Completing the Arc: Targeted Inhibition of RET in Medullary Thyroid Cancer

In Journal of Clinical Oncology, Wells et al present the results of the ZETA (Zactima Efficacy in Thyroid Cancer Assessment) trial, a phase III randomized, double-blind, placebo-controlled trial of vandetanib in patients with sporadic and hereditary medullary thyroid cancer (MTC). Vandetanib (formerly ZD6474) is a small-molecule tyrosine kinase inhibitor of RET, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor (VEGFR) kinases. In ZETA, patients with advanced MTC who were randomly assigned to treatment with vandetanib had significantly longer progression-free survival than those randomly assigned to treatment with placebo. The results of the ZETA trial led the US Food and Drug Administration to approve vandetanib for treatment of symptomatic or progressive MTC earlier this year. This is the first drug approved for MTC and the first TKI approved for any thyroid cancer indication. Thyroid cancer has a rising incidence, with an estimated 45,000 new cases diagnosed in the United States in 2011. MTC accounts for 3% to 5% of total thyroid cancer cases. In 10% to 20% of MTCs, a germline mutation in RET causes the hereditary syndrome of multiple endocrine neoplasia type 2A or 2B (MEN2A/B), which is variably associated with pheochromocytoma and parathyroid hyperplasia. MEN2 syndromes are characterized by strong correlations between mutant RET genotype and clinical phenotype, and treatment decisions are genotype driven. For example, mutations in RET codon 634 commonly lead to both MTC and pheochromocytoma, whereas mutations in codon 883 lead to MTC but rarely to pheochromocytoma. In 80% to 90% of MTCs, the disease arises sporadically in C cells. A majority of sporadic MTCs are caused by the M918T mutation. RET is a receptor tyrosine kinase that binds glial cell line– derived neurotrophic factor (GFR ) receptors bound to ligands of the glial cell line– derived neurotrophic factor (GDNF) family (Fig 1). Activation of RET has been shown to signal through multiple pathways, including Ras/extracellular signal-regulated kinase, phosphotidylinositol-3-kinase, SRC, phospholipase C , Jun-N terminal kinase, and signal transducer and activator of transcription 3. Both sporadic and hereditary MTCs arise from gain of function, activating mutations in RET. Mutations in the extracellular coding region (exons 8, 10, and 11) lead to ligand-independent dimerization and phosphorylation. Mutations in the intracellular kinase domain (exons 13 to 16) activate enzymatic activity and in some cases seem to alter substrate specificity. In some cases of hereditary MTC, mutations in RET cannot be identified, raising the possibility of mutations in other yet to be identified genes. RET function is required for development of sympathetic neurons in the enteric nervous system, and loss of function mutations in RET are a cause of aganglionic megacolon in Hirschprung disease. RET is subject to recurrent translocations in 10% to 30% of papillary thyroid cancers (PTCs). RET is translocated with several partner proteins, most commonly CCDC6 (PTC1) and NCOA4 (PTC3). Individuals exposed to ionizing radiation are at risk for developing PTC with RET translocations. Translocation of RET has been shown to result in constitutive activation of the kinase domain and transformation of papillary thyrocytes. Treatment of PTC cell lines harboring RET/PTC1 rearrangements with vandetanib induced growth arrest in vitro. Vandetanib also inhibited growth in vitro and tumorigenicity in vivo performed with NIH-3T3 cells transformed with RET/PTC3. These studies suggest that vandetanib may have a clinical role in the treatment of patients with RET/PTC-rearranged PTCs. A phase II study of vandetanib in differentiated thyroid cancer has been conducted, but the results have not yet been published. Further clinical investigation might also explore the role of vandetanib as a preventative therapy for patients at high risk of developing PTC postradiation exposure. Are the antitumor effects of vandetanib the result of RET inhibition or inhibition of EGFR, VEGFR, or other kinases? There are in vitro data suggesting that EGFR may be an important target in MTC, suggesting that the dual inhibition of RET and EGFR may contribute to the efficacy of vandetanib. Yet, in a phase II study of the EGFR inhibitor gefitinib in thyroid cancer, no objective responses were observed (four patients with MTC). It is also possible that inhibition of VEGFR2 contributes to the antitumor activity of vandetanib by an antiangiogenic effect. Genetic studies will be required to dissect these possibilities. MTC is associated with hypersecretion of calcitonin, carcinoembryonic antigen, and other neuropeptide hormones. In patients with MTC, elevated calcitonin often causes a secretory diarrhea proportional to the degree of elevation. In ZETA, treatment with vandetanib was associated with dramatic reductions of calcitonin (biochemical response rate: vandetanib, 69% v placebo, 3%), yet it was still associated with diarrhea (diarrhea any grade: vandetanib, 56% v placebo, 26%). Because adverse event data capture the peak, it is difficult to know what the trend in diarrhea was with treatment. Reported stool frequency was not significantly different between vandetanib and placebo. Additional studies may shed more light on the magnitude of symptom improvement with vandetanib treatment. JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 30 NUMBER 2 JANUARY 1