Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer

Fukuoka, Masahiro; Yano, Seiji; Giaccone, Giuseppe; Tamura, Tomohide; Nakagawa, Kazuhiko; Douillard, Jean Yves; Nishiwaki, Yutaka; Vansteenkiste, Johan; Kudoh, Shinzoh; Rischin, Danny; Eek, Richard; Horai, Takeshi; Noda, Kazumasa; Takata, Ichiro; Smit, Egbert F.; Averbuch, Steven D.; Macleod, Angela; Feyereislova, A.; Dong, Rui; Baselga, José

doi:10.1200/jco.2003.10.038

Cited by 2,716 publications

(1,984 citation statements)

References 19 publications

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“…As for future perspectives, open questions relate to how to include new drugs, like pemetrexed (Hanna et al, 2004), erlotinib or gefitinib (Fukuoka et al, 2003), and to whether polychemotherapy can improve the results of single agent treatment. The DISTAL-2 trial will compare weekly docetaxel with combinations of weekly docetaxel plus capecitabine (Nadella et al, 2002), vinorelbine Leu et al, 2001) and gemcitabine (Kosmas et al, 2001;Spiridonidis et al, 2001); for this trial the DISTAL Investigators agreed to apply a slightly modified schedule of docetaxel (i.e.…”

Section: Discussionmentioning

confidence: 99%

A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study

Gridelli

Gallo²,

Maïo³

et al. 2004

Br J Cancer

147

109

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Docetaxel (75 mg m À2 3-weekly) is standard second-line treatment in advanced non-small-cell lung cancer (NSCLC) with significant toxicity. To verify whether a weekly schedule (33.3 mg m À2 for 6 weeks) improved quality of life (QoL), a phase III study was performed with 220 advanced NSCLC patients, p75 years, ECOG PS p2. QoL was assessed by EORTC questionnaires and the Daily Diary Card (DDC). No difference was found in global QoL scores at 3 weeks. Pain, cough and hair loss significantly favoured the weekly schedule, while diarrhoea was worse. DDC analysis showed that loss of appetite and overall condition were significantly worse in the 3-week arm in the first week, while nausea and loss of appetite were more severe in the weekly arm in the third week. Response rate and survival were similar, hazard ratio of death in the weekly arm being 1.04 (95% CI 0.77 -1.39). A 3-weekly docetaxel was more toxic for leukopenia, neutropenia, febrile neutropenia and hair loss; any grade 3 -4 haematologic toxicity was significantly more frequent in the standard arm (25 vs 6%). The weekly schedule could be preferred for patients candidate to receive docetaxel as second-line treatment for advanced NSCLC, because of some QoL advantages, lower toxicity and no evidence of strikingly different effect on survival.

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Section: Discussionmentioning

confidence: 99%

A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study

Gridelli

Gallo²,

Maïo³

et al. 2004

Br J Cancer

147

109

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“…The mutations are more common in adenocarcinomas, in persons of East Asian ethnicity, women and in never smokers. These phenotypic features had already been marked as clinical predictors of response to TKIs before the discovery of the mutations (Fukuoka et al, 2003;Kris et al, 2003). The prevalence of EGFR mutations varies by ethnicity with ranges from 20-40% in Asian populations (Huang et al, 2004;Kosaka et al, 2004;Han et al, 2005;Shigematsu et al, 2005;Tokumo et al, 2005) to 5-20% among Caucasians (Cappuzzo et al, 2005;Marchetti et al, 2005).…”

Section: Egfr Mutations As Biomarkersmentioning

confidence: 99%

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

2009

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“…In phase II clinical trials (Fukuoka et al, 2003;Kris et al, 2003), responses to gefitinib were seen in just 10-28% of non-small-cell lung carcinoma (NSCLC) patients (depending on trial location). When seen, responses were dramatic.…”

Section: Introductionmentioning

confidence: 99%

EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer

2006

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Several somatic mutations within the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have been identified that predict clinical response of non-smallcell lung carcinoma (NSCLC) patients to gefitinib. To test the hypothesis that these mutations cause constitutive EGF receptor signaling, and to investigate its mechanistic basis, we expressed representative examples in a null background and analysed their biochemical properties. Each mutation caused significant EGF-independent tyrosine phosphorylation of EGFR, and allowed the receptor to promote Ba/F3 cell mitogenesis in the absence of EGF, arguing that these are oncogenic mutations. Active mutated receptors are present at the cell surface and are fully competent to bind EGF. Recent structural studies show that the inactive EGFR tyrosine kinase domain is autoinhibited by intramolecular interactions between its activation loop and aC helix. We find that mutations predicted to disrupt this autoinhibitory interaction (including several that have not been described in NSCLC) elevate EGF-independent tyrosine kinase activity, thus providing new insight into how somatic mutations activate EGFR and other ErbB family members.

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Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer

Cited by 2,716 publications

References 19 publications

A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study

A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer

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