A phase II trial of ZD6474 plus docetaxel in patients with previously treated NSCLC: Follow-up results

Heymach, John V.; Johnson, Bruce E.; Prager, Denis J.; Csada, Edit; Roubec, Jaromı́r; Pešek, Miloš; Spásová, I; Hou, Jeannie; Kennedy, S.; Herbst, Roy S.

doi:10.1200/jco.2006.24.18_suppl.7016

Cited by 56 publications

(16 citation statements)

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“…In addition to the option of using anti‐EGFR therapies in combination with anti‐VEGF drugs, there are now available a series of TKs that block both the EGFR and the VEGF receptor TK, such as vandetanib, which has demonstrated significant activity as a single agent and in combination with traditional chemotherapeutics in several human tumor types. (Ciardiello et al, 2003; Heymach et al, 2006; Natale et al, 2006).…”

Section: Secondary Resistancementioning

confidence: 99%

Primary and acquired resistance to anti-EGFR targeted drugs in cancer therapy

et al. 2007

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Section: Secondary Resistancementioning

confidence: 99%

Primary and acquired resistance to anti-EGFR targeted drugs in cancer therapy

et al. 2007

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“…Potential therapeutic targets affecting both the vascular endothelial growth factor (VEGF) pathway. (39,41) Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody to VEGFA that blocks the binding of human VEGF to its receptors. Bevacizumab was first approved for the treatment of metastatic colorectal cancer based on trials that showed an improvement in survival from 15.6 months to 20.3 months when used in combination with 5-fluorouracil and leucovorin.…”

Section: Figmentioning

confidence: 99%

Inhibition of angiogenesis in the treatment of non‐small cell lung cancer

Keedy¹,

Sandler

2007

Cancer Science

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Angiogenesis and its role in the growth and development of metastases has become a topic of increasing importance. In nonsmall cell lung cancer (NSCLC), vascular endothelial growth factor (VEGF) plays an important role in angiogenesis, growth of the primary tumor, and development of metastases. In addition, elevated expression in tissue samples is a negative prognostic feature. For these reasons, VEGF is a worthy target for novel therapies. Recent clinical trials have shown that the anti-VEGF monoclonal antibody bevacizumab adds to the effect of chemotherapy in the metastatic setting. Hypertension and proteinuria are, as expected, commonly seen in this patient population, but the unexpected toxicity of lifethreatening hemoptysis has also been observed. This makes careful patient selection especially important for this class of drugs. Our understanding of the VEGF pathway is increasing, as are the number of available targeted agents. In addition to the monoclonal antibody, bevacizumab, VEGF receptor tyrosine kinase inhibitors, multitargeted kinase inhibitors, and combination VEGF and epidermal growth factor receptor (EGFR) inhibition, are all being evaluated in NSCLC. Small phase I and II trials have suggested modest benefit when used alone; however, we now know that the anti-angiogenic therapies work best in combination with chemotherapy. The results of ongoing trials using these agents in combination with standard therapy will provide more insight into their potential benefit. As it is known that small tumors require angiogenesis to grow and metastasize, the use of anti-angiogenic therapies in the adjuvant setting may provide even greater benefit, and increase the potential cure rate in this population of patients. The results of well-designed phase III trials will be required to truly understand how to best use this class of targeted therapies in resectable and metastatic NSCLC. (Cancer Sci 2007; 98: 1825-1830) N on-small cell lung cancer (NSCLC) remains the leading cause of cancer death in both men and women. In metastatic cases, prognosis remains poor and chemotherapy provides only minimal gains in overall survival. Response rates to combination chemotherapy regimens are approximately 19%, (1) and 1-year survival is less than 40%. There is an urgent need for novel therapies in the treatment of NSCLC. Even in surgically resectable cases, more than half of patients go on to develop metastatic disease in the next 5 years. Multiple chemotherapy combinations have been studied, and no particular regimen has provided a significant improvement in outcomes. As it seems we have reached the maximum benefit possible from standard chemotherapy, there is now an emphasis on targeted therapies. Angiogenesis and non-small cell lung cancer

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“…Pharmacokinetic assessments showed that patients receiving continuous oral dosing with vandetanib 300 mg/day achieved steady-state plasma levels of ≈ 2-3 µ M ( ≈ 1000 ng/mL) [11]. Clinical activity of vandetanib was observed during subsequent Phase II evaluation in patients with advanced non-small-cell lung cancer, as a single agent [13] and combined with docetaxel [14] or carboplatin/paclitaxel [15].…”

Section: Introductionmentioning

confidence: 99%

Dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition with vandetanib sensitizes bladder cancer cells to cisplatin in a dose‐ and sequence‐dependent manner

Flaig

McCoach

et al. 2009

BJU International

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OBJECTIVE To investigate the activity of the combination of vandetanib and cytotoxic agents using in vitro models of bladder cancer, as modern chemotherapy regimens are built around cisplatin, with gemcitabine or a taxane such as docetaxel also commonly added in combination for the treatment of advanced bladder cancer. MATERIALS AND METHODS Human bladder cancer cells HTB3, HT1376, J82, RT4, CRL1749, T24, SUP and HTB9 were cultured. The activity of gefitinib (ZD1839) and vandetanib (ZD6474) was assessed in these eight bladder cancer cell lines with a tetrazolium‐based assay of cell viability. RT4 bladder cancer cells, determined to have moderate cisplatin resistance and also moderate sensitivity to vandetanib, were treated with vandetanib and cisplatin. RT4 and T24 cells were treated with six different regimens. The apoptosis and cell‐cycle analysis were studied by flow cytometry. Expression of p21 and p27 was detected by Western blotting. Fluorescence in situ hybridization (FISH) analysis of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 was performed for all cell lines. RESULTS At equal concentrations, vandetanib was a more potent inhibitor of cell viability, compared to gefitinib. At vandetanib concentrations of ≤2 µM, the combination with cisplatin was synergistic, especially in the treatment sequence of cisplatin followed by vandetanib, and additive with vandetanib followed by cisplatin. An analysis of the cell‐cycle distribution showed that vandetanib treatment induced G1 arrest at high concentrations, but not at lower concentrations. High‐concentration treatment was associated with increased levels of the cyclin‐dependent kinase p27. FISH analysis showed that there was a low level of genomic gain, and no gene amplification. Mutational analysis of exons 18, 19, and 21 of EGFR in each cell line revealed no mutation. CONCLUSION Vandetanib has synergistic activity when given at low concentration with cytotoxic chemotherapy. The addition of vandetanib to cisplatin‐based chemotherapy regimens merits further study.

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A phase II trial of ZD6474 plus docetaxel in patients with previously treated NSCLC: Follow-up results

Cited by 56 publications

References 0 publications

Primary and acquired resistance to anti-EGFR targeted drugs in cancer therapy

Primary and acquired resistance to anti-EGFR targeted drugs in cancer therapy

Inhibition of angiogenesis in the treatment of non‐small cell lung cancer

Dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition with vandetanib sensitizes bladder cancer cells to cisplatin in a dose‐ and sequence‐dependent manner

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