厄洛替尼对比吉非替尼用于经治的晚期非小细胞肺癌（ICOGEN）：一项随机、双盲、III 期非劣效性试验
Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial.
机构信息
Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
出版信息
Lancet Oncol. 2013 Sep;14(10):953-61. doi: 10.1016/S1470-2045(13)70355-3. Epub 2013 Aug 13.
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.
背景
口服表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）伊可替尼在早期临床试验中显示出抗肿瘤活性和良好的毒性。我们旨在研究伊可替尼是否不比吉非替尼在非小细胞肺癌患者中更差。
方法
在这项随机、双盲、III 期非劣效性试验中，我们从中国的 27 个中心招募了晚期非小细胞肺癌患者。符合条件的患者为年龄在 18-75 岁之间，且对一种或多种铂类化疗方案无反应。患者以 1:1 的比例，采用最小化方法，随机分配接受伊可替尼（125mg，每日 3 次）或吉非替尼（250mg，每日 1 次）治疗，直至疾病进展或出现不可接受的毒性。主要终点是无进展生存期，在全分析集进行分析。如果有组织样本，我们会分析 EGFR 状态。所有研究者、临床医生和参与者对患者的分布均不知情。非劣效性边界为 1.14；如果吉非替尼与伊可替尼的风险比（HR）95%置信区间上限小于该边界，则可以确立非劣效性。本研究在 ClinicalTrials.gov 注册，编号为 NCT01040780，在中国临床试验注册中心注册，编号为 ChiCTR-TRC-09000506。
结果
2009 年 2 月 26 日至 2009 年 11 月 13 日期间共纳入 400 名符合条件的患者，其中 1 名患者入组错误并被排除在研究之外，200 名患者接受伊可替尼治疗，199 名患者接受吉非替尼治疗。395 名患者纳入全分析集（伊可替尼组，n=199；吉非替尼组，n=196）。伊可替尼在无进展生存期方面不劣于吉非替尼（HR 0.84，95%CI 0.67-1.05；中位无进展生存期 4.6 个月[95%CI 3.5-6.3] vs 3.4 个月[2.3-3.8]；p=0.13）。最常见的不良反应是皮疹（伊可替尼组 200 名患者中有 81 名[41%]，吉非替尼组 199 名患者中有 98 名[49%]）和腹泻（伊可替尼组 43 名[22%]，吉非替尼组 58 名[29%]）。接受伊可替尼治疗的患者发生药物相关不良事件的比例低于接受吉非替尼治疗的患者（伊可替尼组 121 名[61%] vs 吉非替尼组 140 名[70%]；p=0.046），尤其是药物相关腹泻（伊可替尼组 37 名[19%] vs 吉非替尼组 55 名[28%]；p=0.033）。
结论
伊可替尼可能成为晚期非小细胞肺癌患者治疗的新选择。
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