Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers

J Clin Endocrinol Metab. 2019 May 1;104(5):1417-1428. doi: 10.1210/jc.2018-01478.


Context: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI).

Objectives: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR).

Design: This was a pilot trial that enrolled from June 2014 to January 2016.

Setting: Academic cancer center.

Patients: Patients with RAIR, BRAF mutant thyroid cancer.

Intervention: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation.

Main outcome measure: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I.

Results: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048).

Conclusions: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.

Trial registration: NCT02145143.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cell Dedifferentiation
  • Cell Differentiation*
  • Female
  • Humans
  • Iodine Radioisotopes / therapeutic use*
  • Male
  • Middle Aged
  • Pilot Projects
  • Positron Emission Tomography Computed Tomography
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics
  • Radiation Tolerance
  • Thyroid Cancer, Papillary / diagnostic imaging
  • Thyroid Cancer, Papillary / genetics
  • Thyroid Cancer, Papillary / pathology
  • Thyroid Cancer, Papillary / therapy*
  • Thyroid Neoplasms / diagnostic imaging
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / therapy*
  • Thyrotropin Alfa
  • Vemurafenib / therapeutic use*


  • Iodine Radioisotopes
  • Protein Kinase Inhibitors
  • Thyrotropin Alfa
  • Vemurafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf

Associated data