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

Asahina, Hajime; Yamazaki, Koichi; Kinoshita, Ichiro; Sukoh, Noriaki; Harada, Masao; Yokouchi, Hiroshi; Ishida, Takashi; Ogura, Shinji; Kojima, Takao; Okamoto, Yasushi; Fujita, Yuka; Dosaka‐Akita, Hirotoshi; Isobe, Hiroshi; Nishimura, Masaharu

doi:10.1038/sj.bjc.6603393

Cited by 260 publications

(171 citation statements)

References 40 publications

(43 reference statements)

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“…21 Asahina et al reported response rates of 83% for exon 19 deletions and 67% for L858R patients. 39 The time to progression in the latter trial is similar for both mutant cohorts. Other studies have searched for disparities in the efficacy of EGFR-TKI inhibition between mutation types but have not yielded any definitive findings.…”

Section: Discussionmentioning

confidence: 86%

Epidermal growth factor receptor mutations detected by denaturing high‐performance liquid chromatography in nonsmall cell lung cancer

Cohen

Agulnik

Ang

et al. 2010

Cancer

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BACKGROUND:Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to EGFR‐tyrosine kinase inhibitors (EGFR‐TKI) in patients with nonsmall cell lung cancer (NSCLC).METHODS:The authors tested the possibility that nucleotide sequencing may be poorly suited for detection of mutations in tumor samples and found that denaturing high‐performance liquid chromatography (dHPLC) was an efficient and more sensitive method for screening.RESULTS:These results suggested that some reports based on standard DNA sequencing techniques may have underestimated mutation rates. In the present report, the authors examined the relationship between the presence and type of EGFR mutations detected by dHPLC and various clinicopathologic features of NSCLC, including response to therapy with EGFR‐TKI. Among 251 patients with advanced disease, 100 individuals received EGFR‐TKI. Those whose tumors harbored a detectable EGFR kinase mutation were much more likely to have a partial response (PR) or stable disease (SD) with EGFR‐TKI therapy than patients whose tumor contained no mutation (80% vs 35%; P = .001). Among the individual genotype subgroups, the frequency of a PR or SD was significantly different between patients with an exon 19 deletion compared with those with no detectable mutation (86% vs 35%; P < .001). Furthermore, patients whose tumors expressed an exon 19 mutant EGFR isoform exhibited a trend toward better EGFR‐TKI response (86% vs 67%; P = .171) and improved survival compared with patients whose tumors expressed an exon 21 mutation.CONCLUSIONS:Our findings warrant confirmation in large prospective trials and exploration of the biological mechanisms of the differences between mutation types. Cancer 2010. © 2010 American Cancer Society.

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Section: Discussionmentioning

confidence: 86%

Epidermal growth factor receptor mutations detected by denaturing high‐performance liquid chromatography in nonsmall cell lung cancer

Cohen

Agulnik

Ang

et al. 2010

Cancer

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“…[406][407][408][409] In PC-13 cells, which have no endogenous EGFR expression, transfected mutant EGFR showed high constitutive phosphorylation of itself and of AKT and STAT3, and prolonged cell survival under serum-free conditions. 410 Most recently, erlotinib 411 and gefitinib 412 are showing efficacy as first-line therapy for non-small cell lung cancers.…”

Section: Erbb3 Egfr Mutation and Clinical Responsiveness To Egfr Inhmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) The study included any reports based on the method of DNA isolation from fresh tissue or paraffin-embedded tissue, and the technique used to enhance tumor-derived DNA, which included either microdissection or use of the more sensitive polymerase chain reaction (PCR) amplification techniques. Not all consecutive NSCLC patients were included in the EGFR mutation analysis in every study.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of gefitinib for non‐adenocarcinoma non‐small‐cell lung cancer patients harboring epidermal growth factor receptor mutations: A pooled analysis of published reports

et al. 2011

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The efficacy of gefitinib for patients with non-adenocarcinoma non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is unclear, because only a small percentage of patients enrolled in the clinical trials to evaluate the efficacy of gefitinib for tumors harboring EGFR mutation were nonadenocarcinoma NSCLC. A pooled analysis was conducted to clarify the efficacy of gefitinib for non-adenocarcinoma NSCLC patients harboring EGFR mutations. A systematic search of the PUBMED databases was conducted to identify all clinical reports that contained advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations and treated with gefitinib. The selected patients were advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations who were treated with gefitinib and described in reports containing the data of the histology, status of EGFR mutations and response to gefitinib. This study selected 33 patients from 15 reports. Twenty-seven and three of the 33 patients were squamous cell carcinoma and adenosquamous cell carcinoma, respectively. One patient each had large-cell carcinoma, pleomorphic carcinoma and spindle cell carcinoma. Twenty-one patients (64%) had sensitive EGFR mutations. The response rate (RR), disease control rate (DCR) and median progression-free survival (mPFS) was 27%, 67-70% and 3.0 months, respectively. These factors were statistically significantly inferior in the non-adenocarcinoma NSCLC patients harboring EGFR mutations to adenocarcinoma patients harboring EGFR mutations selected from the same published reports (RR: 27% vs 66%, P = 0.000028; DCR: 67-70% vs 92-93%, P = 0.000014; mPFS: 3.0 vs 9.4 months, P = 0.0001, respectively). Gefitinib is less effective in non-adenocarcinoma NSCLC harboring EGFR mutations than adenocarcinoma harboring EGFR mutations. (Cancer Sci 2011; 102: 1032-1037 G efitinib, one of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), is used for the treatment of non-small-cell lung cancer (NSCLC). Two study groups have demonstrated the presence of EGFR mutations in some NSCLC patients and reported higher response rates (RR) to gefitinib therapy among these patients.(1,2) The deletion of exon 19 and point-mutation of exon 21 from T to G at codon 858 (L858R) are the most frequently encountered EGFR mutations, accounting for 90% of all the cases.(3) Approximately 3% of the mutations occur at codon 719 resulting in the substitution of glycine to cysteine, alanine or serine (G719X). In addition, approximately 3% are in-frame insertion mutations in exon 20.(4) The RR was the highest in patients with exon 19 deletions followed by L858R and G719X (81%, 71% and 56%, respectively).(5) In contrast, there are no reports of a single patient with the exon 20 insertion mutation who responded to EGFR-TKI.(5) Clinical trials were conducted based on these findings, which showed that gefitinib is an effective treatment option for first-line treatment in NSCLC patients harboring sensitive EGFR mutations with median progressio...

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

Cited by 260 publications

References 40 publications

Epidermal growth factor receptor mutations detected by denaturing high‐performance liquid chromatography in nonsmall cell lung cancer

Epidermal growth factor receptor mutations detected by denaturing high‐performance liquid chromatography in nonsmall cell lung cancer

The ERBB3 receptor in cancer and cancer gene therapy

Efficacy of gefitinib for non‐adenocarcinoma non‐small‐cell lung cancer patients harboring epidermal growth factor receptor mutations: A pooled analysis of published reports

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