Gefitinib in Pretreated Non–Small-Cell Lung Cancer (NSCLC): Analysis of Efficacy and Correlation With HER2 and Epidermal Growth Factor Receptor Expression in Locally Advanced or Metastatic NSCLC

Cappuzzo, Federico; Gregorc, Vanesa; Rossi, Elisa; Cancellieri, Alessandra; Magrini, Elisabetta; Paties, Carlo; Ceresoli, Giovanni Luca; Lombardo, Laura; Bartolini, Stefania; Calandri, Cesare; Rosa, Marisa De; Villa, Eugenio; Crinò, Lucio

doi:10.1200/jco.2003.01.039

Cited by 198 publications

(122 citation statements)

References 19 publications

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“…It is of note that the tissue biopsy studied, from the one patient who is an exception, was acquired 16 months before initiation of gefitinib therapy. Expression levels of EGFR did not display any correlation with drug response in our study (data not shown) as has been demonstrated (4,17).…”

Section: Emp-1 Is a Clinical Biomarker Of Both De Novo And Acquired Gsupporting

confidence: 63%

“…Other studies suggest that the presence of EGFR may be a necessary requisite for gefitinib action (14); however, it is clear from both preclinical and clinical studies that efficacy of gefitinib is independent of EGFR expression levels (4,(15)(16)(17). Furthermore, gefitinib showed objective responses in only 11% of patients (17), the remaining patients categorized as de novo resistant or nonresponders. In addition, of the patients who initially demonstrate a significant drug response, most eventually acquire resistance.…”

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confidence: 90%

“…The somatic mutations have been identified only in NSCLC patients, whereas they are absent in other solid tumors such as glioblastoma and colorectal cancer (13). Other studies suggest that the presence of EGFR may be a necessary requisite for gefitinib action (14); however, it is clear from both preclinical and clinical studies that efficacy of gefitinib is independent of EGFR expression levels (4,(15)(16)(17). Furthermore, gefitinib showed objective responses in only 11% of patients (17), the remaining patients categorized as de novo resistant or nonresponders.…”

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confidence: 93%

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Epithelial membrane protein-1 is a biomarker of gefitinib resistance

Jain

Tindell

Laux

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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We describe a molecular resistance biomarker to gefitinib, epithelial membrane protein-1 (EMP-1). Gefitinib is a small-molecule inhibitor that competes for the ATP-binding site on EGF receptor (EGFR) and has been approved for patients with advanced lung cancers. Treatment with gefitinib has resulted in clinical benefit in patients, and, recently, heterozygous somatic mutations within the EGFR catalytic domain have been identified as a clinical correlate to objective response to gefitinib. However, clinical resistance to gefitinib limits the utility of this therapeutic to a fraction of patients, and objective clinical responses are rare. We aimed to assess the molecular phenotype and mechanism of in vivo gefitinib resistance in xenograft models and in patient samples. We generated in vivo gefitinib-resistance models in an adenocarcinoma xenograft model by serially passaging tumors in nude mice in presence of gefitinib until resistance was acquired. EMP-1 was identified as a surface biomarker whose expression correlated with acquisition of gefitinib resistance. EMP-1 expression was further correlated with lack of complete or partial response to gefitinib in lung cancer patient samples as well as clinical progression to secondary gefitinib resistance. EMP-1 expression and acquisition of gefitinib clinical resistance was independent of gefitinib-sensitizing EGFR somatic mutations. This report suggests the role of the adhesion molecule, EMP-1, as a biomarker of gefitinib clinical resistance, and further suggests a probable cross-talk between this molecule and the EGFR signaling pathway.EGF receptor ͉ HER-kinase axis ͉ tyrosine kinase inhibitor ͉ non-small cell lung cancer

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Section: Emp-1 Is a Clinical Biomarker Of Both De Novo And Acquired Gsupporting

confidence: 63%

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confidence: 90%

mentioning

confidence: 93%

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Epithelial membrane protein-1 is a biomarker of gefitinib resistance

Jain

Tindell

Laux

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…It would therefore appear very important to discover biomarkers that predict gefitinib sensitivity, although EGFR protein expression, the most plausible candidate marker, does not correlate with gefitinib efficacy (Cappuzzo et al, 2003).…”

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confidence: 99%

A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations

et al. 2006

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Retrospective analysis has shown that activating mutations in exons 18 -21 of the epidermal growth factor receptor (EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy-naïve NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations (deletions in or near E746-A750, n ¼ 16; L858R, n ¼ 4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48 -93%). After a median follow-up of 12.7 months (range, 3.1 -16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months (95% CI, 6.7 -11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.

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“…Such results suggest that EGFR TKIs should be tested in patients with EGFR þ HER-2-positive breast cancer. However, it should be noted that the clinical activity of gefitinib has recently been reported to be unaffected by HER2 status in a small-scale trial in advanced non-small-cell lung cancer (NSCLC) (Cappuzzo et al, 2003).…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Epidermal growth factor receptor tyrosine kinase inhibitors

Ranson

2004

Br J Cancer

104

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Activation of the epidermal growth factor receptor (EGFR) has been linked to tumour proliferation, invasion, metastasis and angiogenesis in epithelial tumours. Inhibitors of the EGFR have emerged as promising anticancer agents and two main approaches have been developed, humanised monoclonal antibodies and tyrosine kinase inhibitors. This review discusses the current status of EGFR tyrosine kinase inhibitors (EGFR-TKIs) that have entered clinical development. EGFR-TKIs are generally well tolerated and can sometimes produce impressive tumour regression in patients with advanced non-small-cell lung cancer. However, highly predictive or surrogate markers of activity have not been identified and there remains a need for translational research in their future development.

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Gefitinib in Pretreated Non–Small-Cell Lung Cancer (NSCLC): Analysis of Efficacy and Correlation With HER2 and Epidermal Growth Factor Receptor Expression in Locally Advanced or Metastatic NSCLC

Abstract: According to these data, efficacy, toxicity, and symptom outcome in patients with NSCLC treated with gefitinib do not seem to be related to HER2 expression.

Cited by 198 publications

References 19 publications

Epithelial membrane protein-1 is a biomarker of gefitinib resistance

Epithelial membrane protein-1 is a biomarker of gefitinib resistance

A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations

Epidermal growth factor receptor tyrosine kinase inhibitors

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