晚期NSCLC治疗的变革.ppt

,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,资料仅供参考,不当之处，请联系改正。,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,资料仅供参考,不当之处，请联系改正。,晚期,NSCLC,的治疗：我们走过怎样的路？,*中国未批准,1970,1980,1990,2000,中位生期,(,月,),12+,6,2-4,BSC,铂类单药化疗,双药联合化疗,靶向治疗,化疗,+,靶向治疗,卡铂,1989,厄洛替尼,培美曲塞,2004,泰索帝二线,1999,紫杉醇,吉西他滨,1998,长春瑞滨,1994,泰索帝一线,2003,吉非替尼,2003,最佳支持,一线,二线,三线,未批准,顺铂,1978,8-10,2011,贝伐单抗*,2006,埃克替尼,2011,最佳支持治疗,最佳支持治疗,1970s,晚期,NSCLC,：治疗乏术,？,？,？,？,？,？,？,？,无奈之中的选择,最佳支持治疗不治疗,化疗药物广泛应用前，最佳支持治疗对晚期,NSCLC,患者生活质量、生存延长是有帮助的,最佳支持治疗可使,OS,延长,1-3,个月,Pietro Marino et al,，,Chest.1994,Frances A.Shepherd.et al.JCO 2000,最佳支持治疗,含铂化疗,含铂双药,1995,荟萃分析,ECOG1594,首现变革：含铂双药化疗成标准治疗,晚期非小细胞肺癌,试验,化疗,+,支持治疗,支持治疗,观察,-,预期死亡,差异,长疗程烷化剂：,Oxford,120/121,62/67,16.40,43.80,Quebec,20/20,18/18,4.38,7.99,小结,140/141,80/85,12.02,51.79,生物碱,/,依托泊苷：,Gwent 2,96/111,67/75,5.15,38.00,小结,96/111,67/75,5.15,38.00,以顺铂为基础：,RLW 8351,84/86,80/81,8.06,39.94,NCIC CTG,95/97,51/53,11.28,28.24,Southampton,17/17,15/15,1.16,7.55,NRH,44/44,40/43,2.93,18.72,UCLA,31/32,30/31,4.83,14.53,Ancona 1,63/63,65/65,5.72,30.95,AOI-Udine,52/52,50/50,14.98,18.77,CEP-85,23/25,21/24,10.52,6.61,小结,409/416,352/362,51.31,165.31,合计,645/668,499/522,44.44,255.09,化疗,+,支持治疗较优,支持治疗较优,事件数,/,纳入患者数,化疗,vs,最佳支持治疗,Meta-,分析,：,BMJ11:1995,0,20,40,60,80,100,0,6,12,18,24,月,生存概率,支持治疗,+,以顺铂为基础的化疗,(n=416),支持治疗,(n=362),1,年生存率提高,10%(5%,15%),OS,延长,2,个月,NSCLCCG.BMJ 1995;311:899-909,.,与最佳支持治疗相比，化疗使晚期,NSCLC,患者生存获益明显,BMJ 11:1995 Meta-,分析,ECOG1594,：一线含铂两药化疗疗效,Shiller,et al.NEJM 2002,标准化疗方案疗效相似,OS 8,个月，,TTP 4,个月,ORR 20%,1,年生存率,30%,2,年生存率,10%,几种含铂双药方案疗效没有差别,晚期,NSCLC,治疗的转折,以铂类为基础的两药联合疗效优于单药治疗或三药治疗,Delbaldo C.et al.JAMA 2004;292:470,晚期,NSCLC,化疗疗效达到“瓶颈”,Study,Drugs,#Pts,%,St.IV,%,ORR,MST,%,1-YS,Kelly,2001,SWOG 9509,Vnr/Cis,Tax225/Cb,202,208,88,89,28,25,8,8,33,36,Schiller,2002,ECOG 1594,Tax135/Cis,Gem/Cis,Txt/Cis,Tax225/Cb,292,288,293,290,89,86,86,86,21.3,21,17.3,15.3,8.1,8.1,7.4,8.3,31,36,31,35,Scagliotti,2002,ILCP,Vnr/Cis,Gem/Cis,Tax225/Cb,201,205,201,81,81,82,30,30,32,9.5,9.8,9.9,37,37,43,Belani,2002,TAX 326,Vnr/Cis,Txt/Cis,TxT/Cb,404,408,402,67,67,67,25,32,24,10.1,11.3,9.4,41,46,38,Tax:,泰素；,Gem:,健择；,Txt:,泰索帝；,Vnr:,诺维本,变革二：贝伐单抗的引入,晚期非小细胞肺癌（非鳞）,贝伐,+,含铂双药,ECOG4599,含铂双药化疗,1.0,0.8,0.6,0.4,0.2,0,06121824303642,Duration of survival(months),Probability of OS,10.3,12.3,Sandler,et al.NEJM 2006,E4599,：,OS,取得突破性进展,主要研究终点为,OS,，大于,1,年,首次使晚期,NSCLC,患者,OS,超过,1,年,贝伐单抗,+,紫杉醇,/,卡铂治疗晚期非鳞,NSCLC,（,为规避严重不良反应而进行病,理亚型选择）,1,Sandler,et al.NEJM 2006;,2,Manegold,et al.ESMO 2008,1.0,0.8,0.6,0.4,0.2,0,Duration of PFS(months),0612182430,Probability of PFS,CP,Bev 15mg/kg+CP,PFS in E4599,1,6.2 months,HR=0.66,p0.001,PFSBev 15mg/kg,PFS in AVAiL,2,Duration of PFS(months),0612182430,Placebo+CG,Bev 7.5mg/kg+CG,Bev 15mg/kg+CG,6.8 months,HR=0.75,p=0.0003,PFSBev 7.5mg/kg,6.6 months,HR=0.85,p=0.0456,PFSBev 15mg/kg,1.0,0.8,0.6,0.4,0.2,0,Probability of PFS,贝伐单抗联合化疗的生存获益,:,PFS,贝伐单抗的贡献,使晚期,NSCLC,的,OS,首次超过一年第一次使得一种靶向药物进入晚期,NSCLC,的,标准治疗,变革三：以病理亚型指导治疗,晚期非小细胞肺癌（非鳞）,贝伐,+,含铂双药,贝伐,+,含铂双药,培美曲塞,易瑞沙,JMDB JMEI JMEN,ISEL,临床优势人群的出现,JMEI,研究揭示了培美曲塞在非鳞癌方面的优势,培美曲塞,多西他赛,调整后,HR(95%CI),非鳞癌，,N,MST，,月,Median PFS，,月,205,9.3,3.1,194,8.0,3.0,0.778(0.607-0.997),0.823(0.664-1.020),鳞癌，,N,MST，,月,Median PFS，,月,78,6.2,2.3,94,7.4,2.7,1.563(1.079-2.264),1.403(1.006-1.957),Treatment-by-histology interaction was statistically significant(p0.001),Peterson P,et al.Eur J Cancer Suppl.2007;5:363-364.,类型 培美曲塞 多西他赛 培美曲塞顺铂 吉西他滨 培美曲塞 安慰剂,非鳞癌,205 194 618 634 325 156,MST,（月）,9.3 8.0 11.0 10.1 15.5 10.3,调整后,HR 0.78 0.84 0.70,95%CI 0.61-1.0 0.74-0.96 0.56-0.88,P,值,0.048 0.011 0.002,JMEI,（二线）,JMDB,（一线）,JMEN,（维持）,鳞癌,78 79 244 229 116 66,MST,（月）,6.2 7.4 9.4 10.8 9.9 10.8,调整后,HR 1.56 1.23 1.07,95%CI 1.08-2.26 1.00-1.51 0.77-1.50,P,值,0.018 0.050 0.678,培美曲塞根据组织亚型在相关临床实验的疗效分析,2004,年,ISEL,研究发现亚裔、腺癌、不吸烟患者吉非替尼疗效更优,Thatcher N et al,2005,变革四：根据分子亚型选择治疗方案,晚期非小细胞肺癌,非鳞癌,鳞癌,EGFR,基因突变,型肺癌,EGFR,基因野生,型肺癌,EGFR,基因野生,型肺癌,EGFR,基因突变,型肺癌,EGFR,基因野生,型肺癌,EGFR,基因突变,型肺癌,EGFR,基因野生,型肺癌,EGFR,基因突变,型肺癌,EGFR,基因野生,型肺癌,IRESSA,在日本注册一线适应症,ISEL,研究,INTEREST,研究,IPASS,研究,2002,2009,2007,2005,IPASS:,按临床标准选择一线患者,ISEL,INTEREST:,未选择的二线患者,EGFR,蛋白表达,EGFR,基因拷贝数,EGFR,基因突变,EGFR,生物标记物的发现过程,Thatcher et al 2005,Kim et al 2008,Douillard et al;Data presented at WCLC 2007 in Seoul,Korea,Mok et al 2009,Fukuoka 2009,“突变”的发现,J Guillermo Paez,科学,杂志,2004,年,Thomas Lynch,新英格兰医学,杂志,2004,年,IPASS,研究设计,*,不吸烟：吸烟数目,100,支;轻度的曽吸烟者：,戒烟,15 年 且吸烟量,10 年包,;,#,最多,6,个周期,吉非替尼治疗进展后使用卡铂/紫杉醇治疗,入组条件,未经过化疗,年龄,18,岁,腺癌,非吸烟或已戒烟的轻度吸烟,*,生存预期,12,周,PS 0-2,可测量的,IIIB/IV,主要研究终点,无进展生存期,(,非劣效性,),次要研究终点,客观缓解率,总生存,生活质量,疾病相关症状,安全性与耐受性,探索性研究,生物标记,EGFR,基因突变,EGFR,基因拷贝数目,EGFR,蛋白表达,研究终点,T.Mok 2009 NEJM,IPASS,研究亚组分析提示：,EGFR,突变患者吉非替尼一线疗效优于标准化疗,Mok TS,et al.NEJM 2009;361:947-957.,Mok T.Presented at ESMO 2008.,ITT,人群含共变量的,Cox,分析,通过亚组进行治疗的交互检验,p0.0001,HR(95%CI)=,0.48,(0.,36,0.64)p0.0001,吉非替尼组事件数,97(73.5%)C/P,组事件数,111(86.0%),EGFR,突变阳性,吉非替尼,(n=132),卡铂,/,紫杉醇,(n=129),132,71,31,11,3,0,129,37,7,2,1,0,108,103,0,4,8,12,16,20,24,吉非替尼,C/P,0.0,0.2,0.4,0.6,0.8,1.0,无进展生存率,无进展生存患者：,月,EGFR,突变阴性,HR(95%CI)=,2.85,(2.05,3.98,)p0.0001,吉非替尼组事件数,88(96.7%)C/P,组事件数,70(82.4%),91,4,2,1,0,0,85,14,1,0,0,0,21,58,0,4,8,12,16,20,24,0.0,0.2,0.4,0.6,0.8,1.0,无进展生存率,吉非替尼,(n=91),卡铂,/,紫杉醇,(n=85),月,IPASS,科学史上里程碑式的研究，改变了临床实践,我们现在必须考虑，非小细胞肺癌至少有两种类型：,EGFR,突变,EGFR,野生型,Richard L Schilsky,ASCO,主席,“,首次有一个药物在一线治疗的情况下优于化疗药物而又没有化疗药物的毒性。更令人激动的是，我们清楚地知道哪一类患者能从该药物中获益，医疗资源能更合理的分配，患者和医生对治疗效果更充满信心”,-Nick Thatcher,NEJ002,WJOG3405,Lee et al WCLC 2009,Mitsudomi et al Lancet Oncology 2010,Maemondo NEJM 2010Zhou et al ESMO 2010,临床研究的验证（,1,ST,EGFR M+,）,西班牙,SLCG,研究,:,特罗凯治疗EGFR突变患者,Median PFS=14 months,1.0,0.8,0.6,0.4,0.2,0,Probability,01020304050,Time(months),Median OS=27 months,1.0,0.8,0.6,0.4,0.2,0,Probability,01020304050,Time(months),Patients(%),100,75,50,25,0,SD,PR,CR,PD,DCR,90%,Best response,RR,70.6%,SLCG=Spanish Lung Cancer GroupRR=response rate;MUT+=mutation positiveCR=complete response;PR=partial responseSD=stable disease;PD=progressive diseaseDCR=CR+PR+SD;TTP=time to progression,Rosell,et al.NEJM 2009,PFS,OS,TKI,对照标准含铂化疗方案,一线治疗,EGFR,突变患者的临床研究,亚裔,高加索裔,EURTAC,OPTIMAL,NEJSG002,WJTOG3405,临床研究的验证（,1,ST,EGFR M+,）,厄洛替尼,(n=86),化疗,(n=87),HR=0.37(0.250.54),Log-rank,p,0.0001,HR=,0.164,(95%CI:0.1050.256),Log-rank,p0.0001,厄洛替尼,G/C,OPTIMAL,EURTAC,Lee et al WCLC 2009,Mitsudomi et al Lancet Oncology 2010,Maemondo NEJM 2010Zhou et al ESMO 2010,Platinum based doublets(SATURN),Taxane/carboplatin(BMS099),Cisplatin/vinorelbine(FLEX),Bevacizumab triplet(updated adeno E4599),Cisplatin/gemcitabine(AVAIL),Cisplatin/gemcitabine(Scagliotti,sq.),Cisplatin/gemcitabine(erlotinib study),Pemetrexed maintenance(non-sq.histology),Pemetrexed cisplatin(Scagliotti,non-sq.),Erlotinib(TORCH),Erlotinib(poor PS)(TOPICAL),Erlotinib maintenance(SATURN),Cetuximab triplet(BMS099),Cetuximab triplet(FLEX),Bevacizumab triplet(AVAIL),Reck et al,2010;Pirker et al,2009;Lynch et al 2010;Cappuzzo et al 2010;Lee ASCO 2010 abtsr 7504;Gridelli ASCO 2010 abstr 7508;Scagliotti et al 2008;Sandler et al 2006,突变患者一线使用易瑞沙,中位生存期,超越了既往研究结果,易瑞沙,NEJ002,易瑞沙,IPASS M+,亚组,中位生存期（月）,EGFR,突变阳性患者的治疗过程和肿瘤负荷变化,Wu et al.,ESMO 2011,9-134,Niho et al.Lung Cancer 2012 Jan 13.Epub,Editorial supervisors;Aichi Cancer Center,Mitsudomi T,Kitazato University Sasaki J,Ki nki University Nakagawa K,Shizuoka Cancer Center Yamamoto N,Tohoku University,Inoue A,Nippon Medical School,Gennma A,*,中位肿瘤缩小：易瑞沙组,52%/,；化疗组,34%,(,IPASS,),药物起效时间：易瑞沙组,1.41,个月,(I,PASS,),/,化疗组,2.7,个月,(,卡巴,+,紫杉醇,JO19907),中位,PFS,：易瑞沙组,9.5,个月,/,化疗组,6.3,个月,(IPASS),肿瘤负荷,/,大小,(%),(,月,),易瑞沙,易瑞沙,化疗,化疗,起始易瑞沙治疗,起始化疗,EGFR-TKI,的一系列研究确立了根据分子亚型选择治疗方案的新模式,Horn L,Pao W.,J Clin Oncol,2009;26:42325,ISEL.BR21.,IDEL.,初显,SLCG.,IPASS,.,探索,INTEREST.,TRUST,.,NEJ002.,WJTOG3405,.,OPTIMAL.,EURTAC.,本质,现象,根据分子亚型选择治疗的变革并非止步于,EGFR,82,例,ALK,+,NSCLC,患者接受,Crizotinib,治疗的,ORR,达,57%,60,40,20,0,20,40,60,80,100,疾病进展,疾病稳定,确认的部分缓解,确认的完全缓解,肿瘤直径的最大变化比例,(%),30%,*,客观,RR=57%,(95%CI:46-68%),DCR(CR+PR+SD):90%,Kwak et al.NEJM 2010;363:1693703Bang et al.JCO 2010;28:18S abstract 3,*,肿瘤缩小,100%,，且未出现非靶病灶的部分缓解患者,A8081001,Shaw AT,et al.Lancet Oncol.2011;12:1004-1012.,74%,54%,1,2,3,4,0,0,20,40,60,80,100,Yrs,OS From First Crizotinib Dose(%),Median OS:not reached,1-yr OS:74%;2-yr OS:54%,61%of patients in follow-up for OS,with median follow-up of 18 mos,From first crizotinib dose,82,例,ALK,阳性患者,Crizotinib,治疗的生存结果,0,0,20,40,60,80,100%,总生存期,(,年,),1,2,3,4,二线,/,三线克唑替尼,ALK,克唑替尼,(n=30),ALK,对照,(n=23),中位生存期,月,NR,6,1,年生存率,%,70,44,WT/WT,对照,(n=125),11,47,2,年生存率,%,55,12,32,HR=0.49,p=0.02,Shaw et al.,ASCO 2011;Abs#7507,Crizotinib,组与对照组（未使用,Crizotinib,）,在,ALK,阳性,NSCLC,患者的生存比较,2012NCCN,指南将,ALK,与,EGFR,共同列入,NSCLC,指导治疗,II,期临床试验,OAM4558g,:,厄洛替尼,MetMAb(Onartuzumab),治疗,IIIB/IV NSCLC,主要研究终点,整体,ITT,人群的,PFS,其他研究终点,MET,高表达患者的,OS,整体,ITT,人群的,OS,加用,MetMAb*,(n=23),PD,*,If eligible.,A,组,厄洛替尼,150 QD PO+MetMAb 15 mg/kg IV q3w(n=64),B,组,厄洛替尼,150 QD PO+,安慰剂,IV q3w(n=64),一线或二线治疗失败后的,IIIB/IV,期,NSCLC,患者,ECOG PS 0-2(n=128),Spigel D,et al.ASCO 2011.Abstract 7505.,Enrollment from 3/2009 to 3/2010,Data cutoff:June 8,2010,按照吸烟状态、,PS,评分及病理亚型分层,OAM4558g,研究,:PFS,和,OS(ITT),23,例患者从安慰剂组交叉到了,MetMAb,组,1.0,0.8,0.6,0.4,0.2,0,Probability of Progression Free,TTP(Mos),0,18,3,6,9,12,15,PFS HR:1.09,Median,mosHR95%CILog-rank,P,valueEvents,n,2.656,2.248,1.090.73-1.62.69,Placebo+Erlotinib,MetMAb+Erlotinib,1.0,0.8,0.6,0.4,0.2,0,Probability of Survival,OS(Mos),0,21,3,6,9,12,15,OS HR:0.8,Median,mosHR95%CILog-rank,P,valueEvents,n,7.441,8.934,0.800.50-1.28.34,Placebo+Erlotinib,MetMAb+Erlotinib,18,Spigel D,et al.ASCO 2011.Abstract 7505.,Enrollment from 3/2009 to 3/2010,Data cutoff:June 8,2010,在,MET,免疫组化阳性患者中的生存结果,Time to progression(months),0,3,6,9,12,15,18,Probability of progression free,0.0,0.2,0.4,0.6,0.8,1.0,Placebo+erlotinib,3.8,26,MetMAb+erlotinib,12.6,16,Median(mo),HR,(95%CI),Log-rank p-value,No.of events,Overall survival(months),0,3,6,9,12,15,18,21,Probability of survival,0.0,0.2,0.4,0.6,0.8,1.0,Placebo+erlotinib,1.5,27,Median(mo),HR,(95%CI),Log-rank p-value,No.of events,PFS:HR=0.53,OS:HR=0.37,MetMAb+erlotinib,2.9,20,0.53,(0.280.99),0.04,0.37,(0.190.72),0.002,2012ASCO:Crizotinib在ROS-1基因重排患者的疗效,Clinical,Science,Symposium,Clinical,activity,of,crizotinib,in,advanced,non-small,cell,lung,cancer,(NSCLC),harboring,ROS1,gene,rearrangement,Shaw,AT,et,al,Phase,I,trial,#,7508,Shaw,AT,et,al.,2012,ASCO,Abstract,7508.,ROS-1,基因重排是一类新的,NSCLC,分子亚型,ROS-1基因重排患者的临床特征,N=15,年龄,(,岁）,性别,(n),吸烟史,n(%),种族,n(%),组织学类型,n(%),ECOG,PS,n(%),既往治疗,n(%),Shaw,AT,et,al.,2012,ASCO,Abstract,7508,.,平均年龄,(,范围,),男,/,女,从不,/,曾经,高加索裔,/,亚裔,/,其他,腺癌,0/1,从未,/,1/,未报告,54(31,72),8/7,14(93)/1(7),10(67)/4(27)/1(7),15(100),10(67)/5(33),2(13)/12(80)/1(7),ROS-1,基因重排患者使用,Crizotinib,的,ORR,ROS-1,基因重排患者,N=14,CR,PR,SD,PD,其他,ORR(%),中位治疗时间,(,周,),8,周的,DCR,Shaw,AT,et,al.,2012,ASCO,Abstract,7508.,1,7,4,2,0,57.1,25.7,79%,ROS-1,是肺癌治疗的,新靶点,Crizotinib,对,ROS-1,基因重排患者有效,2011ASCO,肺癌突变联合会（,LCMC,）：,1000,例肺腺癌患者样本的驱动基因检测,Kris MG,et al.ASCO 2011.Abstract#7506.,1000,例,IV,期患者,ECOG PS 0-2,肺腺癌,足够的组织标本（石蜡）,知情同意,突变检测,KRAS,EGFR,EML4-ALK,BRAF,HER2,，,PIK3CA,NRAS,MEK1,，,AKT1,，,MET,扩增,中心确认腺癌诊断,（,1,例脱落）,向,LCMC,数,据库报告,向临床医生,报告,据此选择治疗方法,（,EGFR,突变选择,厄洛替尼）,推荐针对突变靶点,的临床试验,各驱动基因的突变率,97%的驱动基因突变相互排斥,我们期待的新变革“靶向大时代”的来临,更多的治疗靶点和对应的有效药物,原有化疗药物预测靶标的发现,分子靶标检测方法的优化、易化,多种驱动基因的一站式检测,患者,血,驱动基因的一站式检测,对应药物,谢 谢！,