Vandetanib (ZACTIMA™; ZD6474): Preclinical and Clinical Development

Vandetanib ( ZACTIMA™; ZD6474) is a once-daily, orally available agent with potential for use in a number of solid tumour types. Vandetanib targets key signalling pathways in cancer by inhibiting vascular endothelial growth factor receptor (VEGFR)-dependent tumour angiogenesis and epidermal growth factor receptor (EGFR)-dependent tumour cell growth and survival. Vandetanib also inhibits RET (rearranged during transfection) kinase activity, which is involved in the development of several human diseases, including medullary and papillary carcinomas of the thyroid. Preclinical studies of vandetanib have demonstrated potent inhibition of VEGFand EGF-stimulated human umbilical vein endothelial cell proliferation in vitro, as well as dose-dependent inhibition of tumour growth in a histologically diverse range of human tumour xenografts. Phase I studies showed vandetanib to be generally well tolerated at doses up to 300 mg per day, with a pharmacokinetic profile that supports once-daily oral administration. Common adverse events included rash, diarrhea and asymptomatic QTc prolongation, all of which were controlled by standard management. Phase II evaluation of vandetanib in patients with advanced, refractory NSCLC (non-small-cell lung cancer) has demonstrated improvements in progression-free survival, both as monotherapy (versus gefitinib) and in combination with docetaxel (versus docetaxel alone). These positive outcomes haveled to the initiation of phase III trials of vandetanib in a broad population of patients with advanced NSCLC. Clinical development is also ongoing in other tumour types, and encouraging evidence of antitumour activity has been reported in patients with metastatic hereditary medullary thyroid cancer.