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Medullary thyroid cancer (MTC), a neuroendocrine tumor arising from the parafollicular C cells of the thyroid gland, is rare and accounts for approximately 5% of all thyroid cancers. The majority of cases of MTC are sporadic, and in roughly 25% of cases, MTC is part of a hereditary cancer syndrome with a well-characterized germline RET mutation: multiple endocrine neoplasia 2A, multiple endocrine neoplasia (MEN) 2B, or familial MTC. Patients with newly diagnosed disease are treated with surgery. Calcitonin and carcinoembryonic antigen (CEA) are useful blood markers and are often used to monitor patients after surgery. Systemic chemotherapy and radiation therapy are not believed to represent important or useful options for most patients with MTC. Patients with metastatic disease are not curable and are often monitored with serial scans and biochemical markers. Metastatic MTC can be quite indolent, and timing to initiate therapy varies greatly among physicians and practices. Until recently, no satisfactory options existed for treating patients with metastatic disease in need of therapy. In 2011, the US Food and Drug Administration approved vandetanib (which targets RET, epidermal growth factor receptor, and vascular endothelial growth factor receptor) for the treatment of patients with symptomatic or progressive, locally advanced, or metastatic MTC. This approval was based on the Zactima Efficacy in Thyroid Cancer Assessment (ZETA) phase III study. In 2012, the US Food and Drug Administration also approved cabozantinib for the same indication on the basis of the Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial reported in the article that accompanies this editorial. The ZETA study was a randomized double-blind phase III trial in which patients were randomly assigned in a 2:1 fashion to receive oral vandetanib 300 mg per day (n 231) or a placebo (n 100) until disease progression. The primary end point was progression-free survival (PFS), and relevant secondary end points were objective response rate, overall survival, biochemical response, safety, and tolerability. Patients who were enrolled onto the ZETA trial were not required to have progressive disease before enrollment but were required to have measurable disease at baseline and a calcitonin level of at least 500 pg/mL. The study showed a significant prolongation of PFS with vandetanib versus the placebo (hazard ratio, 0.46; 95% CI, 0.31 to 0.69; P .001). Statistically significant advantages for vandetanib were also seen for objective response rate, disease control rate, and biochemical response. This study allowed patients receiving the placebo to cross over to vandetanib, and an overall survival advantage was not seen at the time of the initial report. The median duration of treatment in the randomized phase was 90.1 weeks for vandetanib and 39.9 weeks for the placebo. The ZETA trial clearly included many patients with indolent disease, as evidenced by a PFS of 19.3 months in the placebo group (with an estimated PFS of 30 months in the vandetanib group). Adverse events such as diarrhea, rash, nausea, and hypertension occurred in more than 30% of patients receiving vandetanib. More patients required dose reduction of vandetanib compared with the placebo for adverse events or QTc prolongation (35% v 3%). Nineteen patients (8%) developed protocol-defined QTc prolongation, but there were no reports of torsades de pointes. The rate of treatment discontinuation because of toxicity was 12%. Because of this risk of QT prolongation, vandetanib is currently only available through the US Food and Drug Administration Vandetanib Risk Evaluation Mitigation Strategy Program. This program is meant to educate practitioners about the risk, appropriate monitoring, and management of QT prolongation should it occur during vandetanib therapy. The EXAM study that is reported in the article that accompanies this editorial sought to examine the effect of cabozantinib in progressive MTC. Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets three potentially important pathways in MTC: MET, vascular endothelial growth factor receptor 2, and RET. EXAM is a double-blind phase III trial comparing oral cabozantinib at 140 mg per day with a placebo in 330 patients with documented radiographic progression of metastatic MTC. The primary end point is PFS. Other end points are response rate, overall survival, and safety. This study also used a 2:1 randomization schema, but unlike the ZETA trial, the EXAM study did not allow cross over to the active drug. The study met its primary end point of prolongation of PFS: 11.2 months for cabozantinib versus 4 months for the placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.4; P .001). There is no survival advantage noted so far, and analysis is ongoing for the overall survival end point. Objective tumor response rates and biochemical responses were also significantly improved with cabozantinib. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 29 OCTOBER 1

How to Incorporate New Tyrosine Kinase Inhibitors in the Treatment of Patients With Medullary Thyroid Cancer