肺癌ADJUVANT研究(PPT课件)

Gefitinib (G) versus vinorelbine / cisplatin (VP) as adjuvant treatment in stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC) with EGFR activating mutation (ADJUVANT): A randomized, Phase III trial (CTONG 1104),Yi-Long Wu,1 Wen-Zhao Zhong,1 Qun Wang,2 Song-Tao Xu,2 Wei-Min Mao,3 Lin Wu,4 Yi Shen,5 Yong-Yu Liu,6 Chun Chen,7 Ying Cheng,8 Lin Xu,9 Jun Wang,10 Ke Fei,11 Xiao-Fei Li,12 Jian Li,13 Cheng Huang,14 Zhi-Dong Liu,15 Ke-Neng Chen,16 Hong-Hong Yan,1 Xue-Ning Yang1,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,June 5,2017,吉非替尼对比长春瑞滨/顺铂（VP）辅助治疗II-IIIA（N1-N2）期伴有EGFR活化突变的非小细胞肺癌（ADJUVANT）：一项随机，III期研究（CTONG 1104）,研究背景,近20-25%确诊NSCLC的患者适合通过外科切除达到治愈的目的1 ；N2期患者的中位DFS为12.2个月，3年DFS为23%2；以顺铂为基础的辅助化疗是II-IIIA期完全切除NSCLC的标准治疗方案3；,DFS, disease free survival; N, lymph node; NSCLC, non-small-cell lung cancer; OS, overall survival,Arriagada R et al. Lancet 2010;375:1267-12772. Andre F et al. J Clin Oncol 2000;18:2981-29893. Burdett S et al. Cochrane Database Syst Rev 2015;CD011430,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,研究背景,基于9项随机对照临床研究，EGFR TKIs是治疗EGFR突变阳性进展期NSCLC的标准一线治疗方案1；BR19和RADIANT研究中，EGFR TKIs作为可切除NSCLC的辅助治疗方案，获益有限2,3；ADJUVANT (NCT01405079) 研究是首个在完全切除且病理分期为II-IIIA（N1-N2）期的EGFR突变阳性NSCLC患者中，对比吉非替尼与长春瑞滨联合顺铂的辅助治疗。,1. Ke EE, Wu YL. Trend Pharm Sci 2016; 11:887-9032. Goss GD et al. J Clin Oncol 2013; 31: 3320-33263. Kelly K et al. J Clin Oncol 2015; 33: 4007-4014,EGFR, epidermal growth factor receptor; RCT, randomized control trial;TKI, tyrosine kinase inhibitor,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,统计学参数设计考量,现有证据:第7版TNM分期：pN1, N2的中位OS为9-34个月1非TKI辅助治疗组的DFS为31个月2复发风险比为 0.60 (95% CI 0.45, 0.79)3DFS提升基于以下标准判定：DFS提高40% (HR=0.6)采用双侧检验，检验效能80%，显著性界值为0.05对数秩检验需要约220名随机患者（观察到122个事件）,1. Rusch VW et al. J Thorac Oncol 2007;2:603-612 2. Janjigian YY et al. J Clin Oncol 2009; 27 (15 suppl): abstr 7523 3. Winton T et al. N Engl J Med 2005; 352: 2589-2597,CI, confidence interval; HR, hazard ratio,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,ADJUVANT 研究设计,易瑞沙250 mg/day 治疗24个月或直到疾病进展或不可接受的毒性,完全切除且病理分期为II-IIIA (N1-N2)期 NSCLCEGFR活化突变 (exon 19 deletion or exon 21 L858R) ECOG PS 0-1年龄 18 岁 且 75 岁n=220,长春瑞滨 (25 mg/m2 第1、8天) 联合 顺铂 (75 mg/m2 第1填) q3w, 最多4个周期,DFS,主要终点:DFS次要终点:3年DFS率, 5年DFS率, OS, 5年OS率, 安全性, HRQoL (FACT-L, LCSS, TOI), 探索性生物标志物终点,分层因素：EGFR 突变N分期,疗效评估 ：每12周,ECOG PS, Eastern Cooperative Oncology Group Performance Status; DFS，disease-free survival; FACT-L, Functional Assessment of Cancer Therapy Lung; HRQoL, health-related quality of life; LCSS, Lung Cancer Symptom Scale; OS, overall survival; R, randomization; TOI, Trial Outcome Index,R1:1,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,CONSORT 流程图（易瑞沙对比化疗）,评估患者合格性(n=483),不合格患者 (n=1; EGFR 假阳性)拒绝治疗(n=23),终止治疗(n=70) 疾病复发(n=56)患者死亡 (n=3)不良事件 (n=1)医学/伦理依从性差(n=10),ITT人群(N=111)安全性人群(N=87),拒绝治疗(n=5),终止治疗(n=76)疾病复发(n=58)患者死亡(n=7)依从性不好(n=11),ITT人群 (N=111)安全性人群(N=106),ITT, intent-to-treat,继续治疗(n=17),继续治疗(n=30),分配至VP组(n=111),分配至吉非替尼组(n=111),接受化疗 (n=87),接受吉非替尼(n=106),患者随机分配 (n=222),未随机化的患者(n=261)不符合纳入标准 (n=55)EGFR野生型或中心实验室无法测定EGFR 突变状态(n=206),Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,ADJUVANT 研究Site,Presented by:,基线人口统计学特征 (ITT人群),Sex was not available for two patients in the gefitinib arm and one patient in the vinorelbine plus cisplatin arm,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,基线人口统计学特征 (ITT人群),Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,10,药物暴露,18.1,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,主要终点: DFS (ITT人群),100,80,60,40,20,0,0,12,24,36,48,组吉非替尼（易瑞沙）长春瑞滨+顺铂,N111111,事件6559,中位, 月 (95% CI)28.7 (24.9, 32.5)18.0 (13.6, 22.3),复发HR = 0.6095% CI 0.42, 0.87; p=0.005,Disease-free survival (%),时间 (月),8854,5726,105,10,No. 风险患者:吉非替尼长春瑞滨+顺铂,111111,60,0,3年DFS 率34% vs 27%,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China, 10.7 m,DFS亚组分析 (ITT人群),0,1,1,.,5,0,.,5,吉非替尼更好,长春瑞滨/顺铂更好,0.60 (0.33, 1.09),0.58 (0.40, 0.83),0.58 (0.37, 0.92),0.61 (0.40, 0.92),0.56 (0.27, 1.19),0.55 (0.33, 0.92),0.62 (0.37, 1.04),0.89 (0.45, 1.76),0.52 (0.34, 0.80),0.58 (0.40, 0.84),0.85 (0.16, 4.46),0.003,0.094,0.020,0.018,0.132,0.024,0.071,0.743,0.003,0.004,0.852,222,89,130,167,52,115,106,77,143,207,11,总体,总体cox风险比,男,女,吸烟,模型,性别,EGFR 突变状态,淋巴结,病理,否,是,EGFR exon19 deletion,EGFR exon21 L858R,N1,N2,腺癌,非腺癌,0.754,0.896,0.701,0.232,0.506,亚组,患者数,DFS,HR(95%CI),P value,P for interaction,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,不良事件 (10%，安全性人群),AE, adverse event; ALT, alanine aminotransferase; AST, aspartate transaminase,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,HRQoL,OR, odds ratio,研究期间出现临床相关改善的患者比例(%),p=0.025OR 0.48(95% CI 0.25, 0.91),p=0.041OR 0.47(95% CI 0.23, 0.97),p=0.002OR 0.34(95% CI 0.18, 0.67),Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,结论,ADJUVANT 达到主要终点:吉非替