Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 Is Generally Well-Tolerated and Has Activity in Non–Small-Cell Lung Cancer and Other Solid Tumors: Results of a Phase I Trial

Herbst, Roy S.; Maddox, Anne Marie; Rothenberg, Mace L.; Small, Eric J.; Rubin, Eric H.; Baselga, J.; Rojo, Federico; Hong, Waun Ki; Swaisland, Helen; Averbuch, Steven D.; Ochs, Judith; LoRusso, Patricia

doi:10.1200/jco.2002.03.038

Cited by 531 publications

(292 citation statements)

References 31 publications

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“…Gefitinib, an EGFR inhibitor, is a new molecule-targeting treatment for lung cancer. It is reported to have a considerable effect on females and nonsmokers, especially those with adenocarcinoma [6,11,12,21]. Analyses of single and multiple variables indicated better prognoses for patients with adenocarcinoma and patients treated with gefitinib.…”

Section: Discussionmentioning

confidence: 99%

“…Several recent reports suggest an epithelial growth factor receptor (EGFR) inhibitor has been effective in treating lung cancer [6,11,12,21]. The EGFR inhibitor is a new molecule-targeted agent for lung cancer that is reported to have a considerable effect on females and nonsmokers, especially those with adenocarcinoma [6,12].…”

Section: Introductionmentioning

confidence: 99%

“…The EGFR inhibitor is a new molecule-targeted agent for lung cancer that is reported to have a considerable effect on females and nonsmokers, especially those with adenocarcinoma [6,12]. However, its effectiveness in patients with bone metastasis from lung cancer is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Predictors of Survival in Patients With Bone Metastasis of Lung Cancer

Sugiura

Yamada

Sugiura³

et al. 2008

Clinical Orthopaedics &Amp; Related Research

237

192

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The prognosis of patients with bone metastasis from lung cancer has not been well documented. We assessed the survival rates after bone metastasis and prognostic factors in 118 patients with bone metastases from lung cancer. The cumulative survival rates after bone metastasis from lung cancer were 59.9% at 6 months, 31.6% at 1 year, and 11.3% at 2 years. The mean survival was 9.7 months (median, 7.2 months; range, 0.1-74.5 months). A favorable prognosis was more likely in women and patients with adenocarcinoma, solitary bone metastasis, no metastases to the appendicular bone, no pathologic fractures, performance status 1 or less, use of systemic chemotherapy, and use of an epithelial growth factor receptor inhibitor. Analyses of single and multiple variables indicated better prognoses for patients with adenocarcinoma, no evidence of appendicular bone metastases, and treatment with an epithelial growth factor receptor inhibitor. The mean survival period was longer in a small group treated with an epithelial growth factor receptor inhibitor than in the larger untreated group. The data preliminarily suggest treatment with an epithelial growth factor receptor inhibitor may improve survival after bone metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Predictors of Survival in Patients With Bone Metastasis of Lung Cancer

Sugiura

Yamada

Sugiura³

et al. 2008

Clinical Orthopaedics &Amp; Related Research

237

192

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“…In addition, human breast cancer cells overexpressing HER2 or acquiring resistance to the oestrogen receptor (ER) antagonist, fulvestrant (Faslodex,ICI 182,780), have been reported to be particularly sensitive to gefitinib (McClelland et al, 2001;Moulder et al, 2001). Furthermore, phase I trials of gefitinib in patients with solid tumours refractory to standard chemotherapies have shown good tolerability and promising antitumour activity Herbst et al, 2002;Ranson et al, 2002). These findings suggest that gefitinib will be clinically useful in the treatment of patients with hormone-refractory breast cancer.…”

mentioning

confidence: 91%

Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells

et al. 2004

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A high expression level of epidermal growth factor receptor (EGFR)/HER1 has been suggested to lead to a shorter survival time and resistance to endocrine therapy in patients with breast cancer. To test the hypothesis that inhibition of the EGFR signalling pathway affects the antitumour effect of endocrine therapy, an EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, and an oestrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. A total of five human breast cancer cell lines were used. The effects of single or combined treatments with gefitinib and/or fulvestrant on cell growth, cell cycle progression and apoptosis were analysed. Changes in the expression levels of cyclin-dependent kinase inhibitors, p21 and p27, an antiapoptotic factor, Bcl-2, and a proapoptotic factor, Bax, were also investigated. All cell lines tested were sensitive to gefitinib (50% growth inhibitory concentration, 10 -28.5 mM). Breast cancer cell lines with a high expression level of HER1 or HER2 were more sensitive to gefitinib than the others. Gefitinib induced a significant G1 -S blockade in ER-positive KPL-3C cells. Gefitinib induced significant apoptosis in HER1-overexpressing MDA-MB-231 cells. Gefitinib additively increased the antitumour effect of fulvestrant in all three ER-positive cell lines in a medium supplemented with 17b-oestradiol. The combined treatment promoted cell cycle retardation in KPL-3C cells, which is associated with an upregulation of p21 by fulvestrant and gefitinib, respectively. Apoptosis was associated with downregulation of Bcl-2 by gefitinib in MDA-MB-231 cells. These results suggest an additive interaction between the EGFR-TKI gefitinib and the antioestrogen fulvestrant in ER-positive breast cancer cells.

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“…In those clinical trials, various toxicities (mainly, acneiform rash and diarrhoea) were reported although the frequency and severity of these adverse events were relatively low (Dittrich et al, 2002;Herbst et al, 2002;Mendelsohn and Baselga, 2003). We have used self-antigen-derived peptides, such as SART1, SART3, and lck, in phase I clinical studies of individualised peptide vaccination for far advanced cancer patients.…”

Section: E/t Ratio (Times)mentioning

confidence: 99%

Identification of epidermal growth factor receptor-derived peptides immunogenic for HLA-A2+ cancer patients

et al. 2004

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Epidermal growth factor receptor (EGFR) is one of the most appropriate target molecules for cancer therapy because of its relatively high expression in about one-third of all epithelial cancers in correlation with neoplasmic progression. With respect to EGFR-targeted therapies, antibodies and tyrosine-kinase inhibitors have been intensively studied, a novel EGFR-tyrosine-kinase inhibitor ZD1839 has been approved as an anticancer drug, and many other agents are now under clinical trial. In addition, cytotoxic T lymphocyte (CTL)-directed epitope peptides could be another class of compounds useful in EGFR-targeted therapies. However, there is presently no information on CTL-directed peptides of EGFR. Therefore, from the viewpoint of development of peptide-based cancer therapy, this study was intended to determine the EGFR-derived peptides recognised by both cellular and humoral immunities in HLA-A2 þ epithelial cancer patients. We herein report finding of two such types of EGFR-derived peptides at position 479 -488 and 1138 -1147, both of which were recognised by the majority of patients' sera (IgG), and also possessed the ability to induce HLA-A2-restricted peptide-specific CTLs against EGFR-positive tumour cells in peripheral blood mononuclear cells (PBMCs) of epithelial cancer patients. These results may provide a scientific basis for the development of EGFR-based immunotherapy for HLA-A2 þ cancer patients.

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Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 Is Generally Well-Tolerated and Has Activity in Non–Small-Cell Lung Cancer and Other Solid Tumors: Results of a Phase I Trial

Abstract: Rash and diarrhea, generally mild and tolerable at doses

Cited by 531 publications

References 31 publications

Predictors of Survival in Patients With Bone Metastasis of Lung Cancer

Predictors of Survival in Patients With Bone Metastasis of Lung Cancer

Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells

Identification of epidermal growth factor receptor-derived peptides immunogenic for HLA-A2+ cancer patients

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