ALK阳性NSCLC全程化管理-OS获益最大化.ppt

ALK阳性NSCLC全程化管理 如何让患者OS获益最大化,PROFILE 1014:克唑替尼（Crizotinib)与以铂为基础的化疗在未经治疗的ALK 阳性非小细胞肺癌患者中的III期研究:OS数据的更新,Tony S.Mok,1 Dong-Wan Kim,2 Yi-Long Wu,3 Kazuhiko Nakagawa,4 Tarek Mekhail,5 Enriqueta Felip,6 Federico Cappuzzo,7 Jolanda Paolini,8 Tiziana Usari,8 Keith Wilner,9 Fiona Blackhall,10 Benjamin J.Solomon11,Tony S.Mok et al.ESMO 2017 Abstract No.LBA50,PROFILE 1014研究背景,Solomon BJ,et al.N Engl J Med 2014;371:216777,PROFILE 1014 研究设计,主要入组标准FISH法测定ALK阳性a局部晚期，复发或转移非鳞NSCLC无既往治疗的晚期患者ECOG PS 02病灶可测量经治稳定的脑转移患者可入组,N=343,克唑替尼 250 mg BID PO,连续用药(N=172),培美曲塞 500 mg/m2+顺铂 75 mg/m2 或卡铂 AUC 56 q3w,6个周期(N=171),研究终点主要终点PFS(RECIST v1.1,IRR审核)次要终点ORROS安全性 患者生活质量报告(EORTC QLQ-C30,LC13,EQ-5D),随机分组,aALK状态由中心实验室检测，采用Abbotts Vysis ALK Break Apart FISH Probe Kitb分层因素：ECOG PS(0/1 vs.2)，亚洲人 vs.非亚洲人，脑转移（有 vs.无）cIRR审核,b,研究时间：2011-01 2013-07,Solomon BJ,et al.N Engl J Med 2014;371:216777,4,中位随访时间46个月,aThere were no significant differences between the groups in any of the characteristics listed in this table;bRace was self-reported;CECOG PS was assessed at the time of screening;the score was not reported for one patient in the crizotinib group.Scores range from 0 to 5,with higher scores indicating increasing disability;an ECOG PS of 0 indicates that the patient is fully active,1 that the patient is ambulatory but restricted in strenuous activity,and 2 that the patient is ambulatory and capable of self-care but is unable to work.,基线临床特征（ITT人群）a,Solomon BJ,et al.N Engl J Med 2014;371:216777,Tony S.Mok et al.ESMO 2017 Abstract No.LBA50,Solomon BJ,et al.N Engl J Med 2014;371:216777,主要终点：PFS（IRR审核，ITT人群）,a根据基线分层因素分层的双侧log秩检验,主要终点：OS(ITT 人群),两组中位随访46 个月,HR 0.760(95%CI:0.548,1.053);aP=0.0978,80,60,40,20,0,总生存率(%),35月,0,5,10,15,20,25,30,40,45,50,55,60,65,70,No.at risk,a2-sided p-value from the log-rank test stratified by ECOG PS,race,brain metastases.,4 年OS率：克唑替尼组:56.6%化疗组：49.1%,100,Tony S.Mok et al.ESMO 2017 Abstract No.LBA50,克唑替尼组(N=172),化疗组(N=171),进展后患者的序贯治疗,Tony S.Mok et al.ESMO 2017 Abstract No.LBA50,如果未进行交叉治疗患者的OS结果如何?,8,Tony S.Mok et al.ESMO 2017 Abstract No.LBA50,80,60,40,20,0,总生存率(%),60,65,70,+CensoredHR=0.346(95%bootstrap CI:0.081,0.718),100,3540月,0,510 15,2025,30,45,50,55,No.at risk,a 随机化到化疗组的患者中有144(84.2%）在疾病进展后接受克唑替尼二线治疗，随机化到克唑替尼治疗组的患者中有33（19.2%）接受二线培美+顺铂/卡铂化疗。,RPSFT(Rank-Preserving Structural Failure Time)模型假设可观察到未交叉的OS假设:两治疗臂的随机期和交叉期的疗效相同两治疗臂其他全身治疗对OS的影响一致,克唑替尼(N=172),化疗(N=171),59.8(46.6,NR),mOS(95%CI),月,19.2(13.6,NR),使用RPSFT模型对交叉a导致的混杂效应进行校正后最终OS结果,Tony S.Mok et al.ESMO 2017 Abstract No.LBA50,10,疾病进展后序贯治疗对OS的影响：ALK TKI治疗 vs.非 ALK TKI治疗,NR,not reached,Tony S.Mok et al.ESMO 2017 Abstract No.LBA50,No.at risk克唑替尼治疗后其他ALK TKI治疗57 克唑替尼治疗后其他非ALK TKI治疗,化疗后其他ALK TKI治疗57 化疗后其他非ALK TKI 治疗,100,80,60,40,20,0,OS(%),35月409,0,5,10,15,20,25,30,40,45,50,55,60,65,70,5736,1362,5730,1232,5722,1131,5019,971,4516,861,4213,791,701,335,601,253,431,162,301,81,201,30,101,10,10,00,00,+Censored,1,2,3,4,疾病进展后序贯治疗对OS的影响：ALK TKI治疗 vs.非 ALK TKI治疗,Tony S.Mok et al.ESMO 2017 Abstract No.LBA50,总生存率(%),1008060,0,月,0,5,10,15,20,25,30,35,40,45,50,55,60,65,70,57,145,23,57,136,12,57,123,6,57,113,4,50,97,2,45,86,2,42,79,2,40,70,2,33,60,2,25,43,2,16,30,0,8,20,0,3,10,0,1,1,0,0,0,0,No.at risk,克唑替尼治疗后其他ALK TKI治疗,化疗后其他ALK TKI治疗,化疗后未系统治疗,11例死亡;中位OS:未达标+Censored66例死亡;中位OS:49.5个月;(95%CI,41.0,NR),4013例死亡;中位OS:6.1 个月;(95%CI:4.9 19.2)20,随机治疗期疾病进展后：序贯ALK TKI、非ALK TKI治疗和不治疗对整体OS的影响,Luis Paz-Ares.ESMO 2017 Invited Discussant LBA50,12980 and 12990,PP-XLK-CHN-0081 Expiration Date:2018-9-25,安全性：30%出现全因AEs,aAEs in 30%of patients from either data cut off date and are listed in decreasing order of frequency from the 30 November 2013 data cutoff.,bClustered term.,克唑替尼(N=171),Tony S.Mok et al.ESMO 2017 Abstract No.LBA50,通过对两组患者近46个月的中位随访，该研究获得了迄今为止所有IV期NSCLC患者最高的4年生存率数据；克唑替尼组与化疗组的OS差异无统计学意义(HR：0.760 95%CI:0.548,1.053)；克唑替尼治疗后序贯其他TKI药物治疗组的OS最长，而化疗后序贯非TKI或者其他治疗OS最差；化疗不是理想的一线治疗方案；长期克唑替尼治疗未发现意外不良反应。,PROFILE 1014 OS 数据总结,Tony S.Mok et al.ESMO 2017 Abstract No.LBA50,Luis Paz-Ares.ESMO 2017 Invited Discussant LBA50,12980 and 12990,Crizotinib/Ceritinib/Alectinib哪个是ALK阳性NSCLC一线首选TKI？,优选PFS？,ASCEND-4 研究,ALEX 研究,Alice Shaw,et al.N Engi J Med.2017 Aug 31;377(9):829-838,Soria JC et al.Lancet.2017 Mar 4;389(10072):917-929.,Alice Shaw,et al.ASCO 2017 Abstract No.LBA9008,最佳序贯？实现OS最大获益,Benjamin Besse.ESMO 2017 controversy session 10/9/2017,晚期肺癌的治疗是一场马拉松，不只是用单种方案来管理,OS,Based on RECIST PFS:do you really stop at+20%/brain PD?,晚期NSCLC靶向治疗和标准治疗研究显示：ORR与OS、PFS与OS之间无关联,共纳入了自2003年以来提交给FDA的治疗晚期非小细胞肺癌的14项研究（N=12,567）。治疗效应的对数尺度散点图显示：在ORR与总生存之间（R2=0.09）或PFS与总生存之间（R2=0.08）未观察到关联，这可归因于总生存分析的一些混杂因素，如交叉、后续治疗和进展后生存期长。,J Clin Oncol.2015 Mar 20;33(9):1008-14.,Alex 试验,Alectinib尚未体现OS优势,没有Cross-over,Benjamin Besse.ESMO 2017 controversy session 10/9/2017,剖析一代和二代ALK-TKI不同耐药机制,Gainor et al.Cancer discovery 2016,二代ALK-TKI治疗后发生更高比例的ALK耐药突变,一代和二代ALK-TKI不同耐药机制提示：后代ALK-TKI是否该提前？,Gainor et al.Cancer discovery 2016,Mok et al.ESMO 2017,Ascend 4 色瑞替尼vs.化疗,Solomom et al.NEJM 2014,仅化疗ALK+NSCLC,Shaw et al.Lancet Oncol 2011,Profile 1014 一线报告,Profile 1014 当前报告,20 m24%,NR/NR66%,47.5 m/NR63%,Soria et al.Lancet 2017,26.2 m/NR 45%,mOS5y Os,临床试验队列,序贯ALK-TKI可显著延长总生存OS,PP-XLK-CHN-0081 Expiration Date:2018-9-25,ALK阳性的NSCLC患者中crizotinib和alectinib的序贯治疗：多中心回顾性研究,J Thorac Oncol.2017 Feb;12(2):390-396.,克唑替尼 色瑞替尼Gainor et al.Clin Can Res 2015,序贯ALK-TKI可显著延长总生存OS,非临床试验队列,中位OS 49.4m,中位OS 89.6m,克唑替尼 后代TKIsGainor et al.Clin Can Res 2015,PP-XLK-CHN-0081 Expiration Date:2018-9-25,总 结,PROFILE 1014 获得了迄今为止所有IV期NSCLC患者最高的4年生存率和最长OS,ASCEND 4 和ALEX 研究虽然延长PFS 但OS结果尚未成熟，期待其OS公布,临床研究和真实世界研究结果均提示：序贯治疗能显著延长ALK阳性晚期NSCLC的生存,