BRAF Inhibitor Dabrafenib in Patients with Metastatic BRAF-Mutant Thyroid Cancer
- 1 January 2015
- journal article
- research article
- Published by Mary Ann Liebert Inc in Thyroid®
- Vol. 25 (1), 71-77
- https://doi.org/10.1089/thy.2014.0123
Abstract
Background: Mutations of v-raf murine sarcoma viral oncogene homolog B (BRAF) are commonly identified in papillary and anaplastic thyroid carcinoma and are associated with worse prognosis compared with the wild type. BRAF inhibition in papillary thyroid carcinoma cell lines and xenografts inhibits proliferation and decreases downstream phosphorylation. Our objectives were to analyze safety and efficacy of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid carcinoma. Methods: We present the subset of patients with BRAF-mutant thyroid carcinoma enrolled in a larger phase 1 study, the main results of which are reported elsewhere. Results: Fourteen patients with BRAFV600E-mutant thyroid carcinoma were enrolled, of whom 13 (93%) had received prior radioactive iodine. The median duration on treatment was 8.4 months, and seven (50%) patients received treatment for ≥10 months. The most common treatment-related adverse events were skin papillomas (n=8, 57%), hyperkeratosis (n=5, 36%), and alopecia (n=4, 29%), all of which were grade 1. Treatment-related adverse events grade ≥3 included grade 4 elevated lipase and grade 3 elevated amylase, fatigue, febrile neutropenia, and cutaneous squamous cell carcinoma (n=1 for each). Four (29%) partial responses were observed, and nine (64%) patients achieved at least 10% decrease. Only one responder progressed while on the study drug after a response duration of 9.3 months. The other three responders had not progressed, with response duration of 4.6+, 10.4+, and 21.4+ months. With seven (50%) patients showing no progression at the time of study completion, the median progression-free survival was 11.3 months. Conclusions: Dabrafenib was well tolerated and resulted in durable responses in BRAF-mutant differentiated thyroid carcinoma patients.Keywords
This publication has 35 references indexed in Scilit:
- Relief of Feedback Inhibition of HER3 Transcription by RAF and MEK Inhibitors Attenuates Their Antitumor Effects in BRAF-Mutant Thyroid CarcinomasCancer Discovery, 2013
- ENDOCRINE TUMOURS: Approach to the patient with advanced differentiated thyroid cancerActa Endocrinologica, 2012
- Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic ProfilingJournal of Clinical Oncology, 2011
- Inhibition of Mutated, Activated BRAF in Metastatic MelanomaThe New England Journal of Medicine, 2010
- MEK Inhibitor PD0325901 Significantly Reduces the Growth of Papillary Thyroid Carcinoma Cells In vitro and In vivoMolecular Cancer Therapeutics, 2010
- BRAF mutation‐selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic‐potentiated synergism with the mTOR inhibitor temsirolimusInternational Journal of Cancer, 2010
- High Rate of BRAF and RET/PTC Dual Mutations Associated with Recurrent Papillary Thyroid CarcinomaClinical Cancer Research, 2009
- BRAFV600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomasBritish Journal of Cancer, 2007
- Mutations of the BRAF gene in human cancerNature, 2002
- New Guidelines to Evaluate the Response to Treatment in Solid TumorsJNCI Journal of the National Cancer Institute, 2000