Fast track — ArticlesGefitinib 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
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.
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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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