Worldwide, thyroid cancer is the sixteenth most common malignant disease.1 About 298 000 new cases were diagnosed globally in 2012, with the highest incidence reported in North America.1 In the USA, an estimated 62 450 cases of differentiated thyroid cancer were diagnosed in 2015.2 Standard treatments include surgery, suppression of thyroid-stimulating hormone (TSH), and selective treatment with radioactive iodine.3, 4 However, 25–50% of patients with locally advanced or metastatic disease will become refractory to radioactive iodine.3
For patients who are not cured of their disease with surgery and radioactive iodine, few treatment options exist. Previously, the only agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), doxorubicin, showed little effectiveness and was associated with clinically significant toxic effects.5 In the past several years, clinical activity has been recorded with multikinase inhibitors for progressive differentiated thyroid cancer refractory to radioactive iodine.6, 7, 8, 9, 10, 11 Within this group of agents, sorafenib and lenvatinib have been approved by the FDA and the EMA based on results of pivotal phase 3 trials.12, 13 However, disease ultimately progresses in patients treated with either drug, and some individuals do not tolerate the side-effects (eg, hand-foot skin reaction and rash with sorafenib, and hypertension and asthenia with lenvatinib). Therefore, an unmet need remains: to develop additional molecularly targeted agents for treatment of these patients.
Research in context
Evidence before this study
BRAFV600E mutations occur in 37–50% of all patients with papillary thyroid cancer and correlate with aggressive tumour characteristics and decreased ability of tumours to incorporate radioactive iodine. We searched MEDLINE and Embase with the terms “thyroid cancer”, “BRAF inhibitor”, “vemurafenib”, and “dabrafenib” for peer-reviewed articles and abstracts published between Jan 1, 2010, and Dec 1, 2015, with no restriction by language. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAFV600E-positive melanoma, showed clinical benefit in three patients with BRAFV600E-positive papillary thyroid cancer in a phase 1 trial; one patient had a partial response lasting 7·6 months and two patients had stable disease for 11·4 months and 13·2 months. Four responses were also observed in patients with thyroid cancer as part of a phase 1 study of dabrafenib in BRAFV600E solid tumours.
Added value of this study
Our study is the first prospective phase 2 trial to assess vemurafenib in patients with papillary thyroid cancer refractory to radioactive iodine and harbouring the BRAFV600E mutation. Vemurafenib showed antitumour activity in two cohorts of patients: those who had never received a multikinase inhibitor targeting VEGFR and those previously treated with a VEGFR multikinase inhibitor. Best overall response, duration of response, and progression-free survival were encouraging in patients who had never received a VEGFR multikinase inhibitor. Best overall response was also promising in patients previously treated with a multikinase inhibitor targeting VEGFR. The overall toxicity profile was generally consistent with that reported in patients with melanoma treated with a BRAF inhibitor.
Implications of all the available evidence
Vemurafenib has shown activity in patients with progressive, BRAFV600E-positive papillary thyroid cancer refractory to radioactive iodine. Further investigation is warranted.
Most patients with differentiated thyroid cancer have papillary thyroid cancer. The somatic BRAFV600E mutation is found in 37–50% of patients with papillary thyroid cancer, mainly in classic or tall-cell variants.14, 15, 16 Presence of this mutation at diagnosis of papillary thyroid cancer correlates with aggressive tumour characteristics, including extrathyroidal extension, advanced tumour stage at presentation, lymph node or disease metastasis, and, possibly, increased cancer-related mortality.17, 18 Furthermore, tumours harbouring the BRAFV600E mutation have a decreased ability to incorporate radioactive iodine, resulting in treatment failure or recurrent disease.15, 17 The decrease in radioactive iodine uptake might, in part, be a result of dysregulation of the sodium iodide symporter that correlates with the presence of BRAFV600E.15 As a result, patients whose tumours harbour the BRAFV600E mutation might be more likely to need additional systemic treatment for recurrent and metastatic disease.
Vemurafenib is a kinase inhibitor specific for mutated BRAF kinase and is approved for the management of BRAFV600E-positive melanoma.19 Data from preliminary studies suggest that vemurafenib might have activity in BRAFV600E-positive papillary thyroid cancer.20, 21 Therefore, we aimed to assess the activity and safety of vemurafenib in patients with progressive papillary thyroid cancer refractory to radioactive iodine.