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

Autor: Ezra E.W. Cohen, Lori J. Wirth, Marcia S. Brose, Steven I. Sherman, Huibin Yue, Maria E. Cabanillas, Eric J. Sherman, Todd Riehl
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
Indoles
Papillary
Radiation Tolerance
Papillary thyroid cancer
Immunoenzyme Techniques
Iodine Radioisotopes
0302 clinical medicine
Clinical endpoint
Precision Medicine
Vemurafenib
6.2 Cellular and gene therapies
Cancer
Sulfonamides
Tumor
Middle Aged
Prognosis
Survival Rate
Oncology
030220 oncology & carcinogenesis
6.1 Pharmaceuticals
Lymphatic Metastasis
Cohort
Female
medicine.drug
Proto-Oncogene Proteins B-raf
medicine.medical_specialty
Clinical Trials and Supportive Activities
Oncology and Carcinogenesis
Antineoplastic Agents
Article
03 medical and health sciences
Clinical Research
Internal medicine
medicine
Carcinoma
Biomarkers
Tumor
Humans
Oncology & Carcinogenesis
Thyroid Neoplasms
Adverse effect
Survival rate
Aged
Neoplasm Staging
Salvage Therapy
business.industry
Evaluation of treatments and therapeutic interventions
medicine.disease
Carcinoma
Papillary
Surgery
Clinical trial
030104 developmental biology
Mutation
business
Biomarkers
Follow-Up Studies
Zdroj: The Lancet. Oncology, vol 17, iss 9
ISSN: 1474-5488
Popis: Summary 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.
Databáze: OpenAIRE
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