EGFR突变阳性肺癌的治疗策略

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,EGFR,突变阳性肺癌的治疗策略,我们处于肺癌个体化治疗时代,腺癌的驱动基因,LCMC,(USA),MSN,(,法国,),中国,日本,EGFR,17%,13%,40%,50%,KRAS,22%,28%,7%,15%,ELM4-ALK,7%,2%,7%,5%,BRAF,2%,2%,2%,1%,HER2,1%,1%,NA,3%,PIK3CA,1%,1%,4%,NA,PTEN,NA,NA,6%,NA,MET,扩增,1%,1%,5%,4%,Nil,46%,33%,29%,22%,Kris ASCO 2011,Planchard ELCC 2012,Wu JSMO 2011,Mitsudomi JCCO 2010,EGFR,突变带来的个体化治疗,Lynch NEJM 2004,Paez Science 2004,IPASS,：,EGFR,突变与,PFS,Mok et al NEJM 361:947 2009,亚组间治疗交互检验,p0.0001,EGFR,突变亚组,EGFR,无突变亚组,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,吉非替尼,卡铂紫杉醇,处风险,:,91,4,2,1,0,0,85,14,1,0,0,0,21,58,吉非替尼,(n=91),卡铂紫杉醇,(n=85),HR(95%CI)=,0.48,(0.,36,0.64)p0.0001,吉非替尼事件数,97(73.5%),卡铂紫杉醇事件数,111(86.0%),HR(95%CI)=,2.85,(2.05,3.98,)p0.0001,吉非替尼事件数,88(96.7%),卡铂紫杉醇事件数,70(82.4%),0,4,8,12,16,20,24,0.0,0.2,0.4,0.6,0.8,1.0,无进展生存概率,0,4,8,12,16,20,24,0.0,0.2,0.4,0.6,0.8,1.0,无进展生存概率,月,月,ITT,人群,协变量的,Cox,分析,IPASS:,吉非替尼一线治疗改善生活质量,因果分析,P,值来自包括协变量,WHO PS,、吸烟史及性别在内的逻辑回归,吉非替尼,卡铂,/,紫杉醇,OR(95%CI)=3.01(1.79,5.07)p0.001,131,128,131,128,131,128,OR(95%CI)=3.96(2.33,6.71)p0.001,OR(95%CI)=2.70(1.58,4.62)p0.001,n=,持续临床相关改善的患者比例,(%),OR(95%CI)=0.31(0.15,0.65)p=0.002,89,80,89,80,89,80,OR(95%CI)=0.35(0.16,0.79)p=0.011,OR(95%CI)=0.28(0.14,0.55)p0.001,n=,EGFR M+,EGFR M-,Mok et al NEJM 361:947 2009,EGFR TKI,一线治疗,EGFR,突变患者的六项随机研究,作者,研究,N(EGFR,突变,),RR,中位,PFS,Mok et al,IPASS,132,71.2%vs 47.3,9.8 vs 6.4,月,Lee et al,First-SIGNAL,27,84.6%vs 37.5%,8.4 vs 6.7,月,Mitsudomi et al,WJTOG 3405,86,62.1%vs 32.2%,9.2 vs 6.3,月,Maemondo et al,NEJGSG002,114,73.7%vs 30.7%,10.8 vs 5.4,月,Zhou et al,OPTIMAL,154,83%vs,36%,13.1 vs 4.6,月,Rosell et al,EURTAC,175,58%vs 15%,9.7 vs 5.2,月,Mok et al NEJM 2009,Lee et al WCLC 2009,Mitsudomi et al Lancet Oncology 2010,Maemondo NEJM 2010,Zhou et al ESMO 2010,Rossell et al Lancet Oncology 2012,在,克唑替尼,首个临床研究,PROFILE 1001,研究中，,克唑替尼,对于,ALK+,患者良好的疗效（,61%ORR,，,10m PFS,）。,PROFILE 1007:,研究设计,主要入组标准,中心,FISH,检测,ALK,+,IIIB/IV,期,NSCLC,既往,1,次化疗,(,含铂,),ECOG PS 02,可测量疾病,允许接受过治疗的脑转移,N=318,克唑替尼,250 mg BID,PO,q21d,(n=159),培美曲塞,500 mg/m,2,或,多西他赛,75 mg/m,2,IV,d1,q21d,(n=159),PROFILE 1007:NCT00932893,终点,主要,PFS(RECIST 1.1,独立影像学评估,),次要,ORR,DCR,DR,OS,安全性,患者自述结果,(EORTC QLQ-C30,LC13),随,机,PD,后交叉入组到,PROFILE1005,研究的,克唑替尼组,a,分层因素,:ECOG PS(0/1 vs 2),脑转移,(,有,/,无,),与既往,EGFR TKI(,是,/,否,),a,主要终点,:,独立影像学评估的,PFS(ITT,人群,),无进展生存绿,(%),100,80,60,40,20,0,0510152025,时间,(,月,),17393381120,1744915410,处危险,克唑替尼,PEM/DOC,克唑替尼,(n=173),PEM/DOC,(n=174),事件数,n(%),100(58),127(73),中位,(,月,),7.7,3.0,HR(95%CI),0.49(0.37 to 0.64),P,100,支且正吸烟或戒烟,100,支且戒烟,1,年,;,不吸烟：终生吸烟,100,支或从不吸烟,ECOG PS=,东部肿瘤协作组织体力状态,;PD=,疾病进展,;q3w=,每,3,周,;ORR=,总缓解率,;TTP=,至进展时间,ITT=,意向治疗人群,终点,:,PFS(,主要终点,),OS,ORR,TTP,分子标志物分析,;,安全性,;QoL(,次要终点,),分层因素,:,EGFR,突变类型,(,外显子,19,突变,vs,外显子,21 L858R,点突变,),组织学,(,腺癌,vs,非腺癌,),吸烟状态*,(,正或曾吸烟,vs,不吸烟,),Zhou et al Lancet Oncology 2011,总生存,(ITT),处危险患者,厄洛替尼,82,81,73,64,50,40,20,3,0,GC,72,68,60,53,45,39,19,3,0,1.0,0.8,0.6,0.4,0.2,0,0,5,10,15,20,25,30,35,40,时间(月),OS,n,事件数,n(%),中位,(,月,),95%CI,厄洛替尼,82,50(61),22.69,20.0730.39,GC,72,42(58),28.85,22.8731.47,Log-rank p=0.6915,HR(95%CI):1.04(0.691.58),n,Events,n(%),Median,(months),95%CI,单用化疗组,21,17(81),11.70,7.29,22.87,单用,TKI,组,33,22(67),20.67,16.62,28.32,化疗联合,TKI,组,94,50(53),30.39,25.99,NR,*Chemo only,no EGFR TKI:patients from the GC arm who had no further treatment(n=16)or further chemotherapy(n=5),EGFR TKI only,no chemo:patients from the erlotinib arm who are still on treatment(n=7),had no further treatment(n=25)and who were re-challenged(n=1),EGFR TKI and chemo:patients from the erlotinib arm who switched to chemo(n=43),patients from the GC arm who switched to erlotinib in any line(n=51),1.0,0.8,0.6,0.4,0.2,0,0,5,10,15,20,25,30,35,40,Time(months),OS probability,Patients receiving EGFR TKI and chemo vs patients receiving chemo only p=0.0001,Patients receiving EGFR TKI only vs patients receiving chemo only p=0.057,Log-rank p value 1,提示吉非替尼缓解的机会更大,71.2%,47.3%,1.1%,23.5%,Mok et al NEJM 361:947 2009,中位至症状改善时间,8,天,突变阳性患者,突变阳性患者,7,项随机研究的获益,作者,研究,N(EGFR,突变,+),RR,中位,PFS,Mok et al,IPASS,132,71.2%vs 47.3,9.8 vs 6.4,月,Lee et al,First-SIGNAL,27,84.6%vs 37.5%,8.4 vs 6.7,月,Mitsudomi et al,WJTOG 3405,86,62.1%vs 32.2%,9.2 vs 6.3,月,Maemondo et al,NEJGSG002,114,73.7%vs 30.7%,10.8 vs 5.4,月,Zhou et al,OPTIMAL,154,83%vs,36%,13.1 vs 4.6,月,Rosell et al,EURTAC,135,56%vs 18%,9.2 vs 4.8,月,Yang et al,LUX Lung 3,345,56%vs 22%,11.1 vs 6.9,月,Mok et al NEJM 2009,Lee et al WCLC 2009,Mitsudomi et al Lancet Oncology 2010,Maemondo NEJM 2010,Zhou et al ESMO 2010;Yang et al ASCO 2012,取得阳性结果的随机,III,期研究数,培美曲塞一线化疗,1,培美曲塞维持治疗,1,贝伐珠单抗一线治疗,2,III,期肺癌同步放化疗,2,生活质量快速改善的获益,因果分析,P,值来自包括协变量,WHO PS,、吸烟史及性别在内的逻辑回归,吉非替尼,卡铂,/,紫杉醇,OR(95%CI)=3.01(1.79,5.07)p0.001,131,128,131,128,131,128,OR(95%CI)=3.96(2.33,6.71)p0.001,OR(95%CI)=2.70(1.58,4.62)p0.001,n=,持续临床相关改善的患者比例,(%),OR(95%CI)=0.31(0.15,0.65)p=0.002,89,80,89,80,89,80,OR(95%CI)=0.35(0.16,0.79)p=0.011,OR(95%CI)=0.28(0.14,0.55)p0.001,n=,EGFR M+,EGFR M-,Mok et al NEJM 361:947 2009,治疗,CNS,