单击此处编辑母版标题样式,*,ALK,阳性,NSCLC,脑转移的治疗策略,杨镇洲,第,三军医大学,重庆,2016.01.21,重庆,第三附属医院,肿瘤专科医院,内 容,背景,初治时脑转移的治疗,治疗过程中发生脑转移的治疗,治疗策略,血脑屏障,抗肿瘤药物的阿喀琉斯之踵,血脑屏障耐药机制：,1,、内皮细胞,P,糖蛋白等,MDR,基因,高表达，增加药物排除,2,、,内皮细胞排列紧密,，药物无法通过,98%,的小分子药物无法有效通过血脑屏障,理论上,100%,的大分子药物无法通过血脑屏障，但,WM.Pardrigde.NeuroRx,2005,靶向药物脑脊液,/,血浆药物浓度比值,研究药物,血浆浓度,脑脊液浓度,脑,/,血比值,吉非替尼,1,3730nmol/L,39.4nmol/L,0.011,厄洛替尼,2,980nmol/L,19nmol/L,0.02,克唑替尼,3,237nmol/L,0.616nmol/L,0.0026,Jackman DM,et al.J Clin Oncol 2006;.2.Yang H.Targeted Oncology.2014,；,3.Costa DB,et al.J Clin Oncol 2011;29:e443-5.,克唑替尼,IC,50,值：,240 nmol/L,DMSO,0.001,0.01,0.1,1,10,0,20,40,60,80,100,120,A549(,KRAS,G12S),H3255(,EGFR,L858R),HCC827(,EGFR,delE746_A750),H3122(,EML4-ALK,E13A20),克唑替尼,(M),细胞存活率,(%),Ping Yang,et al.J Thorac Oncol.2012;7:9097,ALK,阳性,NSCLC,患者易发生脑、肝转移,ALK,阳性,NSCLC,易发生脑转移,内 容,背景,初治时脑转移的治疗,治疗过程中发生脑转移的治疗,治疗策略,ALK,阳性,NSCLC,克唑替尼治疗前,存在脑转移,MO 07.02 PROFILE1005,、,PROFILE1007,：,克唑替尼用于晚期,ALK,重排非小细胞肺癌,脑转移患者的临床经验,目的：,回顾性研究,PROFILE,1005,和,1007,中,ALK,阳性脑转移患者经过克唑替尼治疗疗效,研究终点：,1.,治疗,12,周颅内和全身,DCR,2.,无疾病进展生存期（,PFS,）,1.,Kim D-W,et al.J Clin Oncol 2012;30(Suppl.)(abstr.7533);,2.,Shaw AT,et al.N Engl J Med 2013;368:23852394.,PROFILE 1005,、,PROFILE 1007,研究中,888,例可评估患者基线特征,临床特征,未治疗脑转移,（,n=109),曾治疗脑转移,（,n=166),无脑转移,（,n=613),中位年龄，年龄（范围）,48(22-77),48(19-81),54(24-83),性别，,n(%),男性,46(42),73(44),264(43),种族，,n(%),亚洲人,76(70),90(54),231(38),白人,31(28),71(43),356(58),其他,2(2),5(3),26(4),吸烟史，,n(%),从未吸烟,70(64),107(64),408(67),曾经吸烟,32(29),53(32),184(30),现在吸烟,7(6),6(4),21(3),组织学，,n(%),腺癌,105(96),159(96),572(93),ECOG,生存质量评分,n(%),0,21(19),40(24),186(30),1,68(62),96(58),332(54),2/3,20(18),30(18),95(15),疾病进展，,n(%),局部进展,6(6),8(5),49(8),转移,103(94),158(95),564(92),脑转移部位分类，,n(%),目标病灶,9(8),9(5),NA,目标和非目标病灶,13(12),9(5),NA,非目标病灶,87(80),148(89),NA,ECOG PS,Eastern Cooperative Oncolog Group performance status;NA,not applicable,克唑替尼对基线有,/,无脑转移（,BM,）患者的,抗肿瘤活性,未治疗脑转移,（,n=109),n,结果,曾治疗脑转移,（,n=166),n,结果,无脑转移,（,n=613),n,结果,12,周疾病控制率，,%,（,95%CI,）,颅内,109,56,(46-66),166,62,(54-70),NA,全身,109,63(54-72),166,65(57-72),613,71(68-75),客观缓解率，,%,（,95%CI,）,颅内,109,7(3-14),166,7(4-12),NA,脑转移目标病灶,22,18,(5-40),18,33,(13-59),NA,全身,109,53(43-63),166,46(39-54),613,55(51-59),中位至肿瘤缓解期（范围）,a,，周,颅内,8,6.0(4.9-12.4),12,6.4(5.9-17.7),NA,全身,58,6.1(2.0-31.4),77,6.1(3.1-35.3),336,6.1(3.0-49.1),中位缓解持续时间,b,（范围）,a,，周,颅内,8,26,(6.1-59.3),12,NR,(6.0-59.9),NA,全身,58,48,(5.3-55.0),77,56,(4.4-95.3),336,49.0(4.1-96.1),中位全身无进展生存,b,（,95%CI,）,c,月,109,8.3,(6.7-14.0),166,13.5,(6.2-16.5),613,9.9(8.8-12.2),DCR,以,SD,为主,克唑替尼治疗后脑转移灶完全缓解病例,使用克唑替尼前,克唑替尼,250mg,每天两次治疗,6,周后,该脑转移（分类为目标病灶）患者曾化疗和姑息性颅内放射治疗。治疗,6,周后病灶完全缓解，并维持,54,周直至数据终止（,courtesy of J-Y Han,National Cancer Center,Goyang,South Korea,）,PROFILE 1014,研究设计,主要入组标准,FISH,法测定,ALK,阳性,a,局部晚期，复发或转移性非鳞,NSCLC,无既往系统性治疗的晚期患者,ECOG PS 02,病灶可测量,经治疗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/m,2,+,顺铂,75 mg/m,2,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,ORR,OS,安全性,患者生活质量报告,(EORTC QLQ-C30,LC13,EQ-5D),随机分组,疾病进展后允许交叉至克唑替尼组,c,a,ALK,状态由中心实验室检测，采用,Abbotts Vysis ALK Break Apart FISH Probe Kit,b,分层因素：,ECOG PS(0/1 vs.2),，亚洲人,vs.,非亚洲人，脑转移,（有,vs.,无）,c,IRR,审核,b,研究时间：,2011,-01,2013,-07,Solomon BJ,et al.N Engl J Med 2014;371:216777,整体人群及基线时有,/,无脑转移的系统,疗效,PFS,and ORR,a,基线特征：克唑替尼组与化疗组均有,22%,患者在随机入组时，伴有脑转移,a,By IRR;,b,at baseline;,c,two-sided log-rank test(ITT population:stratified;patient subgroups with/without baseline brain metastases:unstratified);,d,crizotinib vs.chemotherapy;,e,two-sided Pearson,2,test,克唑替尼显著提高,ITT,人群、基线时有,/,无脑转移人群的疾病有效缓解率,整体人群及基线时有,/,无脑转移的系统,疗效,-PFS,and ORR,a,基线特征：克唑替尼组与化疗组均有,22%,患者在随机入组时，伴有脑转移,a,By IRR;,b,at baseline;,c,two-sided log-rank test(ITT population:stratified;patient subgroups with/without baseline brain metastases:unstratified);,d,crizotinib vs.chemotherapy;,e,two-sided Pearson,2,test,HR,0.45,0.4,0.51,(95%CI),(0.350.60),(0.230.69),(0.380.69),Pc,0.001,0.001,0.001,克唑替尼显著降低,ITT,人群、基线时有,/,无脑转移人群的疾病进展风险,整体,人群及基线时有,/,无脑转移,的,颅内,疗效,PFS,NR,not reached;,a,time from randomization to first documentation of intracranial tumor progression by IRR;,b,two-sided log-rank test,Criz(n=39),Chemo,(n=40),Events,n(%),9(23),12(30),Median,mo,15.7,12.5,HR(95%CI),0.45(0.191.07),P,b,0.063,基线时有脑转移,基线时无脑转移,5,10,15,25,35,26,15,9,7,7,3,1,0,30,20,1,0,0,0,0,0,132,131,Time(months),93,92,56,32,33,11,20,3,7,1,1,0,0,0,Probability of no progression(%),Crizotinib,Chemotherapy,No.at risk,39,40,0,100,80,60,40,20,0,Time(months),Crizotinib,Chemotherapy,No.at risk,5,10,15,25,35,30,20,Probability of no progression(%),0,100,80,60,40,20,0,Criz(n=132),Chemo,(n=131),Events,n(%),16(12),14(11),Median,mo,NR,NR,HR(95%CI),0.69(0.331.45),P,b,0.323,结论,克唑替尼是,ALK,阳性,NSCLC,脑转移患者的标准治疗,克唑替尼治疗,ALK,（,+,）,NSCLC,脑转移为什么有效？,内 容,背景,初治时脑转移的治疗,治疗过程中发生脑转移的治疗,治疗策略,ALK,阳性,NSCLC,克唑替尼治疗后,出现脑转移,回顾性分析,放疗,+,克唑替尼,治疗后持续,克唑替尼,治疗,孤立性,CNS,进展,的,ALK,重排阳性,NSCLC,患者,21,例患者中，,7,例出现单发脑转移进展,患者持续接受克唑替尼治疗至少,4,个月而没有出现疾病进展,其中,1,例,患者在后续的克唑替尼治疗期间出现,复发的孤立性,CNS,失败,，但在再次接受,放疗后重新使用克唑替尼,治疗至少,8.5,个月,日本经验,Takeda M,et al.J Thorac Oncol 2013;8:654-657.,脑转移病灶的克唑替尼治疗疗效,研究结论：对于,CNS,转移病灶控制良好的孤立性,CNS,进展的,ALK,重排,NS