An open label phase II study evaluating first-line EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer patients with tumors showing high EGFR gene copy number

Abstract

BackgroundFirst-line treatment with epidermal growth factor receptor (EGFR) inhibitors in NSCLC is effective in patients with activating EGFR mutations. The activity of erlotinib in patients harboring high EGFR gene copy number has been considered debatable.Patients and MethodsA multicenter, open-label, single-arm phase II clinical trial was performed to test the efficacy of erlotinib in the first-line treatment of NSCLC patients harboring high EGFR gene copy number defined as =4 copies in =40% of cells.FindingsBetween December 2007 and April 2011, tumor samples from 149 subjects were screened for EGFR gene copy number by fluorescence in-situ hybridization (FISH), Out of 49 patients with positive EGFR FISH test, 45 were treated with erlotinib. Median PFS in the intent-to-treat population was 3.3 months (95%CI: 1.83.9 months), and median overall survival was 7.9 months (95% CI: 5.112.6 months). Toxicity profile of erlotinib was consistent with its known safety profile. The trial was stopped prematurely at 63% of originally planned sample size due to accumulating evidence that EGFR gene copy number should not be used to select NSCLC patients to first-line therapy with EGFR TKI. Data on erlotinib efficacy according to EGFR, KRAS and BRAF mutations are additionally presented.InterpretationThis trial argues against using high gene copy number for selection of NSCLC patients to first-line therapy with EGFR TKIs. The study adds to the discussion on efficacy of other targeted agents in patients with target gene amplified tumors.

Driver genes in non-small cell lung cancer: Characteristics, detection methods, and targeted therapies

“…From December 2007 to April 2011, fluorescence in-situ hybridization (FISH) have been screening EGFR gene variation from tumor samples derived from 149 subjects. And FISH test were successfully treated in the majority of 49 patients who conferred positive EGFR [ 23 ]. Thus, FISH play an unshakable role in detection and screening of driver genes.…”

FoxO3a inhibiting expression of EPS8 to prevent progression of NSCLC: A new negative loop of EGFR signaling

“…To study the relationship between FoxO3a expression and gefitinib resistance, we examined FoxO3a expression by immunohistochemical (IHC) staining and detected the amplification of EGFR by fluorescence in situ hybridization (FISH) in tumor tissues from 75 patients with NSCLC. A high EGFR gene copy number is defined as ≥4 copies in ≥40% of cells [ 64 ]. The patients with high EGFR gene copy number were defined as EGFR positive group, and the others were defined as EGFR negative group.…”