Elsevier

The Lancet Oncology

Volume 11, Issue 2, February 2010, Pages 121-128
The Lancet Oncology

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Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial

https://doi.org/10.1016/S1470-2045(09)70364-XGet rights and content

Summary

Background

Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor (EGFR) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib. However, whether gefitinib is better than standard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain.

Methods

We did an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centres in Japan. 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned, using a minimisation technique, to receive either gefitinib (250 mg/day orally; n=88) or cisplatin (80 mg/m2, intravenously) plus docetaxel (60 mg/m2, intravenously; n=89), administered every 21 days for three to six cycles. The primary endpoint was progression-free survival. Survival analysis was done with the modified intention-to-treat population. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.

Findings

Five patients were excluded (two patients were found to have thyroid and colon cancer after randomisation, one patient had an exon 18 mutation, one patient had insufficient consent, and one patient showed acute allergic reaction to docetaxel). Thus, 172 patients (86 in each group) were included in the survival analyses. The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival time of 9·2 months (95% CI 8·0–13·9) versus 6·3 months (5·8–7·8; HR 0·489, 95% CI 0·336–0·710, log-rank p<0·0001). Myelosuppression, alopecia, and fatigue were more frequent in the cisplatin plus docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea were more frequent in the gefitinib group. Two patients in the gefitinib group developed interstitial lung disease (incidence 2·3%), one of whom died.

Interpretation

Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel.

Funding

West Japan Oncology Group (WJOG): a non-profit organisation supported by unrestricted donations from several pharmaceutical companies.

Introduction

Lung cancer is a major cause of cancer-related mortality worldwide.1 However, current standard platinum doublet therapy seems to have reached a therapeutic plateau,2 although it has recently been shown that patients with non-squamous histology who are treated with pemetrexed disodium have better survival than if they are treated with older drugs.3

Targeted therapies are actively being developed to improve efficacy in selected patient populations.4 Small-molecule tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR), such as gefitinib and erlotinib, are the first targeted drugs to enter clinical use for the treatment of lung cancer. Subgroups of patients of east-Asian origin, female sex, adenocarcinoma, and no history of smoking have been shown to be significantly associated with a favourable response to EGFR TKIs.5, 6 In 2004, researchers noted that activating mutations of the EGFR gene present predominantly in patients with the above-mentioned clinical characteristics, and determine sensitivity to EGFR TKIs.7, 8 EGFR mutations are present in the first four exons of the tyrosine kinase domain of the EGFR gene, and about 90% of these EGFR mutations are either short in-frame deletions in exon 19, or point mutations that result in a substitution of arginine for leucine at aminoacid 858 (L858R).7, 8, 9 Subsequent retrospective and prospective trials confirmed that the response rate to gefitinib or erlotinib in patients with EGFR mutations is about 70–80%.10, 11, 12, 13 Furthermore, patients with EGFR mutations have a significantly longer survival than those with wild-type EGFR when treated with EGFR TKIs.14, 15 We proposed that the absence of any survival advantage conferred by gefitinib monotherapy in previous studies16, 17, 18 is due at least in part to a lack of patient selection, and that gefitinib would confer a survival advantage compared with platinum doublet chemotherapy in a first-line setting if eligible patients were selected on the basis of EGFR mutation status. To address this issue, we did a phase 3 trial that compared gefitinib with cisplatin plus docetaxel in patients with an EGFR mutation.

Section snippets

Patients

This study (WJTOG 3405) was a multicentre, randomised, open-label, phase 3, trial of first-line treatment with gefitinib versus cisplatin plus docetaxel for patients with advanced or recurrent non-small-cell lung cancer (NSCLC) harbouring an activating mutation of the EGFR gene. We recruited patients between March 31, 2006, and June 22, 2009, at 36 centres in Japan. All centres were members of the West Japan Oncology Group (WJOG), which is a Japanese non-profit organisation for oncological

Results

118 patients were positive for EGFR mutation at the central laboratory, 106 of whom were randomly allocated a treatment together with 71 patients with EGFR mutations who were tested at the commercial laboratories, giving a modified intention-to-treat population of 172 patients (figure 1). Baseline characteristics were well balanced between the two treatment groups (table 1), with the exception that the gefitinib group had an excess of exon 19 deletion mutations (50 of 86; 58·1%) compared with

Discussion

Our results show that first-line treatment with gefitinib conferred longer progression-free survival than treatment with cisplatin plus docetaxel in a molecularly defined (ie, EGFR mutation positive) group of patients with NSCLC.

In the IPASS study for patients with lung adenocarcinoma with no or former light smoking history, the progression-free survival of patients treated with gefitinib was significantly longer.25 However, the curves crossed at the 6-month timepoint (initially chemotherapy

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