Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial
Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial
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DOI：
10.1016/s1470-2045(16)30033-x
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发表时间：
2016-05-01
期刊：
影响因子：
51.1
通讯作者：
Paz-Ares, Luis
中科院分区：
文献类型：
--
作者：
Park, Keunchil;Tan, Eng-Huat;Paz-Ares, Luis
背景：不可逆的ErbB家族阻滞剂阿法替尼和可逆的EGFR酪氨酸激酶抑制剂吉非替尼被批准用于EGFR突变阳性非小细胞肺癌（NSCLC）的一线治疗。我们的目的是比较阿法替尼和吉非替尼在这种setting.Methods的疗效和安全性，这多中心，国际，开放标签，探索性，随机对照2B期试验（LUX肺7）在13个国家的64个中心。携带常见EGFR突变（19号外显子缺失或Leu 858 Arg）的IIIB或IV期NSCLC初治患者随机（1：1）接受阿法替尼（40 mg/天）或吉非替尼（250 mg/天）治疗，直至疾病进展，或研究者认为获益后继续治疗。使用经验证的数字生成系统（通过交互式语音或基于网络的应答系统实现，区组大小为4）集中进行随机化（按EGFR突变类型和脑转移状态分层）。临床医生和患者对治疗分配不设盲;以设盲方式对肿瘤缓解进行独立审查。共同主要终点为独立中心审查的无进展生存期、至治疗失败时间和总生存期。在意向治疗人群中进行疗效分析，在接受至少一剂研究药物的患者中进行安全性分析。这项正在进行的研究注册于ClinicalTrials.gov，编号为NCT 01466660。结果在2011年12月13日至2013年8月8日期间，319例患者被随机分配（160例接受阿法替尼治疗，159例接受吉非替尼治疗）。中位随访时间为27.3个月（IQR 15.3-33.9）。无进展生存期（阿法替尼组的中位时间为11.0个月[95% CI 1.6-12.9]，吉非替尼组为1.9个月[9.1-11.5];风险比[HR] .73 [95% CI .57-.95]，p=.017）和至治疗失败时间（阿法替尼组的中位时间为13.7个月[95% CI 11.9-15.0]，吉非替尼组为11.5个月[1.1-13.1]; HR 0.73 [95% CI 0.58 - 0.92]，p= 0.0073）显著长于吉非替尼。总体生存数据尚不成熟。最常见的治疗相关3级或4级不良事件为腹泻（20/160例接受阿法替尼治疗的患者[13%] vs 2/159例接受吉非替尼治疗的患者[1%]）、皮疹或痤疮（15例接受阿法替尼治疗的患者[9%] vs 5例接受吉非替尼治疗的患者[3%]）和肝酶升高（0例接受阿法替尼治疗的患者vs 14例接受吉非替尼治疗的患者[9%]）。阿法替尼组17例（11%）患者和吉非替尼组7例（4%）患者发生严重治疗相关不良事件。每组各有10例（6%）患者因药物相关不良事件而停止治疗。阿法替尼组和吉非替尼组分别发生了15例（9%）和10例（6%）致死性不良事件。除1例死亡外，所有死亡均被认为与治疗无关;吉非替尼组1例患者死于药物相关性肝和肾衰竭。解释与吉非替尼相比，阿法替尼显著改善了EGFR突变NSCLC初治患者的结局，耐受性可管理。这些数据对于该患者人群的临床决策具有潜在重要性。
Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting.Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1: 1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660.Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27.3 months (IQR 15.3-33.9). Progression-free survival (median 11.0 months [95% CI 1.6-12.9] with afatinib vs 1.9 months [9.1-11.5] with gefitinib; hazard ratio [HR] .73 [95% CI .57-.95], p=.017) and time-to-treatment failure (median 13.7 months [95% CI 11.9-15.0] with afatinib vs 11.5 months [1.1-13.1] with gefitinib; HR .73 [95% CI .58-.92], p=.0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure.Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.