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

• Published in: Journal of clinical oncology Vol. 35; no. 29; pp. 3315 - 3321
• Main Authors: Cabanillas, Maria E, de Souza, Jonas A, Geyer, Susan, Wirth, Lori J, Menefee, Michael E, Liu, Stephen V, Shah, Komal, Wright, John, Shah, Manisha H
• Format: Journal Article
• Language: English
• Published: United States American Society of Clinical Oncology 10.10.2017
• Subjects: Adult; Aged; Aged, 80 and over; Anilides - adverse effects; Anilides - therapeutic use; Cell Differentiation; Chemotherapy; Clinical Trials; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; ORIGINAL REPORTS; 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
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2017.73.0226

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.