Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study
Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study
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DOI：
10.1016/s1470-2045(17)30729-5
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发表时间：
2018-01-01
期刊：
影响因子：
51.1
通讯作者：
Wu, Yi-Long
中科院分区：
文献类型：
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作者：
Zhong, Wen-Zhao;Wang, Qun;Wu, Yi-Long
背景顺铂为基础的辅助化疗是切除的II-IIIA期非小细胞肺癌（NSCLC）患者的标准治疗。RADIANT和SELECT试验数据表明EGFR突变型IB-IIIA期切除NSCLC患者可从EGFR酪氨酸激酶抑制剂辅助治疗中获益。我们的目的是比较辅助吉非替尼与长春瑞滨加顺铂的疗效完全切除EGFR突变II-IIIA期（N1-N2）NSCLC。方法我们做了一个随机，开放标签，3期临床试验在中国的27个中心。我们招募了年龄在18-75岁之间的完全切除（R 0）、II-IIIA期（N1-N2）、EGFR突变（外显子19缺失或外显子21 Leu 858 Arg）NSCLC患者。患者按N分期和EGFR突变状态分层，并按Pocock和Simon最小化法随机（1：1）接受吉非替尼（250 mg，每日一次）治疗24个月或静脉注射长春瑞滨（25 mg/m2，第1天和第8天）+静脉注射顺铂（75 mg/m2，第1天），每3周一次，共4个周期。主要终点是意向治疗人群（包括所有随机化患者）的无病生存期;安全性人群包括所有接受至少一剂研究药物的随机化患者。本研究的入组已关闭，但生存期随访仍在进行中。该研究注册于ClinicalTrials.gov，编号NCT 01405079。结果在2011年9月19日至2014年4月24日期间，筛选了483名患者，随机分配了222名患者，111名接受吉非替尼治疗，111名接受长春瑞滨加顺铂治疗。中位随访时间为36。5个月（IQR 23 . 8-44 . 8）。吉非替尼组的中位无病生存期显著延长（28 . 7个月[95% CI 24 . 9-32 . 5])与长春瑞滨+顺铂相比（18 . 0个月[13 . 6-22 . 3];风险比[HR] 0 . 60，95% CI 0。42-0 . 87; p=0。0054）。在安全性人群中，吉非替尼组（n=106）中最常报告的3级或更严重不良事件为丙氨酸氨基转移酶和丙氨酸氨基转移酶升高（每种事件各2例[2%]患者，长春瑞滨+顺铂组无患者）。在长春瑞滨+顺铂组（n=87）中，最常报告的3级或更严重的不良事件是中性粒细胞减少症（30例[34%]患者vs吉非替尼组无）、白细胞减少症（14例[16%] vs无）和呕吐（8例[9%] vs无）。7例（7%）接受吉非替尼治疗的患者和20例（23%）接受长春瑞滨加顺铂治疗的患者报告了严重不良事件。吉非替尼组未观察到间质性肺病。没有死亡与治疗相关。解释辅助吉非替尼导致完全切除的II-IIIA期（N1-N2）EGFR突变型NSCLC患者的无病生存期显著长于长春瑞滨加顺铂。基于吉非替尼的上级无病生存率、降低的毒性和改善的生活质量，与辅助化疗相比，吉非替尼可能是这些患者的潜在治疗选择。然而，吉非替尼24个月后的获益持续时间可能有限，总体生存数据尚未成熟。
Background Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II-IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with EGFR-mutant stage IB-IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II-IIIA (N1-N2) NSCLC.Methods We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18-75 years with completely resected (R0), stage II-IIIA (N1-N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1: 1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m(2) on days 1 and 8) plus intravenous cisplatin (75 mg/m(2) on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079.Findings Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36 . 5 months (IQR 23 . 8-44 . 8). Median disease-free survival was significantly longer with gefitinib (28 . 7 months [95% CI 24 . 9-32 . 5]) than with vinorelbine plus cisplatin (18 . 0 months [13 . 6-22 . 3]; hazard ratio [HR] 0 . 60, 95% CI 0 . 42-0 . 87; p=0 . 0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two [2%] patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 [34%] patients vs none with gefitinib), leucopenia (14 [16%] vs none), and vomiting (eight [9%] vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related.Interpretation Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II-IIIA (N1-N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature.