ArticlesErlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial
Introduction
Mutations in EGFR—either small in-frame deletions in exon 19 or aminoacid substitution (leucine to arginine at codon 858 [L858R]) clustered around the ATP-binding pocket of the tyrosine kinase domain—are present in 10–26% of non-small-cell lung cancer (NSCLC) tumours1 and are associated with response to gefitinib and erlotinib.2, 3, 4 Studies of lung cancer cell lines and transgenic mice with EGFR mutations have shown the oncogenic transformation potential of these mutations, with enhanced response to EGFR inhibitors.3, 5, 6
Four prospective randomised clinical trials, all of which were undertaken in Asian patients, showed that gefitinib7, 8, 9 and erlotinib10 as initial treatment for EGFR-mutant NSCLC improved outcomes compared with chemotherapy. The Iressa Pan-Asia Study (IPASS)7 enrolled patients with lung adenocarcinoma who had never smoked or who were previously light smokers, independent from their EGFR mutation status; patients were randomly allocated to receive carboplatin plus paclitaxel or gefitinib. In a subgroup analysis of 261 patients with EGFR mutations, median progression-free survival (PFS) was 9·5 months for patients receiving gefitinib compared with 6·3 months for those receiving chemotherapy (hazard ratio [HR] for progression 0·48, 95% CI 0·36–0·64; p<0·001). By contrast, gefitinib was ineffective in 176 patients with wild-type EGFR (2·85, 2·05–3·98; p<0·001).7 The WJTOG3405 study8 enrolled only individuals with EGFR mutations and randomly allocated participants to receive gefitinib or docetaxel plus cisplatin. Participants in the gefitinib group had a longer median PFS (9·2 months) than did those in the standard chemotherapy group (6·3 months; HR 0·49, 95% CI 0·34–0·71; p<0·0001).8 The NEJ002 study9 also enrolled only patients with EGFR mutations, who were randomly allocated to receive gefitinib or carboplatin plus paclitaxel. Participants in the gefitinib group had a longer median PFS (10·8 months vs 5·4 months; HR 0·30, 95% CI 0·22–0·41; p<0·001) and a higher response rate (73·7% vs 30·7%; p<0·001) than did patients who received carboplatin plus paclitaxel. Results from the OPTIMAL study,10 comparing erlotinib with carboplatin plus gemcitabine in Chinese patients with NSCLC and EGFR mutations, showed an HR for PFS of 0·16 (95% CI 0·10–0·26) in favour of erlotinib (median 13·1 months for erlotinib vs 4·6 months for standard chemotherapy).
In a phase 2 trial,11 Asian and non-Asian patients with advanced NSCLC who were positive for EGFR protein expression or who had a high EGFR gene copy number were randomly allocated to receive erlotinib or erlotinib plus chemotherapy; in a subgroup of nine patients with EGFR mutations who were treated with erlotinib alone, median PFS was 18·2 months.11 In non-Asian patients, two prospective studies have tested the feasibility of screening for EGFR mutations. In a phase 2 study12 of 31 patients with confirmed EGFR mutations from the USA, median PFS for patients treated with gefitinib was 9·2 months. We screened 2105 Spanish patients with advanced NSCLC and identified EGFR mutations in 350 (17%) patients.13 Median PFS in 217 patients treated with erlotinib was 14 months. On the basis of these results, we undertook the European Tarceva versus Chemotherapy (EURTAC) study, in which we aimed to compare erlotinib with platinum-based chemotherapy as first-line treatment for patients with advanced NSCLC. Our trial is the first randomised trial targeting a non-Asian population of patients whose tumours have EGFR mutations.
Section snippets
Study design and participants
In our open-label, multicentre, randomised phase 3 trial we enrolled eligible participants attending hospitals in France, Italy, and Spain. Eligibility criteria included histological diagnosis of stage IIIB (with pleural effusion) or stage IV NSCLC (based on the sixth TNM staging system), measurable or evaluable disease, presence of activating EGFR mutations (exon 19 deletion or L858R mutation in exon 21), age older than 18 years, and no history of chemotherapy for metastatic disease
Results
Between Feb 15, 2007, and Jan 4, 2011, we screened 1227 patients from 42 institutions in Spain, France, and Italy for EGFR mutations. Results were available in less than 7 days from receipt of the tumour sample. We randomly assigned 173 patients with EGFR mutations to receive erlotinib or standard chemotherapy (figure 1). 33 patients were not candidates for cisplatin treatment and received carboplatin. Baseline characteristics were well balanced between the two groups (table 1). All but two
Discussion
To our knowledge, EURTAC is the first prospective head-to-head phase 3 study comparing efficacy and safety of first-line erlotinib with platinum-based chemotherapy in non-Asian patients with advanced NSCLC and EGFR mutations (panel). Patients treated with erlotinib had longer PFS, a higher response rate, and milder side-effects than did those treated with standard chemotherapy.
The HR for progression in our study was 0·37, which is akin to the pooled HR for progression of 0·23 (95% CI 0·19–0·27)
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