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.

Ewa Szutowicz-Zielińska,Małgorzata Suszko-Każarnowicz,Krzysztof Konopa,Aleksander Sowa,Rafał Dziadziuszko,Tomasz Burzykowski,Anna Kowalczyk,Aleksandra Szczęsna,Wojciech Biernat,Jacek Jassem,Magdalena Ratajska,Renata Duchnowska,Janusz Limon

doi:10.18632/oncotarget.13793

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.

Highlights

First and second generation epidermal growth factor receptor (EGFR) inhibitors, erlotinib, gefitinib and afatinib, have established role in the treatment of patients with lung carcinomas harboring activating EGFR mutations
We present here the final results of this trial, together with molecular analysis of EGFR, KRAS and BRAF mutation status in the tumor
Between December 2007 and April 2011, tumor samples from 149 patients were subjected to the molecular screening for the number of the EGFR gene copy number

Summary

Introduction

First and second generation EGFR inhibitors, erlotinib, gefitinib and afatinib, have established role in the treatment of patients with lung carcinomas harboring activating EGFR mutations. The cut-off point of EGFR positivity (defining “high gene copy number”) was previously determined as ≥4 EGFR copies in ≥40% of tumor cells, or numerous gene clusters observed in at least 10% of tumor cells [8] With these background data, investigators at Central and East European Study Group (CEEOG) initiated the first-line multicenter, open-label, single arm, phase II trial (FLIKER), to evaluate the efficacy of EGFR TKI erlotinib in NSCLC patients with tumors harboring high EGFR gene copy number defined as above. Investigators at Central and East European Study Group (CEEOG) initiated the first-line multicenter, open-label, single arm, phase II trial (FLIKER), to evaluate the efficacy of EGFR TKI erlotinib in NSCLC patients with tumors harboring high EGFR gene copy number defined as above This trial was commenced before a general adoption of EGFR mutations for selection of lung cancer patients to EGFR inhibitor treatment. The activity of erlotinib in patients harboring high EGFR gene copy number has been considered debatable

Methods

Results

Conclusion