A new study shows that the BRAF inhibitor vemurafenib may induce partial responses and stable disease in patients with papillary thyroid cancer that has become refractory to radioactive iodine. However, the drug led to a variety of serious adverse events in roughly 65% of patients, including the development of some squamous cell carcinomas.

A new study suggests that the BRAF inhibitor vemurafenib (Zelboraf; Genentech) may be effective in the 25% to 50% of patients with papillary thyroid cancer who develop resistance to radioactive iodine, a standard treatment.

For patients with advanced or metastatic disease refractory to radioactive iodine, oncologists may prescribe lenvatinib (Lenvima; Eisai) or sorafenib (Nexavar; Bayer), multikinase inhibitors that block VEGFR. When tumors develop resistance to these drugs, oncologists have no other FDA-approved treatments to try. Yet because up to 50% of people with papillary thyroid cancer carry the BRAF V600E mutation, researchers have hypothesized that vemurafenib, already approved for patients with melanoma with the mutation, might provide another treatment option.

To test this possibility, Marcia Brose, MD, PhD, of the University of Pennsylvania in Philadelphia, and colleagues performed the first phase II trial of vemurafenib in papillary thyroid cancer. All 51 patients in the study carried the BRAF V600E mutation and had tumors refractory to radioactive iodine. The researchers divided them into two groups: One included 26 patients who had never been treated with multikinase inhibitors, and the other included 25 who had tumors that no longer responded to these drugs. Both groups received vemurafenib.

Among the patients who had never received multikinase inhibitors, the median progression-free survival (PFS) was 18.2 months, with 73% showing a partial response or achieving stable disease for at least 6 months. In the group that had previously been treated with multikinase inhibitors, the median PFS was 8.9 months, and 55% had a partial response or stable disease for at least 6 months. Because the trial didn't have a control group, the researchers couldn't determine whether the drug would outperform a placebo, but the results indicate that vemurafenib is “definitely active” in both groups of patients, says Brose.

Sixty-two percent of the patients who'd never been treated with multikinase inhibitors developed serious adverse events, versus 68% of the patients who had previously received multikinase inhibitors. These side effects included fatigue, diarrhea, pneumonia, and lymphopenia. In addition, 14 patients developed squamous cell carcinomas (SCC), which wasn't surprising: Vemurafenib has been tied to SCCs in patients with melanoma, and data suggest that it may stimulate existing lesions that carry RAS mutations. However, none of the secondary cancers in the current study harbored these mutations, so their cause is unknown.

Regardless, “this medication warrants further investigation in a phase III setting,” says Brose. “These patients have progressive disease that will kill them,” she says, noting that they can be monitored for SCCs.

The results suggest that vemurafenib is “able to stop [the cancer] for a certain amount of time,” says Linwah Yip, MD, of the University of Pittsburgh Medical Center in Pennsylvania, who wasn't connected to the study. She agrees that the data support further testing of the drug. “This could be an additional option” for patients, she says.

However, Herbert Chen, MD, of the University of Alabama at Birmingham School of Medicine, does not share the enthusiasm. “The drug had minimal clinical benefit,” he says, noting that there were no complete responses. “The side effects, particularly the potential to cause other cancers, are worrisome,” he adds. “I think we need to come up with better options.”

Brose says that no phase III trials of vemurafenib in thyroid cancer have been scheduled, but that other BRAF V600E–targeting drugs might also help patients who are refractory to radioactive iodine. For example, a phase II trial is testing dabrafenib (Tafinlar; GlaxoSmithKline) and the MEK inhibitor trametinib (Mekinist; GlaxoSmithKline) in those patients. –Mitch Leslie