EGFR-TKI耐药后治疗策略.ppt

四川大学华西医院肿瘤中心邹立群,EGFR-TKI耐药后治疗策略,EGFR-TKI耐药机制EGFR-TKI原发性耐药机制,原发性耐药 使用EGFR-TKI后未曾出现过临床获益 7-13%EGFR基因敏感突变NSCLC患者一线TKI治 疗无获益,EGFR-TKI耐药机制EGFR-TKI原发性耐药机制EGFR-TKI获得性耐药机制,继发性耐药 接受EGFR-TKI治疗后曾经出现疗效（肿瘤缓解、进展延迟、症状改善等）而后又恶化 将发生于所有EGFR基因敏感突变且TKI初始治疗 有效的NSCLC患者,EGFR TKI获得性耐药的临床定义,之前接受过EGFR TKI单药的治疗或者肿瘤含有可能的EGFR敏感突变类型(例如:G719X,exon 19 deletion,L858R,L861Q)在接受EGFR TKI治疗后临床获益,肿瘤评价CR或PR(按照RESIST或WHO标准),或SD(大于6个月)在最近的30天内接受持续的吉非替尼或厄罗替尼治疗,根据RESIST或者WHO标准评价体内肿瘤进展,Jackman DM et al;J Clin Oncol.2010;28(2):357-60.,EGFR-TKI获得性耐药的基因表现,Lecia V.Sequist et al.Sci Transl Med 3,75ra26(2011);,原位变异,旁路激活,原位扩增,EGFR-TKI获得性耐药后的治疗,Pao et al.2010.,耐药后的治疗选择,化疗再次尝试TKIEGFR-TKI+化疗新靶点药物,EGFR 一线IRESSA治疗后二线化疗缓解率,Maemondo M,et al.NEJM 2010;362:2380-2388.,耐药后的治疗选择,化疗再次尝试TKIEGFR-TKI+化疗新靶点药物,TKI Re-challenge 两种模式,根据来自上海市胸科医院的数据，评估吉非替尼治疗失败后使用厄洛替尼治疗的可行性,Chinese Medical Journal 2011,吉非替尼治疗失败后两种模式的OS比较,Chinese Medical Journal 2011,(8.5m vs.4.2m,P=0.146),耐药后的治疗选择,化疗再次尝试TKIEGFR-TKI+化疗新靶点药物,耐药后化疗+TKI和化疗的对比实验,入组患者N=78,化疗+厄罗替尼N=34,化疗N=44,EGFR 突变状态:70名(90%)患者突变TKI中位治疗时间15个月(范围4-51个月)8民患者突变状态未知TKI中位治疗时间11个月(范围5-16个月),两组基线特征均衡但联合治疗组有更多的病人接受厄罗替尼作为初始TKI治疗,2012 ASCO abstract#7524,风险比0.20(0.05-0.78)P=0.02,化疗 特罗凯治疗获得性耐药的患者,EGFR-TKI存在获得性耐药(Jackman标准)的患者接受后续化疗或化疗+特罗凯治疗化疗必须在EGFR-TKI停药的4周内启动由独立评估者对治疗应答进行评估，对评估者实施治疗方案盲法,Goldberg SB,et al.J Clin Oncol 2012;30(Suppl.15 Pt I):486s(Abs.7524),ORR客观应答率；PFS无进展生存,HR 0.79(0.48-1.29)P=0.34,治疗的最佳应答,化疗+特罗凯,相比基线的自家改善百分比(%),40,20,0,20,40,60,80,PD or SDPR,化疗,40,20,0,20,40,60,80,PR,PD/SD,PR,PD/SD,Goldberg SB,et al.J Clin Oncol 2012;30(Suppl.15 Pt I):486s(Abs.7524),PD=疾病进展，SD=疾病稳定，PR=部分缓解,研究结论,继续TKI同步化疗可能会成为有价值的治疗策略尤其是对症状有进展的患者能获得更高缓解率需要进一步证实,2012 ASCO abstract#7524,IMPRESS：进展时化疗吉非替尼,欧洲/日本/亚洲研究N=约2502012年第一季度开始,耐药后的治疗选择,化疗再次尝试TKIEGFR-TKI+化疗新靶点药物,针对耐药靶点的治疗策略,EGFR获得性耐药治疗：针对T790M,不可逆抑制EGFRBIBW 2992(Afatinib)PF299804HKI-271,etc联合EGFR-TKI与EGFR-单抗,LUX-LUNG-1：Afatinib+BSC vs.BSC 治疗复发/转移NSCLC,Miller VA,et al.ESMO 2010,IIB/III期临床研究(N=585),Maximum decrease in tumor size from baseline(independent review),Miller VA,et al.ESMO 2010,LUX-LUNG-1(updated 2011)Activity by Independent Review,Hirsch V et al.WCLC 2011,Dose Escalation 3-6 pts/cohortAfatinib 40 mg PO daily+doses IV Cetuximab Q2wk,MTD Expansion CohortUp to 80 EGFR mutation-positive pts to be enrolled:40 T790M-positive40 T790M-negative,Janjigian YY,et al.ASCO 2011,Phase Ib Study:Afatinib+Cetuximab for Pts with NSCLC&Acquired Resistance to EGFR-TKIs,Afatinib+Cetuximab(update),In all pts(n=55),the combination of Afatinib and Erbitux was active,with a confirmed ORR of 35%,and a DCR of 95%The combination was equally active in the subgroup of pts with T790M mutations,with a confirmed ORR of 31%and a DCR of 94%,Horn,Abstract O19.07,IASLC WCLC 2011,WCLC 2011 Competitive Analysis:Highlights Report|18 July 2011,Neratinib:Phase II Trial in Patients WithAdvanced NonSmall-Cell Lung Cancer,Neratinib:Phase II Trial in Patients WithAdvanced NonSmall-Cell Lung Cancer,终点包括客观应答率应答持续时间无进展生存总生存安全性/耐受性药效学,药代动力学终点血清HER2水平EGFR胞外结构域水平,Dacomitinib 45 mg/天 根据组织学分组A组为腺癌（n=30）B组为非腺癌（n=4）,至少1种既往化疗有厄洛替尼治疗史 KRAS野生型(n=34),美国仍在进行中II期研究，阶段性患者基线，疗效和安全性结果作为摘要提交2009年ASCO年会,PA Janne,et al,J Clin Oncol 2009 27:15s(suppl;abstr 8063),Dacomitinib治疗厄洛替尼耐药且至少一种既往化疗失败的晚期NSCLC,Dacomitinib 治疗厄洛替尼耐药且至少一种既往化疗失败的晚期NSCLC,共有20名患者接受了应答评估其中达到疾病稳定的患者人数：腺癌组：9/18非腺癌组：1/2中位疾病稳定时间：11.5（6-32）周在如下患者中观察到疾病控制：停用厄洛替尼时间较短（8周）已知突变状态为EGFR T790M突变最常见的不良事件为：皮肤表现（3级不良事件占19%）胃肠道表现（3级不良事件占13%）共有2位患者出现4级不良事件，两人均属于疾病进展者,PA Janne,et al,J Clin Oncol 2009；27:15s(suppl;abstr 8063),不可逆TKI(Pan-HER 抑制剂)汇总,Neratinib(HKI-272)*TKI耐药患者RR 2%,PFS 15周(Sequist,JCO 2010)Afatinib(BIBW-2992)*TKI耐药患者RR 7%，PFS约13周(Miller，Lan Onc 2012)Dacomitinib(PF-299804)*TKI耐药患者RR 7%(Janne ASCO，2009),EGFR获得性耐药治疗：针对MET,联合抑制EGFR与MET通路,MET Inhibitors,Monoclonal antibodyHGF:AMG102(rilotumumab),SCH900805(AV229,ficlatuzumab)MET:MetMAb(onartuzumab)Small molecule inhibitorARQ197(tivantinib)XL-184(cabozantinib)XL880(foretinib),PF02341066(crizotinib),INC280,MetMAb+厄洛替尼用于NSCLC的II期研究(OAM4558g),主要研究终点Met Dx+患者的PFSITT人群的PFS,*若符合条件，允许交叉至对组,1,(n=23),分层因素吸烟史 PS组织学,IIIB/IV期 NSCLC2/3线NSCLCECOG PS 02需获得组织标本(n=128),R,1,厄洛替尼 150mg qd+MetMAb 15mg/kg IV q3w,PD,若符合条件可加用MetMAb*,厄洛替尼 150mg qd+安慰剂,PD,MET诊断阳性(MET Dx+):50%肿瘤细胞Met组化染色强度为2+或3+,Spigel D et al.ESMO 2010 Spigel D et al.J Clin Oncol 2011 Spigel D et al.WCLC 2011,主要终点：PFS,Met Dx+,Met Dx-,Spigel D et al.J Clin Oncol 2011,ARQ 197:一种全新的选择性酪氨酸激酶抑制剂,c-Met的非ATP竞争性抑制剂全新作用机制使c-MET1的非活化构象稳定在许多肿瘤移植物模型（包括NSCLC）中，该化合物均证实具有广谱的抗肿瘤活性ARQ197+EGFR抑制剂的体内抗肿瘤活性均大于ARQ197单药及EGFR抑制剂单药联合EGFR-TKI 厄洛替尼的I期临床研究证实了安全性与线性的PK,1.Mun shi N,et al.Mol Cancer Ther 2010,Epub ahead of print2.Unpublished,courtesy of ArQule.Inc and Kyowa Hakko Kirin Co.Ltd.3.Lauxl et al.ASCO 20094.Goldman et al.IASLC 2009,比较厄洛替尼联合ARQ197与厄洛替尼联合安慰剂治疗既往未接受EGFR抑制剂治疗的局部晚期或转移性NSCLC患者的一项全球随机对照II期临床研究,Schiller JH et al.Proc ASCO 2010;Abstract LBA7502.,*Cox regression model.With permission from Schiller JH et al.Proc ASCO 2010;Abstract LBA7502.,PFS(ITT population),Overall survival(ITT population),HR=0.81;p=0.24Adjusted HR=0.68;p 0.05,HR=0.81;p=0.24Adjusted HR=0.68;p=0.52*,ARQ-197+erlotinib 提高了PFS总生存和erlotinib单药相当,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,10,20,30,40,50,Time from randomization(weeks),Erlotinib+ARQ 197 16.1 wks(n=84)Erlotinib+Placebo 9.7 wks(n=83),1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,10,20,40,60,70,Survival time(weeks),Proportion of patients surviving,Erlotinib+Placebo 29.4 wks(n=83)Erlotinib+ARQ 197 36.6 wks(n=84),50,30,Proportion of patients progression free,*Cox regression model.With permission from Schiller JH et al.Proc ASCO 2010;Abstract LBA7502.,ARQ 197-209:PFS and OS in non-squamous cell histology patients(n=117),PFS(investigator assessed),Overall survival,HR=0.71;p=0.12Adjusted HR=0.61;p 0.05*,HR=0.72;p=0.18Adjusted HR=0.58;p 0.05*,ARQ197+erlotinib在腺癌中优势明显,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,10,20,30,40,50,Erlotinib+ARQ 197 18.9 wks(n=58)Erlotinib+Placebo 9.7 wks(n=59),1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,10,20,40,60,70,Erlotinib+ARQ 197 43.1 wks(n=58)Erlotinib+Placebo 29.4 wks(n=59),50,30,Proportion of patients surviving,Proportion of patients progression free,Time from randomization(weeks),Time from randomization(weeks),根据基因分组的PFS,Schiller JH et al.Proc ASCO 2010;Abstract LBA7502.,0,5.0,0.5,1.0,1.5,2.0,FavorsARQ 197/erlotinib,FavorsErlotinib/placebo,Squamous cellNonsquamous cellc-MET FISH 4c-MET FISH 5EGFR mutantEGFR wtKRAS mutantKRAS wt,26/2458/5919/188/116/1151/4810/549/45,HR=1.05HR=0.71HR=0.71HR=0.45HR=1.23HR=0.70HR=0.18HR=1.01,13.7(8.0-18.1)18.9(15.0-31.1)15.4(8.1-24.4)24.1(16.3-NE)24.1(8.0-32.1)13.7(8.1-18.1)9.7(7.9-NE)15.4(8.1-18.1),8.4(7.9-21.0)9.7(8.0-16.0)15.3(7.1-16.3)15.6(7.9-31.4)21.0(8.1-36.0)8.1(7.9-9.9)4.3(1.1-8.0)9.9(8.0-16.0),ARQ 197/erlotinib,Placebo/erlotinib,N,Median PFS(95%CI,weeks),Unadjusted HR(95%CI),ARQ 197：交叉患者,Schiller JH,et al.J Clin Oncol 2010,结 论,ARQ-197联合厄洛替尼二/三线治疗既往未接受EGFR-TKI治疗的NSCLC患者耐受性良好，能延长PFS非鳞癌、KRAS突变与EGFR野生型患者有特别获益,Schiller JH,et al.J Clin Oncol 2010,比较厄洛替尼联合ARQ 197与厄洛替尼联合安慰剂治疗复治局部晚期或转移性非鳞癌NSCLC患者的一项随机、双盲、安慰剂对照、III期研究,Sandler A,et al.J Clin Oncol 2011,Met抑制剂的临床研究汇总,ARQ-197:特异性 MET 抑制剂 Sequist,et al.JCO 2011MetMAb:Met-mab+厄洛替尼治疗Met扩增阳性患者Spiegel,et al.ASCO 2011Crizotinib:对ALK和MET均有效XL-184,MET+RET+VEGFRandomized phase II of E.+/-XL-184 in TKI resistant pts,not report yetPF-02341066Still in phase,治疗EGFR TKI获得性耐药的策略,转换为化疗出现进展后继续使用 EGFR TKI在TKI基础上加入化疗尝试不同类型的特异性针对耐药机制的靶向性药新一代TKI可以有助于克服T790M，但需要更多的临床数据 靶向药物的联合可望进一步提高疗效,谢 谢!,