Clinical Development of Vandetanib: A Review of Ongoing Phase III Clinical Trials in Advanced NSCLC

Abstract

Vandetanib (Zactima™, ZD6474) is a once-daily oral anticancer drug in phase III development for non–small-cell lung cancer (NSCLC). Additional studies in other tumor types are under way, such as those found in thyroid, breast, prostate, and colorectal cancers. In NSCLC, vandetanib targets tumor cell angiogenesis and proliferation via selective inhibition of the vascular endothelial growth factor receptor–2 and epidermal growth factor receptor tyrosine kinases. Vandetanib also inhibits RET kinase activity, an important factor in the proliferation of certain types of thyroid cancer. Promising results from phase I/II studies have led to the initiation of phase III studies of vandetanib in a broad population of patients who were previously treated for advanced NSCLC. To date, vandetanib has been generally well tolerated in clinical trials at daily doses of ≤ 300 mg, with common adverse events including rash, diarrhea, and asymptomatic QTc prolongation. The designs of the phase III vandetanib-alone and combination trials were based on the results of vandetanib in 2 phase II trials in advanced NSCLC (vandetanib vs. gefitinib and docetaxel with 100 mg or 300 mg vandetanib vs. docetaxel). The primary endpoint of both studies was prolongation of progression-free survival. In both studies, the primary endpoint was achieved. Progression-free survival was 11.9 weeks for vandetanib versus 8.1 weeks for gefitinib (hazard ratio, 0.63; 1-sided P = 0.013) and 18.7 weeks for vandetanib 100 mg with docetaxel versus 12 weeks for docetaxel (hazard ratio, 0.64; 1-sided P = 0.037; for the 300-mg arm, P = 0.231). Higher objective response rates and disease control rates were also observed in the vandetanib arms, although overall survival was not significantly prolonged. Currently, 4 phase III registration trials are being conducted with vandetanib alone or in combination with chemotherapy in patients with pretreated advanced NSCLC. Overall, these trials will evaluate the efficacy and safety of vandetanib in the second-/third-line setting. An overview of phase III trials including study design, endpoints, and current status will be presented.