title: Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: Department of Otorhinolaryngology: Head and Neck Surgery, and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: brosem@mail.med.upenn.edu.
authors.forename: Marcia S
authors.initials: MS
authors.lastname: Brose
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Cabanillas
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Wirth
authors.affiliation: Product Development Clinical Oncology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Riehl
authors.affiliation: Biostatistics, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Huibin
authors.initials: H
authors.lastname: Yue
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Steven I
authors.initials: SI
authors.lastname: Sherman
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sherman
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000532:radiotherapy / Q000556:secondary; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000627:therapeutic use*; D007457:Iodine Radioisotopes / Q000009:adverse effects*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011836:Radiation Tolerance / Q000187:drug effects*; D016879:Salvage Therapy; D013449:Sulfonamides / Q000627:therapeutic use*; D015996:Survival Rate; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D007457:Iodine Radioisotopes; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf