Multicentre prospective phase II trial of gefitinib for advanced non-small cell lung cancer with epidermal growth factor receptor mutations: results of the West Japan Thoracic Oncology Group trial (WJTOG0403)

Abstract

The purpose of this study was to evaluate the efficacy of gefitinib and the feasibility of screening for epidermal growth factor receptor (EGFR) mutations among select patients with advanced non-small cell lung cancer (NSCLC). Stage IIIB/IV NSCLC, chemotherapynaive patients or patients with recurrences after up to two prior chemotherapy regimens were eligible. Direct sequencing using DNA from tumour specimens was performed by a central laboratory to detect EGFR mutations. Patients harbouring EGFR mutations received gefitinib. The primary study objective was response; the secondary objectives were toxicity, overall survival (OS), progression-free survival (PFS), 1-year survival (1Y-S) and the disease control rate (DCR). Between March 2005 and January 2006, 118 patients were recruited from 15 institutions and were screened for EGFR mutations, which were detected in 32 patients -28 of whom were enrolled in the present study. The overall response rate was 75%, the DCR was 96% and the median PFS was 11.5 months. The median OS has not yet been reached, and the 1Y-S was 79%. Thus, gefitinib chemotherapy in patients with advanced NSCLC harbouring EGFR mutations was highly effective. This trial documents the feasibility of performing a multicentre phase II study using a central typing laboratory, demonstrating the benefit to patients of selecting gefitinib treatment based on their EGFR mutation status.

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

“…Thirty-three patients with advanced or recurrent non-adenocarcinoma NSCLC who had the somatic EGFR mutations and were treated with gefitinib were selected from 15 reports. (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) Table 1 summarizes the 15 identified clinical reports. The 15 reports included five prospective studies and 10 retrospective studies including four studies using the data of expanded access programs of gefitinib.…”

“…(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.…”

Molecular pathology of lung cancer: key to personalized medicine

“…13,[17][18][19][20][21] The incidence of EGFR mutations in unselected tumors with non-small cell histology ranges from 10 to 50%, depending upon the ethnic makeup of the patient population and the detection methods used for mutation analysis; 95% of such mutations have been found in adenocarcinomas. 12,13,16,[22][23][24][25][26][27][28][29][30][31][32][33][34] Although the exact molecular mechanisms resulting from these somatic mutations are not completely understood, it seems clear that mutant EGFR has enhanced tyrosine kinase activity. Tyrosine kinase is an enzyme that transports phosphates from adenosine triphosphate (ATP) to a protein's tyrosine residue.…”

Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non‐small cell lung cancer

“…(10)(11)(12)(13)(14) Indeed, we and others have prospectively demonstrated a high response rate to EGFR TKI therapy in NSCLC patients with EGFR mutations. (15)(16)(17)(18)(19)(20)(21) An increased copy number of the EGFR gene, as revealed by fluorescence in situ hybridization (FISH), has also emerged as an effective molecular marker of EGFR TKI sensitivity in NSCLC. (22)(23)(24) We previously showed that EGFR mutation and EGFR amplification are associated in human NSCLC cell lines and that endogenous EGFR expressed in such cell lines positive for both of these EGFR alterations are activated constitutively.…”