Vandetanib for the treatment of non-small-cell lung cancer

INTRODUCTION: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways. AREAS COVERED: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens. EXPERT OPINION: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

Epidermal growth factor receptor inhibitors in non-small-cell lung cancer

The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and in the progression of many human malignancies, including non-small-cell lung cancer (NSCLC). EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR is a valuable molecular approach in cancer therapy. This receptor is overexpressed in up to 80% of NSCLC cases. Thus, several molecules inhibiting this critical biologic pathway have been synthesized and tested as a single agent or in combination with other anticancer modalities in a wide of clinical trials, including reversible and irreversible small tyrosine kinase inhibitors, such as gefitinib and erlotinib, dual vascular endothelial growth factor receptor EGFR tyrosine kinase inhibitors, such as vandetanib (ZD-6474), and monoclonal antibodies, such as cetuximab, which have shown promising activity in patients with NSCLC. This review focuses on the preclinical and clinical results available with EGFR inhibitors in the treatment of NSCLC patients.     

Sunitinib: a newly approved small-molecule inhibitor of angiogenesis

The advent of targeted therapies has allowed treatment to be directed at signaling pathways integral to tumor growth and survival. Sunitinib (SU11248, sunitinib malate; Pfizer Inc., New York, NY, USA) is a novel oral small-molecule multitargeted receptor tyrosine kinase inhibitor that has demonstrated direct antitumor activity and antiangiogenic action. It targets the vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), stem-cell factor receptor and Fms-like tyrosine kinase receptor 3 receptor tyrosine-kinases. In January 2006, sunitinib malate was granted approval by the U.S. Food and Drug Administration for the treatment of gastrointestinal stromal tumor after disease progression on, or intolerance to, imatinib mesylate, as well as for the treatment of metastatic renal cell cancer. This review will discuss the development of sunitinib, particularly in acute myeloid leukemia, imatinib-resistant gastrointestinal stromal tumors and renal cell cancer. The review will also discuss ongoing trials with sunitinib in other malignancies such as neuroendocrine tumors and breast cancer, as well as its potential future development in combination therapy with other agents and in other malignancies.     

Vandetanib: An overview of its clinical development in NSCLC and other tumors

Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR) and Ret tyrosine kinases involved in tumor growth, progression and angiogenesis. Phase I studies indicated that the recommended dose of vandetanib as a single agent is 300 mg/day. Rash, diarrhea, hypertension and asymptomatic Q-Tc prolongation were the most common adverse events. Four randomized phase III clinical trials evaluated the efficacy of vandetanib in non-small cell lung cancer (NSCLC) in combination with docetaxel (ZODIAC), pemetrexed (ZEAL) or as a single agent (ZEST and ZEPHYR). Only the ZODIAC trial met its primary endpoint (progression-free survival [PFS]), while no study showed an advantage in overall survival with vandetanib. No significant antitumor activity has been observed in small cell lung cancer, advanced ovarian, colorectal, breast, prostate cancer and multiple myeloma. In advanced metastatic medullary thyroid cancer, one randomized phase III clinical trial has demonstrated that vandetanib can significantly improve response rate, PFS and time to worsening of pain. Several key questions remain to be addressed regarding the identification of clinical or molecular biomarkers predictive of response, the choice of the optimal dose or schedule of vandetanib and the safety of long-term administration. The results of ongoing trials in untreated patients with advanced NSCLC and other tumors should better define the optimal clinical application of vandetanib.     

Vandetanib for the treatment of non-small-cell lung cancer

Introduction: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways.

Areas covered: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens.

Expert opinion: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

Anti-epidermal growth factor receptor drugs in cancer therapy

The epidermal growth factor receptor is a cell membrane growth factor receptor that plays a key role in cancer development and progression. Epidermal growth factor receptor-activated signalling pathways control cell proliferation, apoptosis, angiogenesis and metastatic spread in the majority of human epithelial cancers. Targeting the epidermal growth factor receptor represents a valuable molecular approach to cancer therapy. Promising strategies in clinical development include monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity which prevent epidermal growth factor receptor autophosphorylation and propagation of downstream intracellular signals. Several anti-epidermal growth factor receptor agents are in clinical development for cancer therapy. Among these, IMC-225 (cetuximab), a chimeric human-mouse monoclonal IgG1 antibody, OSI-774 (Tarceva) and ZD1839 (Iressa), two small molecule epidermal growth factor receptor-selective tyrosine kinase inhibitors, are currently in Phase II and III development as single agents or in combination with conventional therapies, such as radiotherapy or chemotherapy. Results from Phase I - II trials in advanced cancer demonstrate that these drugs have an acceptable tolerability and an interesting clinical activity in patients with a variety of tumour types.     

Anti-epidermal growth factor receptor drugs in cancer therapy

The epidermal growth factor receptor is a cell membrane growth factor receptor that plays a key role in cancer development and progression. Epidermal growth factor receptor-activated signalling pathways control cell proliferation, apoptosis, angiogenesis and metastatic spread in the majority of human epithelial cancers. Targeting the epidermal growth factor receptor represents a valuable molecular approach to cancer therapy. Promising strategies in clinical development include monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity which prevent epidermal growth factor receptor autophosphorylation and propagation of downstream intracellular signals. Several anti-epidermal growth factor receptor agents are in clinical development for cancer therapy. Among these, IMC-225 (cetuximab), a chimeric human-mouse monoclonal IgG1 antibody, OSI-774 (Tarceva^?) and ZD1839 (Iressa^?), two small molecule epidermal growth factor receptor-selective tyrosine kinase inhibitors, are currently in Phase II and III development as single agents or in combination with conventional therapies, such as radiotherapy or chemotherapy. Results from Phase I – II trials in advanced cancer demonstrate that these drugs have an acceptable tolerability and an interesting clinical activity in patients with a variety of tumour types.     

Potential synergies for combined targeted therapy in the treatment of neuroendocrine cancer

Well differentiated neuroendocrine tumours (WDNET) are a diverse group of cancers that are often advanced at the time of diagnosis and generally do not respond significantly to traditional chemotherapy. A number of intriguing therapeutic targets have emerged, including somatostatin receptors, insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R), the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and vascular endothelial growth factor receptor. Functional somatostatin receptors and IGF-1R as well as dysregulated mTOR--a key pathway component for both growth factor signalling and protein synthesis--have been identified in human neuroendocrine tumour (NET) cell lines. Somatostatin analogues (SSA) and mTOR inhibitors have exhibited in vitro and in vivo antitumour activity against NET and have shown effects on the IGF-1 pathway in preclinical studies. SSA inhibit PI3K/Akt signalling upstream of mTOR, suggesting that the combination of an SSA and an mTOR inhibitor may have greater efficacy than either as single agents. Recent clinical trial experience has provided some encouraging findings and prompted the design of additional studies of this dual-targeted approach to treating advanced WDNET. Results of ongoing trials of dual-targeted therapy combinations will define future therapies for advanced WDNET.     

Epidermal growth factor receptor and signal transduction: potential targets for anti-cancer therapy

Agents targeting the epidermal growth factor receptor (EGFR) pathway hold particular promise for the treatment of patients with advanced disease, for whom standard chemotherapy is generally palliative. Expression of EGFR on numerous types of solid tumors, and the association of EGFR activation with tumorigenic processes including proliferation, anti-apoptosis and metastatic spread, make this pathway a particularly compelling target for rational drug design. The two classes of anti-EGFR agents in late-stage clinical testing include antibodies directed toward the extracellular EGFR domain (cetuximab, panitumumab) and small molecule tyrosine kinase inhibitors (gefitinib, erlotinib), which inactivate the receptor enzyme activity. However, important issues remain to be addressed. These include the development of appropriate predictive markers for response, such as improved tests for EGFR activity, correlation of rash with response and potential pharmacogenomic approaches; the sequencing and combination of these agents with chemotherapy and irradiation; and the possible role of these agents in the treatment of patients with earlier stage disease.     

Vandetanib: in medullary thyroid cancer

Vandetanib, an orally active, small-molecule, multitargeted tyrosine kinase inhibitor, demonstrates potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, epidermal growth factor receptor (EGFR) and the rearranged during transfection (RET) tyrosine kinase receptor. The large (n=331), randomized, double-blind, multinational ZETA trial compared vandetanib at a dosage of 300 mg once daily with placebo in patients with unresectable, locally advanced or metastatic, hereditary or sporadic, medullary thyroid cancer. During a median follow-up period of 2 years, vandetanib demonstrated statistically significant clinical benefits over placebo with respect to the primary endpoint, namely progression-free survival (PFS), and a range of secondary endpoints, which included objective response rate, disease control rate, time to worsening of pain and calcitonin biochemical response rate. The PFS benefit with vandetanib was mostly consistent across patient subgroups based on baseline characteristics and disease status. Although the correlation between RET mutation status and clinical outcome could not be clearly evaluated in this trial, it is notable that, among patients with sporadic disease, vandetanib not only demonstrated a PFS benefit in the subgroup confirmed as having a RET mutation, but also in the subgroup for whom the RET mutation status was unknown. Vandetanib was generally well tolerated in the ZETA trial; the majority of adverse events were manageable according to standard clinical practice alone or in combination with vandetanib dose reductions. The adverse event of most concern is corrected QT interval prolongation, particularly in view of the long terminal elimination half-life of the drug.     

Recent advances in targeted therapy for non-small cell lung cancer

Non-small-cell lung cancer (NSCLC) is characterized by wide molecular heterogeneity. In recent years, novel agents that target specific, aberrant molecular pathways in NSCLC have been under rigorous evaluation. Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, improves survival for advanced NSCLC patients who progressed following one or two prior chemotherapy regimens. Novel molecular predictive markers, such as EGFR mutations and gene amplification, are at present under evaluation to select patients for therapy with erlotinib. Another area of progress is the recent demonstration that bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), extended survival when administered in combination with chemotherapy for patients with non-squamous NSCLC. Promising anticancer activity has also been noted with agents that inhibit the VEGF receptor tyrosine kinase in patients with advanced NSCLC. Inhibitors of the proteosomal complex, histone deacetylase, mammalian target of rapamycin pathway, and other growth factor receptor-mediated signaling are under investigation for treatment of NSCLC. These developments have paved the way for a new era of tailor-made therapies based on clinical or molecular/genetic profiles in the treatment of NSCLC. This article reviews the recent advances in targeted therapy of advanced NSCLC.     

Recent advances in targeted therapy for non-small cell lung cancer

Non-small-cell lung cancer (NSCLC) is characterized by wide molecular heterogeneity. In recent years, novel agents that target specific, aberrant molecular pathways in NSCLC have been under rigorous evaluation. Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, improves survival for advanced NSCLC patients who progressed following one or two prior chemotherapy regimens. Novel molecular predictive markers, such as EGFR mutations and gene amplification, are at present under evaluation to select patients for therapy with erlotinib. Another area of progress is the recent demonstration that bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), extended survival when administered in combination with chemotherapy for patients with non-squamous NSCLC. Promising anticancer activity has also been noted with agents that inhibit the VEGF receptor tyrosine kinase in patients with advanced NSCLC. Inhibitors of the proteosomal complex, histone deacetylase, mammalian target of rapamycin pathway, and other growth factor receptor-mediated signaling are under investigation for treatment of NSCLC. These developments have paved the way for a new era of tailor-made therapies based on clinical or molecular/genetic profiles in the treatment of NSCLC. This article reviews the recent advances in targeted therapy of advanced NSCLC.     

Addition of PTK787/ZK 222584 can lower the dosage of amsacrine to achieve equal amounts of acute myeloid leukemia cell death

Acute myeloid leukemia (AML) is a disease with a poor prognosis. It has been demonstrated that AML cells express the vascular endothelial growth factors, VEGFA and VEGFC, as well as kinase insert domain-containing receptor (VEGFR2), the main receptor for downstream effects, resulting in an autocrine pathway for cell survival. This study investigates the role of the VEGFR inhibitor PTK787/ZK 222584 in leukemic cell death, and the possibility of an additional effect on cell death by a chemotherapeutic drug, amsacrine. In three AML cell lines and 33 pediatric AML patient samples, we performed total cell-kill assays to determine the percentages of cell death achieved by PTK787/ZK 222584 and/or amsacrine. Both drugs induced AML cell death. Using a response surface analysis, we could show that, in cell lines as well as in primary AML blasts, an equal magnitude of leukemic cell death could be obtained when lower doses of the more toxic amsacrine were combined with low dosages of the less toxic VEGFR inhibitor. This study shows that PTK787/ZK 222584 might have more clinical potential in AML when combined with a chemotherapeutic drug such as amsacrine. In future, it will be interesting to study whether the complications and the long-term effects of chemotherapy can be reduced by lowering the dosages of amsacrine, and by replacing it with other drugs with lower toxicity profiles, such as PTK787/ZK 222584.     

Inhibition of angiogenesis in cancer patients

Treatment with antiangiogenic agents as standard anticancer therapy with or without classical chemotherapy is rapidly approaching. The clinical efficacy of bevacizumab in colorectal cancer in combination with chemotherapy caused a revival of the antiangiogenic strategy. By combining this agent with a tyrosine kinase receptor epidermal growth factor receptor blocker (erlotinib), remarkable responses were seen in renal cell cancer. It has been thought that blocking these biological pathways would cause no drug-related toxicity, but a whole new pattern of relatively mild side effects compared with classical chemotherapy, including skin rash, fatigue and hypertension, has been observed. In combination with chemotherapy, other serious side effects, such as bleeding and thrombosis, also occur. Here, the preclinical and clinical data of antiangiogenic agents in clinical trials at this moment are summarised.     

Inhibition of angiogenesis in cancer patients

Treatment with antiangiogenic agents as standard anticancer therapy with or without classical chemotherapy is rapidly approaching. The clinical efficacy of bevacizumab in colorectal cancer in combination with chemotherapy caused a revival of the antiangiogenic strategy. By combining this agent with a tyrosine kinase receptor epidermal growth factor receptor blocker (erlotinib), remarkable responses were seen in renal cell cancer. It has been thought that blocking these biological pathways would cause no drug-related toxicity, but a whole new pattern of relatively mild side effects compared with classical chemotherapy, including skin rash, fatigue and hypertension, has been observed. In combination with chemotherapy, other serious side effects, such as bleeding and thrombosis, also occur. Here, the preclinical and clinical data of antiangiogenic agents in clinical trials at this moment are summarised.     

Anticancer therapeutics: "Addictive" targets, multi-targeted drugs, new drug combinations.

The annual meeting of the American Association for Cancer Research (AACR) provided a panoramic view of new developments and trends in cancer research. In the area of new drug development, a recurrent theme was receptor tyrosine kinase (TK) inhibitors, with multi-targeted, small molecule inhibitors - highly potent against a family of receptors such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor (PDGFR) and the receptor tyrosine kinase KIT - taking centre stage. Several agents interfering with intracellular targets that are components of key oncogenic signaling pathways, such as RAF kinase, phosphatidylinositol 3-kinase (PI3K)/Akt or Src, are in preclinical and early clinical development. "Addictive" targets, such as the Bcr-Abl fusion protein in chronic myeloid leukemia (CML), are critical for maintaining the malignant phenotype and hence represent an Achilles' heel for selective drugs. Significantly, novel targeted therapeutics currently in clinical development do not generally lead to cures or long-term survival for most intractable cancers; resistance may eventually develop. Anti-metastatic agents and anti-adhesion drugs, which collectively act on tumor cell-stroma interactions (anti-stromal therapy), are also actively pursued. In addition, forms of cell death other than apoptosis - cellular senescence, cancer cell-specific cell-cycle processes and the hypoxic environment - are being explored in order to identify novel targets for more selective therapy. This report also highlights developments aimed at more safe and effective drug combinations. Evaluating drug combinations, and elucidating the rationale for combinations of old (cytotoxic) and new (biological) anticancer agents, are promising research areas and taxane-based combinations are presented as examples. The report is based on presentations at AACR 2005 and related publications of the first half of 2005.     

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.     

Role of early plasma membrane events in chemotherapy-induced cell death.

Most current anticancer therapies induce tumor cell death through the induction of apoptosis. However, the pathways leading to cell death are not always understood. For example, for several DNA-damaging agents the specific biochemical lesions (DNA damage) have been associated with the induction of apoptosis. However, several of these DNA-damaging agents (cisplatin, 1-beta-arabinofuranosylcytosine, daunorubicin or doxorubicin) as well as other antitumor agents, such as edelfosine or resveratrol, have been recently shown to induce apoptosis via signaling through plasma membrane lipid rafts involving the death receptor pathway. In this review we focus on the role of early plasma membrane events in chemotherapy-induced cell death. Special attention is given to changes in plasma membrane fluidity, activation of the acid sphingomyelinase and the Fas death pathway in response to chemotherapy as well as their possible interrelationships.     

Peroxisome Proliferator‐Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies

Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr‐Abl. Furthermore, coupling imatinib with peroxisome proliferator‐activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator‐activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator‐activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator‐activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail.     

Vandetanib, a novel multitargeted kinase inhibitor, in cancer therapy

In clinical trials thus far, single-targeted kinase inhibitors have shown only limited success in demonstrating survival benefits in cancer. This has led to the development of multitargeted kinase inhibitors capable of disrupting various mitogenic pathways in both cancer cells and associated vasculature. Vandetanib is a novel multitargeted kinase inhibitor exhibiting potent activity against vascular endothelial growth factor receptor-2 (VEGFR-2; kinase insert domain-containing receptor [KDR]) and, to a lesser extent, epidermal growth factor receptor (EGFR) and RET kinase. Vascular endothelial growth factor (VEGF) and VEGFR-2 play a pivotal role in regulating angiogenesis and vascular permeability in cancers. In addition to its antiangiogenic effects, vandetanib acts against EGFR, which is overexpressed or mutated in several solid tumors. Furthermore, vandetanib exerts activity against oncogenic RET kinase, the overexpression of which is common in medullary and papillary thyroid carcinomas. Therefore, the multitargeted kinase inhibitor vandetanib represents a new approach, targeting both tumor cells and tumor-associated endothelial cells. Preclinical studies of vandetanib have demonstrated antitumor efficacy against multiple human cancer xenografts in subcutaneous, orthotopic and metastatic models. Phase I clinical trials have demonstrated that vandetanib is well tolerated. Common adverse events included rash, diarrhea and asymptomatic QTc prolongation. Phase II clinical studies in patients with non-small-cell lung cancer have shown promising results, employing vandetanib as both monotherapy and in combination with docetaxel. Phase II studies in other cancers have likewise been initiated. This review summarizes preclinical and clinical studies of vandetanib for the treatment of cancers.