Vemurafenib Effective for BRAF-Mutant Thyroid Cancer

Marcia Brose, MD, PhD

Treatment with vemurafenib (Zelboraf) demonstrated an objective response rate (ORR) of up to 38.5% for patients with radioactive iodine (RAI)-refractory BRAF V600E-mutant papillary thyroid cancer who were multikinase inhibitor (MKI)-naive, according to findings from a phase II study published in Lancet Oncology.

In addition to responses, 9 of the 26 MKI-naive patients (35%) treated with vemurafenib had stable disease for at least 6 months. The overall disease control rate was 73%. The median progression-free survival (PFS) with vemurafenib was 18.2 months and the median overall survival (OS) was not yet reached.

“For this group of patients, who have little to no options, that’s a significant improvement,” Marcia Brose, MD, PhD, an associate professor of Otorhinolaryngology, Head and Neck Surgery, at the Hospital of the University of Pennsylvania, said in a statement. “This promising clinical trial is the next step in a series of trials to identify new drugs that are fundamentally shifting the horizon — improving the outcome for patients with advanced differentiated thyroid cancer.”

In the open-label study, 51 patients with BRAF mutations were selected out of 116 participants. Twenty-six patients (51%) had not received a prior VEGFR MKI (cohort 1) and 25 (49%) had received prior treatment (cohort 2). Vemurafenib was administered at a starting dose of 960 mg twice daily to a majority of patients; however, a dispensing error in cohort 2 resulted in 1 patient receiving a dose of 480 mg twice daily. The median cumulative dose of vemurafenib in cohort 1 was 619.3 g and in cohort 2 it was 293.8 g.

Approximately half of patients were ≥65 years, and most had metastatic disease (88% to 92%). In the pretreated group, the prior number of therapies was ≥3 for 36% of patients. The most common (84%) prior therapy was sorafenib (Nexavar). In cohort 1, 73% of patients had not received a prior treatment for advanced disease, with the remaining patients having received chemotherapy.

In the pretreated cohort, 3 patients dropped out of the study prior to receiving treatment. Of the 22 remaining patients, 6 had a partial response (27.3%) and another 6 had stable disease for at least 6 months (27.3%). The overall disease control rate was 55%, the median PFS was 8.9 months, and the median OS was 14.4 months.

At the time of the analysis, which was April 2014, 73% of patients enrolled in cohort 1 had discontinued therapy, 27% of which were from adverse events (AEs). In cohort 2, 80% had discontinued, 28% of which were from AEs.

Grade 1 increases in thyroid stimulating hormone (TSH) were reported in 8% and 4% of patients, in cohort 1 and cohort 2, respectively. Two patients enrolled in cohort 2 experienced grade 5 AEs, one of which was dyspnea and the other was multi-organ failure. Serious AEs were experienced by 62% of those in cohort 1 and by 68% of those in cohort 2.

Grade 3/4 AEs were experienced by 65% of those in cohort 1 and by 68% of those in cohort 2. The most common grade 3/4 AEs in cohort 1 and 2, respectively, were squamous cell carcinoma of the skin (27% and 20%), lymphopenia (8% and 8%), and increased gamma-glutamyltransferase (4% and 12%).

“Due to our prior successes in treating these patients with sorafenib and lenvatinib, patients are doing better, but they still ultimately progress, and additional agents with different mechanisms of action are needed,” Brose said. “Vemurafenib is the first non-VEGFR inhibitor to show activity in this patient population and as such is an important addition to our treatment options for these patients.”

A phase II study is currently assessing vemurafenib as a neoadjuvant treatment for patients with locally advanced thyroid cancer. This study, which hopes to enroll 22 patients, has a primary endpoint of percent change in extracellular-signal-regulated kinase. The secondary endpoint is ORR (NCT01709292).

Brose MS, Cabanillas ME, Cohen EEW, et al. Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial [Published online July 22, 2016]. Lancet Oncol. 2016; doi:10.1016/S1470-2045(16)30166-8.