Elsevier

The Lancet Oncology

Volume 14, Issue 10, September 2013, Pages 953-961
The Lancet Oncology

Articles
Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial

https://doi.org/10.1016/S1470-2045(13)70355-3Get rights and content

Summary

Background

Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer.

Methods

In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18–75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506.

Findings

400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67–1·05; median progression-free survival 4·6 months [95% CI 3·5–6·3] vs 3·4 months [2·3–3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033).

Interpretation

Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer.

Funding

Zhejiang Beta Pharma (China), the Chinese National Key Special Program for Innovative Drugs, the 863 Project, and Zhejiang Provincial Key Special Program.

Introduction

Lung cancer is the leading cause of cancer-related death worldwide.1 Chemotherapy has been the cornerstone of treatment for non-small-cell lung cancer for many years. However, the development of EGFR tyrosine kinase inhibitors (TKIs) has led to substantial clinical improvements in treatment outcomes. Gefitinib and erlotinib are EGFR TKIs that were shown to greatly improve clinical outcomes and safety when compared with chemotherapy or placebo in second-line or further-line treatment, resulting in a recommendation for EGFR TKI monotherapy in unselected populations.2, 3 EGFR mutations can increase tumour sensitivity to EGFR TKIs4, 5 and are more common in Asian people (40–50%) than in white people (10%);6, 7, 8, 9 therefore, EGFR TKIs might be particularly beneficial in Asian populations.

Icotinib, an orally administered EGFR TKI, has potent antitumour activity in vitro and in vivo.10 Moreover, icotinib showed high specificity and selectivity to its target EGFR in a preclinical kinase profiling study: only EGFR and its mutants were inhibited among 88 kinases profiled.10 A favourable safety profile was noted in phase 1 and 2 trials; the most common adverse events included rash and diarrhoea, and no cases of interstitial lung disease were reported.11, 12 The clinical benefit of icotinib was further shown in a phase 2 study13 in which 103 patients were enrolled at ten dose levels. Objective responses were noted in 29·2% of patients, disease control was achieved in 78·1%; three complete responses were reported.13

One of the major differences between icotinib and other TKIs such as gefitinib is the half-life in the body. According to previous findings,14 icotinib has a shorter half-life than gefitinib, owing to the different profiles of the P450 metabolism enzymes that metabolise these drugs. The half-life is about 40 h for gefitinib and about 6–8 h for icotinib;11, 15 therefore, gefitinib is taken once per day, whereas icotinib is taken three times per day (maximum tolerated dose 625 mg). The therapeutic window for icotinib—defined as the tolerable and effective dose range—was 100–625 mg three times per day.13

On the basis of the promising results with icotinib, we did a phase 3 randomised head-to-head trial (ICOGEN) at several sites across China to test the hypothesis that icotinib has similar clinical benefits and tolerability to gefitinib in patients with non-small-cell lung cancer.

Section snippets

Study design and patients

ICOGEN was a randomised, double-blind, head-to-head, phase 3 trial designed to assess whether icotinib is non-inferior to gefitinib in patients with locally advanced or metastatic non-small-cell lung cancer after failure of at least one platinum-based chemotherapy regimen. We recruited patients from 27 hospitals in China.

Eligible patients had histologically or cytologically confirmed, locally advanced (stage IIIB) or metastatic (stage IV) non-small-cell lung cancer with progression after at

Results

417 patients were recruited for the eligibility assessment and 400 (96%) were enrolled between Feb 26, 2009, and Nov 13, 2009 (figure 1). One patient was excluded because of incorrect randomisation, and 399 were randomly assigned to receive icotinib (200 patients) or gefitinib (199 patients; figure 1). The study groups were similar at baseline (table 1). All 399 patients were included in the safety set, whereas 395 patients were included in the full analysis set (199 assigned to icotinib and

Discussion

Our results show that icotinib is non-inferior to gefitinib in terms of progression-free survival; overall survival and tumour responses were also much the same with the two drugs. Although a retrospective analysis and a phase 2 study recently compared the effect of gefitinib and erlotinib in pretreated patients with non-small-cell lung cancer,20, 21 to our knowledge, this study is the first to prospectively compare two molecularly targeted agents head to head in pretreated patients with

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