EGFR-TKI耐药后治疗策略last

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,EGFR-TKI,耐药后治疗策略,酪氨酸激酶：单药用于晚期治疗无法根治,疾病,分期,药物,中位,TTP,参考文献,CML,原始细胞危象,伊马替尼,10,月,Sawyers et al, 2002,(,缓解持续,),GIST,晚期,伊马替尼,17,月,Heinrich et al, 2004,(,无事件生存,),肺癌,晚期,吉非替尼,/,厄洛替尼,9-10,月,Mitsudomi et al, 2009,Rosell et al, 2012,肺癌,晚期,克唑替尼,10,月,Camidge et al, 2011,黑色素瘤,晚期,Vemurafenib,7,月,Sosman et al, 2012,重复活检：观察越多，发现越多,Sequist et al. Sci Transl Med 2011, Adapted; Sequist, ASCO 2012.,同时有,EGFR,扩增,机制不明,SCLC,转化,T790M,TKI,获得性耐药的临床定义,EGFR,TKI,单药的治疗,存在,EGFR,敏感突变,或客观临床获益,疾病进展,(RECIST,标准,),肿瘤评价,SD(,大于,6,个月,),肿瘤评价,CR,或,PR,Jackman DM et al; J Clin Oncol. 2010; 28(2):357-60.,问题一：基于影像学评估的,RECIST,标准是否适用于,TKI,的耐药？,(Continuous treatment beyond progression),61,名,EGFR M+,获得性耐药患者准备参加,MSKCC,的临床试验,EGFR-TKI,停药后的疾病,“,复燃,”,EGFR TKI,PD,获得性耐药,7,21,天,洗脱期,临床试验,14 disease flare,47 completed washout,mPFS,19,个月,Chaft, et al. Clin Cancer Res 2011,2,3,%,发生疾病快速进展导致住院或死亡（,flare,）,中位发生时间：停药后,8,天,相关因素,: TTP,短,(P=0.002),胸膜转移,(P=0.03), CNS,转移,(P=0.01),与,T790M,无关,仍有依赖,TKI,控制的肿瘤,获得性耐药的局部治疗：,MSKCC,经验,184,颅外,PD,患者,(7+,年,),中，,18,例接受局部治疗,排除,CNS PD,自局部治疗时间,中位,TTP,：,10,个月,中位至新的全身治疗时间：,22,个月,中位,OS,：,41,个月,Yu HA, et al. 2012 ASCO Abstract 7527.,局部治疗方法,N=18,肺,15,射频消融,(RFA),2,放疗,2,肺叶切除,7,楔形切除,1,全肺切除,3,淋巴结放疗,(,纵隔,/,锁骨上,),1,肾上腺切除,2,0,0,0,12,24,36,48,20,40,60,80,100,20,40,60,80,100,12,24,36,48,60,0,时间,(,月,),时间,(,月,),无进展生存率,总生存率,PFS (%),OS (%),局部消融联合持续,TKI,治疗单个病灶进展患者,来自科罗拉多大学的,65,例,致癌基因驱动癌症,(EGFR,突变或,ALK,阳性,),所有患者接受,EGFR TKI,或克唑替尼,PFS 1,定义为进展,4,个部位,所有侵犯部位均给予局部消融治疗和持续,TKI,治疗,PFS 2,定义为自局部治疗起至二次进展的时间,Weickhardt AJ,et al. JTO.2012 Dec;7(12):1807-14 .,局部消融联合持续,TKI,治疗单个病灶进展患者,38,例,ALK+,患者，,28,例,(74%),进展,中位,PFS1 = 9.0,个月,27,例,EGFR,突变患者，,23,例,(85%),进展,中位,PFS1 = 13.8,个月,所有患者中位,PFS1 = 10.3,个月,51,个进展患者中，,25,人适合局部治疗并继续原靶向治疗,Weickhardt AJ,et al. JTO.2012 Dec;7(12):1807-14 .,首先进展,部位,N,PFS1,(95% CI),PFS2,(95% CI),CNS,和,/,或,eCNS,25,9.8,个月,8.8 13.8,6.2,个月,3.7 8.0,接受局部消融治疗和持续,TKI,治疗患者的,PFS,PFS1: 9.8m,PFS1 + PFS2: 9.8m+6.2m,0,25,50,75,100,0,6,12,18,24,30,36,时间,(,月,),PFS (%),Weickhardt AJ,et al. JTO.2012 Dec;7(12):1807-14 .,耐药后化疗,+TKI,和化疗的对比研究,EGFR,突变状态：,70,例,(90%),患者突变：,TKI,中位治疗时间,15,个月,(,范围,4-51,个月,),8,例患者突变状态未知：,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患者接受厄洛替尼作为初始,TKI,治疗,入组患者,N=78,化疗,+,厄洛替尼,N=34,化疗,N=44,Goldberg SB et al. 2012 ASCO Abstract 7524.,化疗,厄洛替尼治疗获得性耐药的患者,化疗,+,厄洛替尼,(N=34),化疗,(n=44),OR/HR,95%CI; P,值,ORR (%),41,18,OR 0.20 (0.05-0.78),0.02,中位,PFS (,月,),4.4,4.2,HR 0.79 (0.48-1.29),0.34,Goldberg SB et al. 2012 ASCO Abstract 7524.,对,EGFR-TKI,存在获得性耐药,(Jackman,标准,),的患者接受后续化疗或化疗,+,厄洛替尼治疗,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. 2012 ASCO Abstract 7524.,化疗,+,厄洛替尼,相比基线的自家改善百分比,(%),40,20,0,20,40,60,80,PD,或,SD,PR,化疗,40,20,0,20,40,60,80,PD,或,SD,PR,PR,PD/SD,PR,PD/SD,治疗的最佳疗效,活化,EGFR,突变患者疾病进展后持续易瑞沙治疗：日本研究,回顾性分析,134,例,EGFR,基因突变患者,外显子,19,缺失突变,/L858R,突变：,71/63,易瑞沙起始治疗的中位,PFS,：,9.5 (95%CI=7.9-11.1),个月,易瑞沙治疗,PD,后的中位生存时间,14.3 (95%CI=11.7-16.9),个月,PD,后中位易瑞沙治疗时间,3.2,个月,Asami K, et al. Lung Cancer 2013; 79:276-282.,易瑞沙组,短期,3M,(n=66),长期,3M,(n=68),P,值,PD,前：,CR/PR,44 (67%),31 (46%),0.01,出现,PD,时,PFS,9,个月,49 (74%),58 (85%),0.11,ECOG PS 0-1,25 (38%),49 (72%),9,个月，无继发,EGFR T790M,；另,2,例易瑞沙再次治疗后,PFS9,个月，有继发,EGFR T790M,突变,从另,2,例,PFS9,个月的患者中提取脑脊液，后续给予厄洛替尼并在,2,周内获得,PR,，没有检测到,EGFR T790M,突变,Asami K, et al. Lung Cancer 2013; 79:276-282.,易瑞沙组,P,值,HR,95%CI,ECOG PS,0.048,0.6,0.36-0.99,PFS,9,个月,0.27,0.8,0.5-1.2,既往评估病灶进展,0.02,0.6,0.39-0.92,易瑞沙长期治疗组,9.5,年,),活化,EGFR,突变患者对吉非替尼,(30%),或厄洛替尼,(70%),治疗获得性耐药,RR 4%,；,SD 63%,；中位无,EGFR-TKI,治疗间期,5,个月,(,范围,2-46,个月,),无,EGFR-TKI,间期越长，,TTP,获益越大,无,EGFR-TKI,治疗间期,6,个月,vs. 5,年,(n=28),性别：男,/,女,(%),29.3/70.7,10.7/89.3,吸烟状态：否,/,是,/,未知,(%),64.8/32.2/3.0,78.6/17.9/3.6,分期：,IIIA/IIIB/IV (%),1.5/19.7/80.3,0/28.6/71.4,WHO PS,：,0/1/2/,未知,(%),18.3/69.1/12.6/0.6,32.1/64.3/3.6/0.0,组织学：腺癌,/,鳞癌,/,大细胞癌,/,其他,(%),90.3/7.3/0.9/2.7,96.3/0/3.6/3.6,中位治疗时间,(,天,),267.0,926,吉非替尼再次挑战,(%),19.4,50.0,进展后继续吉非替尼治疗,(%),27.8,39.3,再次挑战：,OS,Namba Y, et al. 2012 ESMO, abstract 1253P.,100,80,60,40,20,0,0,200,400,600,800,1000,1200,1400,时间,(,天,),吉非替尼再挑战,(n=65),：中位,1272,天,未接受吉非替尼再挑战,(n=270),：中位,774,天,P,0.001,OS (%),吉非替尼再次挑战,OS,的,COX,分析,Namba Y, et al. 2012 ESMO, abstract 1253P.,单变量分析,多变量分析,点估计值,95%CI,P,值,点估计值,95%CI,P,值,下限,上限,下限,上限,性别,女,/,男,0.728,0.547,0.970,0.0304,0.874,0.624,1.224,0.4338,分期,IV/IIIB,1.437,1.012,2.042,0.0430,1.355,0.947,1.940,0.0961,年龄,5160/50,0.815,0.491,1.354,0.1368,0.748,0.445,1.258,0.0269,6170/50,0.945,0.583,1.531,0.936,0.570,1.539,7180/50,1.280,0.775,2.115,1.227,0.730,2.064,81/50,1.480,0.673,3.254,2.087,0.936,4.652,组织学,腺癌,/,非腺癌,1.035,0.330,3.246,0.9530,0.960,0.300,3.075,0.9452,PS,连续值,1.122,0.984,1.281,0.0863,1.162,0.999,1.353,0.0519,吸烟状态,连续值,1.116,1.032,1.208,0.0061,1.104,1.008,1.210,0.0335,再次给予 吉非替尼,是,/,否,0.519,0.371,0.726,0.0001,0.517,0.364,0.734,0.0002,问题三：获得性耐药患者的管理策略？,晚期非小细胞肺癌,EGFR-TKI,临床失败模式与后续管理,研究人群,120 trial patients,107 routine patients,分组因素,疾病控制时间,Duration of disease control,肿瘤负荷演变,靶病灶,VDI,(volume doubling time),非靶病灶评分,(1-4,分,),：,原有病灶、胸腔内新发、胸腔外新发、新发恶性胸水，任一进展记为,1,分,临床症状,6,项,0,分：无症状,1,分：症状稳定,2,分：任一症状恶化或新发,227,例,III/IV,期,NSCLC,患者,Yang JJ,et al. Lung Cancer. 2013 Jan;79(1):33-9.,三种临床失败模式,57.3%,(130/227),24.2%,(55/227),18.5%,(42/227),爆发进展,:,缓慢进展,局部进展,Yang JJ,et al. Lung Cancer. 2013 Jan;79(1):33-9.,疾病控制,3,个月,与以往评估相比，肿瘤负荷快速增加,症状评分达到,2,疾病控制,6,个月,与以往评估相比，肿瘤负荷轻微增加,症状评分达到,1,疾病控制,3,个月,孤立性颅外进展或颅内进展,症状评分达到,1,不同失败模式的生存分析,N,中位,(,月,),P,爆发,130,9.3,缓慢,42,12.9,0.007,局部,55,9.2,N,中位,P,爆发,130,17.1,缓慢,42,39.4,3,个月,RECIST,评价：厄洛替尼治疗后,PR,或,CR,的患者或,EGFR,外显子,19,或,21,突变,EGFR,突变与,MET,扩增的患者,PD,后病灶活检,停止厄洛替尼治疗,2,周,接受阿法替尼,40mg/d PO,，治疗,2,周,阿法替尼,40mg PO,每日并联合西妥昔单抗,每,2,周静脉用药,(I,期临床研究的剂量,),Janjigian YY, et al. ASCO 2011; Abstract 7525.,EGFR,突变状态与,MTD,时的最佳疗效,确认的,RR,：,40%,；临床获益率：,90%,Janjigian YY, et al. ASCO 2011; Abstract 7525.,70,60,50,40,30,20,10,0,-10,-20,-30,-40,-50,-60,-70,-80,-90,-100,0,16,4,8,12,20,24,28,32,36,40,44,48,自基线减小的最大比例,(%),T790M+,T790M-,无突变,无价值,全新的抗,EGFR T790M,突变选择型的,EGFR,激酶抑制剂,Zhou WJ, et al. Nature 2009; 462:1070-1074.,N,N,N,H,Y,N,N,X,CI,N,H,0,20,40,60,80,100,0,20,40,60,80,100,0,20,40,60,80,100,200,180,160,140,120,100,100,80,60,40,20,0,4,000,3,000,2,000,1,000,100,80,60,40,20,0,4,000,3,000,2,000,1,000,100,80,60,40,20,0,4,000,3,000,2,000,1,000,100,80,60,40,20,0,4,000,3,000,2,000,1,000,100,80,60,40,20,0,H3255,PC9,H1975,PC9 GR,E746_A750/T790M,L858R/T790M,E746_A750,L858R,IC,50,(Nm),IC,50,(Nm),CL-387,785,HKI-272,WZ3146,WZ4002,WZ8040,WZ3146,X,=O,Y,=H,WZ4002,X,=O,Y,=OMe,WZ8040,X,=S,Y,=H,易瑞沙,通过,MET,扩增引起的,TKI,耐药,对照,(%),对照,吉非替尼,吉非替尼,吉非替尼浓度,Engelman et al. Science 2007; 316:1040.,克服,EGFR TKI,耐药的治疗策略,(,进行中的研究,),机制,策略,临床研究,(,例,),T790M,EGFR,抑制剂的联合,T-790M,特异性,TKI,MET+PI3K,抑制剂,Hsp90,抑制剂,阿法替尼,+,西妥昔单抗,CO-1686, AP26113,GDC-0973+GDC-0941,AUY922,C-MET,扩增,EGFR+c-MET,抑制剂,厄洛替尼,+,克唑替尼,Dacomitinib+,克唑替尼,SCLC,转化,铂类,/,依托泊苷,+/-EGFR TKI,无,PIK3CA,EGFR+PI3K,抑制剂,吉非替尼,+BKM120,厄洛替尼,+GDC-0941,未知,EGFR,抑制剂联合,Hsp90,抑制剂,阿法替尼,+,西妥昔单抗,厄洛替尼,+AUY922,EGFR,mut+,NSCLC,Resistance,EGFR TKI,T790M,MET,amp,HGF overexp,Misc,New agents,Chemotherapy,EGFR TKI,continuation + chemotherapy,获得性耐药的治疗策略,Local therapy RT, Surgery,T790M mutation,Met amp,PIK3CA,SCLC,HER2-amp,MAPK1 amp,AXL expression,Sequist et al Sci Trans Med,2011,Cheung HW et al Cancer Discovery 2011,Etcan et al Cancer Discovery 2012,Takezawa et al Cancer Discovery 2012,Zhang et al Nature Genetics 2012,总结,几乎所有接受靶向治疗的患者都会因为耐药的出现而复发,耐药受到一系列不同的分子学机制调控,单个患者中会出现多重耐药机制,以耐药为靶点的联合治疗策略很有可能对治疗结局有最大的影响,目前工作的终点在于发现其他类型的耐药，包括,CNS,的耐药机制,临床实践中的问题,建议靶向治疗失败的患者再次接受耐药肿瘤活检与参加临床研究,当出现机会时，考虑对耐药部位给予较为激进的局部治疗,由于脑部和脑膜复发常见，因此应监测,CNS,，尤其是,EGFR,基因突变,阳性,NSCLC,患者,合适时在全身治疗方案中维持,TKI,谢谢,