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Vandetanib (ZD6474), a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR) and Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinases: Current Status and Future Directions

^aClinical Trials Unit, National Cancer Institute, Napoli, Italy; ^bCellular Biology and Biotherapy, National Cancer Institute, Napoli, Italy; ^cCentro di Ricerche Oncologiche di Mercogliano (CROM), Mercogliano (AV), Italy

Key Words. Vandetanib • VEGFR • EGFR • RET • Clinical trials

Correspondence: Correspondence: Francesco Perrone, M.D., Ph.D., National Cancer Institute, Via Mariano Semola, 80131 Naples, Italy. Telephone: 390815903522; Fax: 390817702938; e-mail: francesco.perrone{at}uosc.fondazionepascale.it or fr.perrone{at}agora.it

Received November 26, 2008; accepted for publication March 2, 2009.

Disclosures: Alessandro Morabito: None; Maria Carmela Piccirillo: None; Fabiano Falasconi: None; Gianfranco De Feo: None; Antonia Del Giudice: None; Jane Bryce: None; Massimo Di Maio: None; Ermelinda De Maio: None; Nicola Normanno: None; Francesco Perrone: None. Section editors <disclosures to come>. The article discusses unlabeled, investigational, or alternative uses of vandetanib (manufactured by AstraZeneca) in clinical trials in solid tumors. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias.

Vandetanib is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis: vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and REarranged during Transfection tyrosine kinase activity. Phase I clinical trials have shown that vandetanib is well tolerated as a single agent at daily doses 300 mg. In the phase II setting, negative results were observed with vandetanib in small cell lung cancer, metastatic breast cancer, and multiple myeloma. In contrast, three randomized phase II studies showed that vandetanib prolonged the progression-free survival (PFS) time of patients with non-small cell lung cancer (NSCLC) as a single agent when compared with gefitinib or when added to chemotherapy. Rash, diarrhea, hypertension, fatigue, and asymptomatic QTc prolongation were the most common adverse events. Antitumor activity was also observed in medullary thyroid cancer. Four randomized phase III clinical trials in NSCLC are exploring the efficacy of vandetanib in combination with docetaxel, the Zactima in cOmbination with Docetaxel In non-small cell lung Cancer (ZODIAC) trial, or with pemetrexed, the Zactima Efficacy with Alimta in Lung cancer (ZEAL) trial, or as a single agent, the Zactima Efficacy when Studied versus Tarceva (ZEST) and the Zactima Efficacy trial for NSCLC Patients with History of EGFR-TKI chemo-Resistance (ZEPHYR) trials. Based on a press release by the sponsor of these trials, the PFS time was longer with vandetanib in the ZODIAC and ZEAL trials; the ZEST trial was negative for its primary superiority analysis, but was successful according to a preplanned noninferiority analysis of PFS. Ongoing phase II and III clinical trials will better define the appropriate schedule, the optimal setting of evaluation, and the safety of long-term use of vandetanib.

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