BACKGROUND: About half of patients with papillary thyroid cancer have tumours 
with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase 
inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three 
patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. 
We aimed to establish the activity of vemurafenib in patients with 
BRAF(V600E)-positive papillary thyroid cancer.
METHODS: We did an open-label, non-randomised, phase 2 trial at ten academic 
centres and hospitals worldwide in patients aged 18 years or older with 
histologically confirmed recurrent or metastatic papillary thyroid cancer 
refractory to radioactive iodine and positive for the BRAF(V600E) mutation. 
Participants either had never received a multikinase inhibitor targeting VEGFR 
(cohort 1) or had been treated previously with a VEGFR multikinase inhibitor 
(cohort 2). Patients received vemurafenib 960 mg orally twice daily. The primary 
endpoint was investigator-assessed best overall response in cohort 1 (confirmed 
on two assessments 4 weeks or longer apart). Analyses were planned to have a 
minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done 
in safety, intention-to-treat, and per-protocol populations. This trial is 
closed and is registered at ClinicalTrials.gov, number NCT01286753.
FINDINGS: Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to 
the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 
18·8 months (IQR 14·2-26·0) in cohort 1 and 12·0 months (6·7-20·3) in cohort 2. 
Partial responses were recorded in ten of 26 patients in cohort 1 (best overall 
response 38·5%, 95% CI 20·2-59·4). Grade 3 or 4 adverse events were recorded in 
17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the 
most common grade 3 and 4 adverse events were squamous cell carcinoma of the 
skin (seven [27%] in cohort 1, five [20%] in cohort 2), lymphopenia (two [8%] in 
each cohort), and increased γ-glutamyltransferase (one [4%] in cohort 1, three 
[12%] in cohort 2). Two individuals in cohort 2 died due to adverse events, one 
from dyspnoea and one from multiorgan failure, but neither was treatment 
related. Serious adverse events were reported for 16 (62%) of 26 patients in 
cohort 1 and 17 (68%) of 25 patients in cohort 2.
INTERPRETATION: Vemurafenib showed antitumour activity in patients with 
progressive, BRAF(V600E)-positive papillary thyroid cancer refractory to 
radioactive iodine who had never been treated with a multikinase inhibitor. As 
such, this agent represents a potential new treatment option for these patients.
FUNDING: F Hoffmann-La Roche.