VEGFR Inhibitor–Resistant Thyroid Cancer Responds to Cabozantinib

Multikinase inhibitors targeting the vascular endothelial growth factor receptor (VEGFR) have been approved for the treatment of radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, most patients develop resistance, and no second- or third-line therapies are available. MET can promote resistance to VEGFR inhibitors, and the multikinase inhibitor cabozantinib, which targets MET, RET, and VEGFR, achieved responses in a phase I trial of patients with VEGFR inhibitor–resistant DTC. Based on these findings, Cabanillas and colleagues evaluated cabozantinib as a salvage therapy in a single-arm phase II trial in 25 patients with RAI-refractory DTC that had progressed on prior VEGFR-targeted therapy. The primary endpoint was the objective response rate. Overall, 10 patients (40%) achieved partial responses, 13 patients (52%) experienced stable disease, and 2 (8%) were nonevaluable. The median duration of partial response was 11.3 months, the median progression-free survival was 12.7 months, and the median overall survival was 34.7 months. Partial responses were observed in 10 of 21 patients (48%) who had received only one prior VEGFR-targeted therapy, and no partial responses were observed in the 4 patients who had received two prior VEGFR-targeted therapies, although tumor reductions occurred in the 3 of these patients who were evaluable. Cabozantinib was generally well tolerated. The majority of treatment-related adverse events were mild to moderate and most commonly included fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension, but there was one treatment-related death. Taken together, these findings suggest that cabozantinib is tolerable and has antitumor activity in patients with VEGFR inhibitor–resistant RAI-refractory DTC, supporting its use as a salvage therapy in this patient population.

Cabanillas ME, de Souza JA, Geyer S, Wirth LJ, Menefee ME, Liu SV, et al. 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 Aug 17 [Epub ahead of print].

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