Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial

Thyroid. 2022 Oct;32(10):1184-1192. doi: 10.1089/thy.2022.0115. Epub 2022 Jul 5.

Abstract

Background: Oncogenic BRAF mutations are commonly found in advanced differentiated thyroid cancer (DTC), and reports have shown efficacy of BRAF inhibitors in these tumors. We investigated the difference in response between dabrafenib monotherapy and dabrafenib + trametinib therapy in patients with BRAF-mutated radioactive iodine refractory DTC. Methods: In this open-label randomized phase 2 multicenter trial, patients aged ≥18 years with BRAF-mutated radioactive iodine refractory DTC with progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 13 months before enrollment were eligible. Patients were randomly assigned to receive dabrafenib alone or dabrafenib + trametinib. The primary endpoint was objective response rate by modified RECIST (minor response of -20% to -29%, partial and complete response) within the first 24 weeks of therapy. Trial Registration Number: NCT01723202. Results: A total of 53 patients were enrolled. The objective response rate (modified RECIST) was 42% (11/26 [95% confidence interval {CI} 23-63%]) with dabrafenib versus 48% (13/27 [CI 29-68%]) with dabrafenib + trametinib (p = 0.67). Objective response rate (RECIST 1.1) was 35% (9/26 [CI 17-56%]) with dabrafenib and 30% (8/27 [CI 14-51%]) with dabrafenib + trametinib. Most common treatment-related adverse events included skin and subcutaneous tissue disorders (17/26, 65%), fever (13/26, 50%), hyperglycemia (12/26, 46%) with dabrafenib alone and fever (16/27, 59%), nausea, chills, fatigue (14/27, 52% each) with dabrafenib + trametinib. There were no treatment-related deaths. Conclusions: Combination dabrafenib + trametinib was not superior in efficacy compared to dabrafenib monotherapy in patients with BRAF-mutated radioiodine refractory progressive DTC.

Keywords: BRAF; kinase inhibitor; targeted therapy; thyroid cancer.

Publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma*
  • Adolescent
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Humans
  • Iodine Radioisotopes / therapeutic use
  • Melanoma* / drug therapy
  • Mutation
  • Oximes / adverse effects
  • Proto-Oncogene Proteins B-raf / genetics
  • Pyridones / adverse effects
  • Pyrimidinones / adverse effects
  • Thyroid Neoplasms* / drug therapy
  • Thyroid Neoplasms* / genetics
  • Thyroid Neoplasms* / radiotherapy

Substances

  • dabrafenib
  • Proto-Oncogene Proteins B-raf
  • Iodine Radioisotopes
  • Pyrimidinones
  • Pyridones
  • Oximes
  • BRAF protein, human

Associated data

  • ClinicalTrials.gov/NCT01723202