Elsevier

The Lancet Oncology

Volume 13, Issue 3, March 2012, Pages 239-246
The Lancet Oncology

Articles
Erlotinib 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

https://doi.org/10.1016/S1470-2045(11)70393-XGet rights and content

Summary

Background

Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC.

Methods

We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m2 on day 1 plus docetaxel (75 mg/m2 on day 1) or gemcitabine (1250 mg/m2 on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m2 or AUC 5 with gemcitabine 1000 mg/m2) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225.

Findings

Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5–5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25–0·54; p<0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes.

Interpretation

Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors.

Funding

Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

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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