Vemurafenib Active in BRAF-Mutated Thyroid Cancer

Results of a phase II study indicated that the BRAF inhibitor vemurafenib was active in patients with BRAFV600E–mutated papillary thyroid cancer who were refractory to radioactive iodine.

“To our knowledge, our trial represents the first prospective clinical trial and the largest dataset to assess treatment with vemurafenib for this patient population,” Marcia S. Brose, MD, of the Abramson Cancer Center, University of Pennsylvania, and colleagues wrote in Lancet Oncology. “Although the clinical usefulness of screening all patients with papillary thyroid cancer for BRAF V600E mutations at the time of diagnosis remains to be elucidated, our data suggest that screening for these mutations in the setting of disease refractory to radioactive iodine could identify potential treatment options offering clinical benefit for these patients.”

Vemurafenib is currently approved for the treated of BRAF V600E–positive melanoma. These mutations also occur in about 37% to 50% of patients with papillary thyroid cancer, and are associated with more aggressive tumors. A phase I trial of vemurafenib found that three patients with BRAF V600E–positive thyroid cancer had clinical benefit from the drug.

This phase II trial, conducted at 10 centers, included 51 patients enrolled into two cohorts. Cohort 1 was patients who had never received a multikinase inhibitor targeting VEGFR; cohort 2 was patients who had. All patients received vemurafenib 960 mg orally twice daily. The primary endpoint was best overall response in cohort 1.

In cohort 1, a best overall response of partial response occurred in 38.5% of patients, with nine patients achieving stable disease for at least 6 months. Seventy-three percent of patients were considered to have achieved disease control. The median progression-free survival was 18.2 months with a median duration of response of 16.5 months. The median overall survival not yet reached.

“The median progression-free survival for cohort 1 suggests that targeting the BRAF V600E mutation might provide additional treatment options in patients with papillary thyroid cancer who harbor this mutation and have never been treated with a multikinase inhibitor,” the researchers wrote.

In cohort 2, a best overall response of partial response occurred in 27.3% of patients, and 27.3% of patients achieved stable disease for at least 6 months. Fifty-five percent of patients achieved disease control. The median progression-free survival was 8.9 months with a median duration of response of 7.4 months and a median overall survival of 14.4 months.

“A greater proportion of patients in cohort 1 achieved a response and had longer progression-free survival compared with those in cohort 2. However, most patients in cohort 2 were heavily pretreated and had been exposed to many other agents in addition to a VEGFR multikinase inhibitor,” the researchers wrote, adding that despite this, the best overall response rate and median progression-free survival still suggest a clinical benefit for these patients.

Sixty-five percent of patients in cohort 1 and 68% of patients in cohort 2 had a grade 3 or 4 adverse events, the most common of which were squamous cell carcinoma of the skin, lymphopenia, and increased γ-glutamyl transferase. Serious adverse events occurred in 62% of patients in cohort 1 and 68% of patients in cohort 2.