is the most important, accounting for about 40% of papillary thyroid cancers. “In papillary thyroid cancer, the BRAF tumors are more likely to be aggressive, to recur, and to be radioiodine resistant,” he said. BRAF mutations also occur in several other solid tumors, a fact that has added weight to this body of research.
The BRAF mutation interferes with tumor-suppressor genes and silences genes that metabolize iodine. It also increases the production of vascular endothelial growth factor (VEGF), making these tumors a potential target for antiangiogenics—drugs that shut off rampant tumor-feeding vascular growth.
Two small phase I trials of BRAF inhibitors have raised cautious enthusiasm, Dr. Sherman said.
Exelixis Inc. has released results of a trial of its compound, XL281, in 29 patients, 5 of whom had papillary thyroid cancer. The five patients with papillary thyroid cancer, two with a confirmed BRAF mutation, have had stable disease for up to 68 weeks, according to the company Web site.
PLX4032 is another BRAF inhibitor in phase I clinical trial, this one in joint development by Plexxikon Inc. and Roche.
“In these studies we are seeing stabilized disease, although not an overwhelmingly dramatic response, by inhibiting BRAF,” Dr. Sherman said.
A second group of trials has examined the effect of directly inhibiting VEGF receptors. Last year, Dr. Sherman published the results of a phase II trial of motesanib in differentiated thyroid cancer. The open-label trial comprised 93 patients with progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer. Stable disease occurred in 67% of the patients, and was maintained for 24 weeks or longer in 35% (N. Engl. J. Med. 2008;359:31–42).
BRAF-mutation tumors were particularly sensitive to motesanib. “The ability to stop the tumor's growth was twice as high in BRAF tumors,” Dr. Sherman said.
Two other 2008 trials examined the effects of sorafenib and axitinib in advanced thyroid cancers, with similar results, he said. “The thing all three trials have in common is the inhibition of the VEGF receptor. From these studies, we think there is strong evidence that antiangiogenic drugs offer a useful treatment for patients with metastatic differentiated thyroid cancer.”
The American Thyroid Association now recommends that patients with these tumors who are not enrolled in clinical trials be treated with one of the approved kinase inhibitors, preferably sorafenib.
Dr. Sherman said he has received research grants, honoraria, and speaking and consulting fees from numerous companies involved in cancer drug development, including Exelixis Inc., Amgen Inc., Bayer, and Plexxikon.