Elsevier

The Lancet

Volume 366, Issue 9496, 29 October–4 November 2005, Pages 1527-1537
The Lancet

Articles
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer)

https://doi.org/10.1016/S0140-6736(05)67625-8Get rights and content

Summary

Background

This placebo-controlled phase III study investigated the effect on survival of gefitinib as second-line or third-line treatment for patients with locally advanced or metastatic non-small-cell lung cancer.

Methods

1692 patients who were refractory to or intolerant of their latest chemotherapy regimen were randomly assigned in a ratio of two to one either gefitinib (250 mg/day) or placebo, plus best supportive care. The primary endpoint was survival in the overall population of patients and those with adenocarcinoma. The primary analysis of the population for survival was by intention to treat. This study has been submitted for registration with ClinicalTrials.gov, number 1839IL/709.

Findings

1129 patients were assigned gefitinib and 563 placebo. At median follow-up of 7·2 months, median survival did not differ significantly between the groups in the overall population (5·6 months for gefitinib and 5·1 months for placebo; hazard ratio 0·89 [95% CI 0·77–1·02], p=0·087) or among the 812 patients with adenocarcinoma (6·3 months vs 5·4 months; 0·84 [0·68–1·03], p=0·089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n=375; 0·67 [0·49–0·92], p=0·012; median survival 8·9 vs 6·1 months) and patients of Asian origin (n=342; 0·66 [0·48–0·91], p=0·01; median survival 9·5 vs 5·5 months). Gefitinib was well tolerated, as in previous studies.

Interpretation

Treatment with gefitinib was not associated with significant improvement in survival in either coprimary population. There was pronounced heterogeneity in survival outcomes between groups of patients, with some evidence of benefit among never-smokers and patients of Asian origin.

Introduction

Lung cancer causes more than 1 million cancer-related deaths each year worldwide;1 non-small-cell lung cancer (NSCLC) accounts for about 80% of all cases of lung cancer. With current first-line platinum-based chemotherapy regimens, median survival is 7–10 months.2, 3, 4 With docetaxel, the only second-line treatment option available until lately, median survival is 5·7–7·5 months compared with 4·6–5·6 months for best supportive care alone.5 Current third-line chemotherapy regimens provide little benefit, as shown in a retrospective analysis by Massarelli and colleagues, who reported median survival from the start of last treatment of 4 months.6 The small survival benefits obtained with these treatment regimens are commonly offset by their substantial toxic effects. For patients who are refractory to or intolerant of the current chemotherapy regimens, treatment options are limited and new therapies are needed.

The epidermal-growth-factor receptor (EGFR) forms part of a signalling pathway that regulates tumour-cell proliferation, invasion, angiogenesis, metastasis, and apoptosis. EGFR is commonly overexpressed in NSCLC, so novel agents that inhibit the EGFR have been developed as potential treatments in this disorder. When this study was planned, clinical phase II data for two inhibitors of EGFR tyrosine kinase, gefitinib and erlotinib, were available. Gefitinib (250 mg/day) was the first molecularly targeted agent to be approved for the treatment of advanced NSCLC, on the basis of data from two large phase II trials of gefitinib monotherapy (250 vs 500 mg/day) in previously treated patients with advanced NSCLC.7, 8 In these trials, response rates and survival were the same for 250 mg/day and 500 mg/day gefitinib, but the frequency and severity of adverse events were greater at the higher dose. At the lower dose, the objective response rate was 12–18%, and higher objective response rates were observed in women, never-smokers, and patients with adenocarcinoma (in both trials7, 8) and in Japanese patients (in the trial by Fukuoka and colleagues8 only).7, 8, 9 Encouraging survival data (median survival 7–8 months; 1-year survival 27–35%) have been supported by data from more than 21 000 patients treated as part of an Expanded Access Programme, among whom 1-year survival was 30%.10 In a phase II trial of erlotinib in previously treated patients with NSCLC, the results were similar: the response rate was 12·3%, median survival was 8 months, and 1-year survival was 40%.11

The ISEL (Iressa Survival Evaluation in Lung Cancer) study was one of the post-marketing trials requested by the US Food and Drug Administration. It was a randomised, placebo-controlled, phase III study designed to assess the survival advantage of gefitinib plus best supportive care in patients with advanced NSCLC who were refractory to or intolerant of their latest chemotherapy regimen.

Section snippets

Trial design and participants

ISEL, a double-blind, placebo-controlled, parallel-group, multicentre, randomised, phase III survival study was undertaken in 210 centres in 28 countries across Europe, Asia, Central and South America, Australia, and Canada. All patients provided written informed consent, and trial approval was obtained from the ethics committee at each trial centre. The study followed the Declaration of Helsinki12 and Good Clinical Practice guidelines. The primary endpoint was survival in the overall

Results

The trial profile is shown in figure 1. 1692 patients were randomised (average eight patients per centre); 1129 were assigned gefitinib and 563 placebo. Baseline characteristics were well balanced between the two treatment groups (table 1). 36% of patients were recruited from central and eastern Europe, 24% from Asia, 16% from northern Europe, 14% from Central and South America, 7% from southern Europe, 2% from Australia, and 1% from Canada. In each treatment group, 48% of patients had

Discussion

The results of ISEL show that treatment with gefitinib was not associated with a significant increase in overall survival in either the overall or adenocarcinoma coprimary population. This result is disappointing given the degree of tumour shrinkage seen in the phase II trials of gefitinib7, 8 and the finding of the phase III erlotinib study (BR21) of a 2-month increase in survival in previously treated patients with NSCLC (similar to that achieved with docetaxel in the second-line setting).5,

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