First-Line Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer Harboring Somatic EGFR Mutations (original) (raw)
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British journal of cancer, 2007
Classical' mutations in the EGFR tyrosine kinase domain (exons 18, 19 and 21) have been associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with NSCLC. The aim of the current study was to evaluate whether other than the classical G719X, DEL19 and L858R mutations of EGFR confer sensitivity to TKIs. Genomic DNA was extracted from microdissected formalinfixed paraffin-embedded tumour tissue from 86 patients treated with gefitinib. Exons 18, 19 and 21 were amplified and subjected to direct sequencing. Eleven (13%) patients harboured the classical exon's 18, 19 and 21 mutations, while 14 (16%) had 'other' variants. There was a significantly higher percentage of 'never-smoker' patients with 'classical' EGFR mutations (P ¼ 0.002). Among patients with 'classical' mutations 3 patients achieved PR and 7 SD, while in the 'other' mutations group 10 patients had SD as best response. In the wild-type group, there were 3 patients with PR and 25 with SD. Median TTP was 16, 64 (P ¼ 0.002) and 21 weeks and median survival was 36, 78 and 67 weeks for patients with wild-type, 'classical' and 'other' EGFR mutations, respectively. The clinical relevance of 'other' EGFR mutation variants remains uncertain and requires further assessment in a prospective study.
Oncology Letters, 2017
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are routinely used to treat non-small cell lung cancer (NSCLC) in patients with common activating mutations of the EGFR gene. The aim of the study was to compare the efficacies of EGFR-TKIs in patients with common (exon 19 deletions and exon 21 p.Leu858Arg) and rare EGFR mutations. A retrospective analysis of 180 NSCLC patients with common (n=167) and rare (n=13) EGFR mutations treated with erlotinib (n=98), gefitinib (n=66) and afatinib (n=16) was performed. EGFR mutations were determined using RT-PCR and the EntroGen EGFR Mutations Analysis kit. Partial and complete response (PR and CR), progression-free survival (PFS), and overall survival (OS) were analyzed. Demographic and clinical factors had no impact on PFS or OS in patients treated with EGFR-TKIs. Erlotinib, gefitinib, and afatinib showed similar efficacies based on treatment response, median PFS, and OS. The type of EGFR mutation had no impact on median OS; however, median PFS was significantly longer in patients with the exon 19 deletion compared to patients with the exon 21 p.Leu858Arg substitution and rare EGFR gene mutations (P=0.013). Patients with common EGFR mutations showed significantly longer median PFS than those with rare EGFR mutations (10 vs. 5 months; P=0.009). Erlotinib, gefitinib, and afatinib show similar efficacies in NSCLC patients with both common and rare EGFR mutations. When undergoing EGFR-TKI treatment, patients with rare EGFR mutations showed similar OS but poorer PFS. Further investigation into the associations between particular rare EGFR mutations and EGFR-TKIs treatment outcomes is required.
Journal of Thoracic Oncology, 2007
Introduction: We evaluated the efficacy of gefitinib monotherapy prospectively in patients with advanced or pretreated non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Methods: Patients with NSCLC were examined for EGFR exon 19 deletion mutations by fragment analysis and for EGFR L858R point mutations by the Cycleave polymerase chain reaction technique. EGFR mutation-positive patients with locally advanced, metastatic, or recurrent/refractory NSCLC that was not curable with surgery or thoracic radiotherapy were candidates for gefitinib treatment administered at 250 mg/day until disease progression. Results: Mutations of the EGFR gene were detected in 27 (41%) of 66 patients. Ten had exon 19 deletion, and 17 had L858R. Twentyone patients harboring EGFR mutations were treated with gefitinib and were considered assessable for responses and adverse events. Nineteen patients with EGFR mutations achieved objective responses (three complete responses and 16 partial responses), resulting in an overall response rate of 90.5% (95% confidence interval, 69.6%-98.8%). The median progression-free survival was 7.7 months (95% confidence interval, 6.0 mo to not reached). The median overall survival has not been reached. Common adverse events were skin toxicity, diarrhea, and elevated aminotransferases, but no pulmonary toxicity was observed. Conclusions: Detection of common EGFR mutations seems to be useful for selecting patients with NSCLC who would likely benefit from gefitinib monotherapy.
Anticancer research
Subsets of non-small cell lung cancer (NSCLC) patients who carry activating somatic mutations of the epidermal growth factor receptor (EGFR) have demonstrated an increased probability of obtaining objective responses to the receptor tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. However, a substantial proportion of the cases with somatic mutations, which suggest sensitivity to gefitinib, are primary resistant to it. A primary resistant case of lung adenocarcinoma that was found to carry both delE746-A750 and a G796A mutation in the EGFR is reported. In vitro, a stable clone of cells bearing the G796A mutation was approximately 50,000-fold less sensitive to gefitinib in comparison to cells carrying the delE746-A750 mutant EGFR. This study suggests that screening tumour samples for a range of EGFR mutations may improve our ability to identify the patients most likely to benefit from EFGR TKIs.
Pooled analysis of clinical outcome for EGFR TKI-treated patients with EGFR mutation-positive NSCLC
Journal of Cellular and Molecular Medicine, 2014
Patients with non-small-cell lung cancer (NSCLC) appear to gain particular benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKI) if their disease tests positive for EGFR activating mutations. Recently, several large, controlled, phase III studies have been published in NSCLC patients with EGFR mutation-positive tumours. Given the increased patient dataset now available, a comprehensive literature search for EGFR TKIs or chemotherapy in EGFR mutation-positive NSCLC was undertaken to update the results of a previously published pooled analysis. Pooling eligible progression-free survival (PFS) data from 27 erlotinib studies (n = 731), 54 gefitinib studies (n = 1802) and 20 chemotherapy studies (n = 984) provided median PFS values for each treatment. The pooled median PFS was: 12.4 months (95% accuracy intervals [AI] 11.6-13.4) for erlotinib-treated patients; 9.4 months (95% AI 9.0-9.8) for gefitinib-treated patients; and 5.6 months (95% AI 5.3-6.0) for chemotherapy. Both erlotinib and gefitinib resulted in significantly longer PFS than chemotherapy (permutation testing; P = 0.000 and P = 0.000, respectively). Data on more recent TKIs (afatinib, dacomitinib and icotinib) were insufficient at this time-point to carry out a pooled PFS analysis on these compounds. The results of this updated pooled analysis suggest a substantial clear PFS benefit of treating patients with EGFR mutation-positive NSCLC with erlotinib or gefitinib compared with chemotherapy.
Cancers
Recent findings suggest that a fraction of EGFR-mutant non-small-cell lung cancers (NSCLC) carry additional driver mutations that could potentially affect the activity of EGFR tyrosine kinase inhibitors (TKIs). We investigated the role of concomitant KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of 133 EGFR mutant patients, who received first-line therapy with EGFR TKIs between June 2008 and December 2014. Analysis of genomic DNA by Next Generation Sequencing (NGS) revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA, or MET, in 29/133 cases (21.8%). A p.T790M mutation was found in 9/133 tumour samples (6.8%). The progression free survival (PFS) of patients without other mutations was 11.3 months vs. 7 months in patients with other mutations (log-rank test univariate: p = 0.047). In a multivariate Cox regression model including the presence of other mutations, age, performance status, ...