EGFRTKI耐药后治疗策略

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,深入学习实践科学发展观,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,LOGO,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,LOGO,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,深入学习实践科学发展观,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,LOGO,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,LOGO,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,EGFRTKI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,EGFR-TKI,联合化疗,第三代,EGFR-TKI,第二代,EGFR-TKI,联合西妥昔单抗,化疗,第二代,EGFR-TKI,联合,cMET,抑制剂,第二代,EGFR- TKI,联合,HDAC,抑制剂,第二代,EGFR-TKI,联合,IFGF1R,抑制剂,EGFR-TKI,如何处理,EGFR,突变型,NSCLC,的获得性耐药,Pao et al. 2010.,耐药后的治疗选择,化疗,再次尝试,TKI,EGFR-TKI,+,化疗,新靶点药物,EGFR,一线,IRESSA,治疗后二线化疗缓解率,总体缓解率,(%),一线,二线,一线,二线,Maemondo M, et al. NEJM 2010; 362:2380-2388.,耐药后的治疗选择,化疗,再次尝试,TKI,EGFR-TKI,+,化疗,新靶点药物,TKI Re-challenge,两种模式,EGFR-TKI,EGFR-TKI,(,原药,or,换药,),P,D,EGFR-TKI,EGFR-TKI,(,原药,or,换药,),C,T,P,D,P,D,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,既往,G,疗效,(%),E,疗效,(%),PR,5 (25),0 (0),SD,9 (45),7 (35),PD,6 (30),13 (65),PFS,277,天,31,天,总计,SD,突变,+,10,5,突变,-,5,0,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),1.0,0.8,0.6,0.4,0.2,0,5,10,15,20,时间,(,月,),再次给药前无治疗,再次给药前有治疗,生存率,耐药后的治疗选择,化疗,再次尝试,TKI,EGFR-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),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,化疗,+,特罗凯,(N=34),化疗,(n=44),ORR, (%),41,18,中位,PFS (,月,),4.4,4.2,HR 0.79(0.48-1.29),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 SD,PR,化疗,40,20,0,20,40,60,80,PD or SD,PR,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,EGFR,突变的,晚期,NSCLC,根据,RECIST,标准判断为,PD,EGFR TKI,吉非替尼,+,培美曲塞,/,铂类,培美曲塞,/,铂类,共同,PI,：,Soria J; Mok T,主要终点：,PFS,欧洲,/,日本,/,亚洲研究,N=,约,250,2012,年第一季度开始,耐药后的治疗选择,化疗,再次尝试,TKI,EGFR-TKI,+,化疗,新靶点药物,针对耐药靶点的治疗策略,Mechanism,Strategy,T790M,Combination EGFR inhibitors,T790M-specific TKIs,MEK+PI3K inhibitors,Hsp90 inhibitors,C-MET,amplification,EGFR+c-MET inhibitors,SCLC transformation,Platinum/etoposide +/- EGFR TKI,PIK3CA,EGFR+PI3K inhibitors,unknown,Combination EGFR inhibitors,Hsp90 inhibitors,EGFR,获得性耐药治疗：针对,T790M,不可逆抑制,EGFR,BIBW 2992 (Afatinib),PF299804,HKI-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/cohort,Afatinib 40 mg PO daily +,doses IV Cetuximab Q2wk,Eligibility,NSCLC with EGFR mutation (G719X, exon 19 deletion, L858R, L861Q),Systemic disease progression on continuous erlotinib or gefitinib within 30 days,MTD Expansion Cohort,Up to 80 EGFR mutation-,positive pts to be enrolled:,40 T790M-positive,40 T790M-negative,Janjigian YY, et al. ASCO 2011,Phase Ib Study: Afatinib + Cetuximab for Pts with NSCLC & Acquired Resistance to EGFR-TKI,s,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,Discontinued treatment(n=91),Disease progression(n=72),Adverse event(n=6),Symptomatic deterioration(n=6),Subject request(n=3),Investigator request(n=2),Death(n=1),other(n=1),Not evaluable for response(n=3),Discontinued treatment(n=48),Disease progression(n=37),Adverse event(n=4),Symptomatic deterioration(n=3),Subject request(n=1),Investigator request(n=1),Death(n=1),other(n=1),Not evaluable for response(n=3),Discontinued treatment(n=28),Disease progression(n=23),Adverse event(n=1),Symptomatic deterioration(n=1),Subject request(n=1),Investigator request(n=1),Death(n=1),other(n=0),Not evaluable for response(n=3),Arm A,Prior EGFR TKI EGFR mutation,(n=91),Arm B,EFGR Wild Type,(n=45),Arm C,TKI na,ve with clincal characteristics of TK response,(n=28),Screened subjects,(n=295),Screened failure(n=128),Not eligible(n=90),Decline/death(n=27),Withdrew consent(n=11),Subjects who recelved study drug,(Safety/ITT populatlon),(n=167),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：,（,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 antibody,HGF: AMG102 (rilotumumab), SCH900805 (AV229, ficlatuzumab),MET: MetMAb (onartuzumab),Small molecule inhibitor,ARQ197 (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,PFS,ITT,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,NSCLC,2/3,线,NSCLC,ECOG 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 D,x,+):50%,肿瘤细胞,Met,组化染色强度为,2+,或,3+,1+,2+,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 print,2. Unpublished , courtesy of ArQule. Inc and Kyowa Hakko Kirin Co. Ltd.,3. Lauxl et al. ASCO 2009,4. 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.,Endpoints,Primary: PFS,Secondary: ORR, OS,Subset analyses,Crossover: ORR,R,A,N,D,O,M,I,Z,E,PD,ARQ 209 enrolled 167 advanced NSCLC patients,Study accrual over 11 months (10/089/09),Randomization stratified by sex, age, smoking, histology, performance status, prior therapy and best response, and geography,NSCLC,Inoperable locally adv/metastatic dz,1 prior chemo (no prior EGFR TKI),Erlotinib 150 mg PO QD + ARQ-197 360 mg PO BID28-day cycle,Erlotinib 150 mg PO QD + placebo28-day cycle,* 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,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,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),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,4,c-MET FISH 5,EGFR mutant,EGFR wt,KRAS mutant,KRAS wt,26 / 24,58 / 59,19 / 18,8 / 11,6 / 11,51 / 48,10 / 5,49 / 45,13.7 (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),34,例患者,交叉入组,2 PR,2,12 PD,23,例可评价疗效,1,9 SD,3,根据,RECIST,的最佳疗效,(n=23),1.,基线,+1,基线后扫描，未入组原因包括：,临床进展,(N=4),有效但未接受首次进展后的扫描,(N=2),死亡,(N=1),剂量延迟,(N=1),退出知情同意,(N=1),研究者决定,(N=1),2,.,患者,# 24,EGFR IND,KRAS WT,C-MET 4,3. 18+,周,患者,# 58,EGFR MUT,KRAS WT,C-MET 5,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,NSCLC,不可手术的局部晚期或转移性疾病,既往接受,1,次,化疗（既往未接受,EGFR-TKI,）,厄洛替尼,150mg po qd,+ ARQ197,360mgpo Bid,厄洛替尼,150mg,po qd +,安慰剂,主要终点为,OS,计划入组,988,例患者，分层因素,：,既往治疗次数,性别,吸烟史,EGFR,与,KRAS,突变状态,随,机,Met,抑制剂的临床研究汇总,ARQ-197:,特异性,MET,抑制剂,Sequist, et al. JCO 2011,MetM,Ab: Met-mab+,厄洛替尼治疗,Met,扩增阳性患者,Spiegel, et al. ASCO 2011,Crizotinib,:,对,ALK,和,MET,均,有效,XL-184, MET + RET + VEGF,Randomized phase II of E. +/- XL-184 in TKI resistant pts, not report yet,PF-02341066,Still 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,!,人有了知识，就会具备各种分析能力，,明辨是非的能力。,所以我们要勤恳读书，广泛阅读，,古人说“书中自有黄金屋。,”通过阅读科技书籍，我们能丰富知识，,培养逻辑思维能力；,通过阅读文学作品，我们能提高文学鉴赏水平，,培养文学情趣；,通过阅读报刊，我们能增长见识，扩大自己的知识面。,有许多书籍还能培养我们的道德情操，,给我们巨大的精神力量，,鼓舞我们前进,。,