Elsevier

The Lancet

Volume 372, Issue 9652, 22–28 November 2008, Pages 1809-1818
The Lancet

Articles
Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial

https://doi.org/10.1016/S0140-6736(08)61758-4Get rights and content

Summary

Background

Two phase II trials in patients with previously-treated advanced non-small-cell lung cancer suggested that gefitinib was efficacious and less toxic than was chemotherapy. We compared gefitinib with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer who had been pretreated with platinum-based chemotherapy.

Methods

We undertook an open-label phase III study with recruitment between March 1, 2004, and Feb 17, 2006, at 149 centres in 24 countries. 1466 patients with pretreated (≥one platinum-based regimen) advanced non-small-cell lung cancer were randomly assigned with dynamic balancing to receive gefitinib (250 mg per day orally; n=733) or docetaxel (75 mg/m2 intravenously in 1-h infusion every 3 weeks; n=733). The primary objective was to compare overall survival between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high epidermal growth factor receptor (EGFR)-gene-copy number in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00076388.

Findings

1433 patients were analysed per protocol (723 in gefitinib group and 710 in docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for overall survival (593 vs 576 events; hazard ratio [HR] 1·020, 96% CI 0·905–1·150, meeting the predefined non-inferiority criterion; median survival 7·6 vs 8·0 months). Superiority of gefitinib in patients with high EGFR-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR 1·09, 95% CI 0·78–1·51; p=0·62; median survival 8·4 vs 7·5 months). In the gefitinib group, the most common adverse events were rash or acne (360 [49%] vs 73 [10%]) and diarrhoea (255 [35%] vs 177 [25%]); whereas in the docetaxel group, neutropenia (35 [5%] vs 514 [74%]), asthenic disorders (182 [25%] vs 334 [47%]), and alopecia (23 [3%] vs 254 [36%]) were most common.

Interpretation

INTEREST established non-inferior survival of gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced non-small-cell lung cancer.

Funding

AstraZeneca.

Introduction

Lung cancer, including non-small-cell lung cancer, is a major cause of death due to cancer worldwide,1, 2 largely because most patients are diagnosed with advanced-stage disease. Treatment for these patients consists of chemotherapy and supportive care, but response rates are modest and recurrence eventually occurs for most patients after standard first-line platinum-based doublet therapy. Docetaxel (75 mg/m2) was approved for second-line treatment of advanced non-small-cell lung cancer after findings from two phase III trials TAX 317 and TAX 320 showed improved outcomes.3, 4 Docetaxel improved survival and quality of life compared with best supportive care (median survival 7·5 vs 4·6 months)3 and compared with vinorelbine or ifosfamide chemotherapy (median survival 5·7 vs 5·6 months; 1-year survival 32% vs 19%).4 The side-effects with docetaxel include diarrhoea, neuropathy, and frequent grade 3 and 4 neutropenia.3, 4, 5, 6

Other cytotoxic agents5 and molecular-targeted agents such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors7 have been investigated as potential alternatives to increase efficacy or reduce toxic effects in this disease setting. In the JMEI trial, pemetrexed has shown similar efficacy to docetaxel and lower overall toxic effects,5 whereas the BR.21 trial reported a significant survival advantage for erlotinib compared with placebo in patients who were not required to be refractory to their previous treatment.8

Furthermore, results from two randomised phase II trials (IDEAL 1 and 2)9, 10 suggested that gefitinib—an EGFR tyrosine kinase inhibitor given orally—was efficacious and less toxic, compared with previous results, than was chemotherapy in patients with previously-treated non-small-cell lung cancer. Two studies have compared gefitinib with docetaxel in pretreated non-small-cell lung cancer: the SIGN trial6 and the Japanese phase III V-15-32 trial.11 Both studies showed no significant difference between gefitinib and docetaxel in terms of overall survival or progression-free survival. These studies also noted similar or improved response rates, improved quality of life, and a more favourable toxicity profile for gefitinib.

Two phase III trials of gefitinib in advanced non-small-cell lung cancer followed on from the IDEAL phase II studies: Iressa Survival Evaluation in Lung Cancer (ISEL)12 and Iressa NSCLC Trial Evaluating REsponse and Survival versus Taxotere (INTEREST), which we report here. The INTEREST study compared an EGFR tyrosine kinase inhibitor with chemotherapy in pretreated advanced non-small-cell lung cancer. Additionally, INTEREST aimed to investigate the relations between widely studied clinical patient characteristics and EGFR-related biomarkers and clinical outcome.

Section snippets

Study design and patients

INTEREST was a multicentre, randomised, open-label, phase III trial of gefitinib (Iressa, AstraZeneca, Macclesfield, UK) versus docetaxel (Taxotere, Sanofi-Aventis, Paris, France) in patients who were pretreated with platinum with locally advanced or metastatic non-small-cell lung cancer. We recruited patients from 149 centres in 24 countries from Europe; Asia; and North, Central, and South America between March 1, 2004, and Feb 17, 2006. The primary objective was to compare overall survival

Results

Figure 1 shows the trial profile. 1466 patients were randomly assigned at 149 centres in 24 countries (803 [55%] Europe, 308 [21%] Asia, 223 [15%] North America, and 132 [9%] Central and South America). Patient demographics and baseline characteristics were much the same between treatment groups (table 1). 1433 patients were included in the per-protocol population; ten patients assigned to gefitinib and 23 assigned to docetaxel were excluded, mainly because of failure to start study treatment (

Discussion

Although several agents including docetaxel, pemetrexed, erlotinib and, in some countries, gefitinib are approved for second-line treatment of non-small-cell lung cancer, few phase III clinical trials have compared these treatments directly for efficacy. INTEREST has established equivalent efficacy between a molecularly-targeted agent and a cytotoxic chemotherapy in advanced non-small-cell lung cancer, showing gefitinib to be non-inferior in overall survival and similar in tumour response and

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