Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor-Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial

J Clin Oncol. 2017 Oct 10;35(29):3315-3321. doi: 10.1200/JCO.2017.73.0226. Epub 2017 Aug 17.


Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anilides / adverse effects
  • Anilides / therapeutic use*
  • Cell Differentiation*
  • Disease Progression
  • Disease-Free Survival
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Prospective Studies
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyridines / adverse effects
  • Pyridines / therapeutic use*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Salvage Therapy*
  • Signal Transduction / drug effects
  • Therapeutics
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / enzymology
  • Thyroid Neoplasms / mortality
  • Thyroid Neoplasms / pathology
  • Time Factors
  • United States


  • Anilides
  • Protein Kinase Inhibitors
  • Pyridines
  • cabozantinib
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Receptors, Vascular Endothelial Growth Factor