EGFR突变阳性肺癌的治疗策略课件

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),11.70,7.2922.87,单用,TKI,组,33,22 (67),20.67,16.6228.32,化疗联合,TKI,组,94,50 (53),30.39,25.99NR,*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,转移的获益,外显子,19,突变患者，吉非替尼治疗前与治疗,1,个月后,Poon and Mok Oncology 67:174, 2004,主要终点：,PFS,次要终点：,ORR,，,6,个月生存率，,1,年生存率，安全性数据,颅内病灶,PD,或,出现脑转移症状,厄洛替尼,150mg/,天,IV,期,NSCLC,一线含铂双药治疗后,无症状脑转移,腺癌或,EGFR,突变,（,n=4,8,）,TKI,单药治疗（,CTONG 0803,）,治疗伴无症状脑转移的,NSCLC,Wu et al Annals Oncology ePub Nov 2012,8 EGFR,突变,+/15,例野生型,/25,例未知,RR 58.3%,PFS,9.6,月,PFSi (,颅内,) 10.1,月,OS 18.9,月,Wu et al Annals Oncology ePub Nov 2012,TKI,单药治疗（,CTONG 0803,）,治疗伴无症状脑转移的,NSCLC,选择更好的,EGFR TKI,？,不同临床研究中,EGFR,活化突变,NSCLC,的,PFS,厄洛替尼,吉非替尼,中位,PFS (,月,),16,14,12,10,8,6,4,2,0,SLCG,EURTAC,OPTIMAL,IPASS,First-SIGNAL,WJTOG 3405,NEJSG 002,WJTOG3405: IIIB/IV,期患者,(,全组中位,PFS 9.2,个月,),Rosell, et al. NEJM 2009; Janne, et al. ASCO 2010; Zhou, et al. ESMO 2010;,Mok, et al. NEJM 2009Lee, et al. WCLC 2010; Mitsudomi, et al. Lancet Oncol 2010; Maemondo, et al. NEJM 2010 ; Yang et al ASCO 2012,注册研究,中,EGFR,活化突变,NSCLC,的,PFS,厄洛替尼,吉非替尼,中位,PFS (,月,),16,14,12,10,8,6,4,2,0,EURTAC,IPASS,WJTOG3405: IIIB/IV,期患者,(,全组中位,PFS 9.2,个月,),Rosell, et al. NEJM 2009; Mok, et al. NEJM 2009 Yang et al ASCO 2012,LUX,lung 3,Kim 2011,：头对头比较,易瑞沙与厄洛替尼的临床研究,前瞻性、头对头比较两个,TKI,疗效的临床研究,Kim ST, et al. Lung Cancer 2011; doi:10.1016/j.lungcan.2011.05.022.,易瑞沙,250mg/d,(n=48),厄洛替尼,150mg/d,(n=48),客观缓解率,无进展生存期,不良反应,总生存期,生活质量,随机分组,主要入组条件,IIIB/IV,期,NSCLC (,包括复发,/,转移性,NSCLC),年龄,18,岁,预期生存,12,周,体力状态,0-2,既往不可耐受或一线治疗失败,EGFR,基因敏感突变或在下列,3,项临床特点中至少有,2,项,女性,腺癌,不吸烟,客观缓解率易瑞沙组与厄洛替尼组,客观缓解率,(%),P=0.269,Kim ST, et al. Lung Cancer 2011; doi:10.1016/j.lungcan.2011.05.022.,无进展生存期易瑞沙组与厄洛替尼组相当,中位,PFS,易瑞沙,(n=48),4.9,个月,厄洛替尼,(n=48),3.1,个月,无进展生存概率,时间,(,月,),24,1.0,0,6,12,18,0.8,0.6,0.4,0.2,0.0,P=0.336,Kim ST, et al. Lung Cancer 2011; doi:10.1016/j.lungcan.2011.05.022.,易瑞沙耐受性良好，不良反应发生率低,Kim ST, et al. Lung Cancer 2011; doi:10.1016/j.lungcan.2011.05.022.,不良事件发生率,(%),P=0.003,P=0.027,CTONG 0901:,厄洛替尼,vs,吉非替尼治疗,EGFR,外显子,21,突变患者,晚期,NSCLC,腺癌,EGFR,外显子,21,突变,一线治疗,PS 0-1,随,机,厄洛替尼,150mg qd,吉非替尼,250mg qd,1,1,N= 200,更多易瑞沙与厄洛替尼头对头的对比，请期待,CTONG0901,研究,LUX Lung 3: ASCO 2012,随机,2:1,根据,EGFR,突变分层,(,Del19/L858R/,其他,),与种族,(,亚裔,/,非亚裔,),阿法替尼,40 mg/d,顺铂,+,培美曲塞,75 mg/m,2,+ 500 mg/m,2,i.v. q21d,最多,6,周期,主要终点,: PFS (RECIST 1.1,独立评估,),次要终点,: ORR, DCR, DoR,肿瘤缩小, OS, PRO,安全性, PK,IIIB,(,湿性,)/,IV,期非腺癌,(AJCC,第,6,版,),EGFR,突变肿瘤,(,中心实验室检测,; Therascreen EGFR29* RGQ PCR),主要,PFS,分析,(,独立评估,),样本量：需要,217,个独立,事件数,以检测到,HR 0.64(,或中位,PFS,从,7,个月延长到,11,个月,),，,90%,的效力、双侧,5%,的显著性水平下,Yang et al ASCO 2012,PFS,1.0,0.8,0.6,0.4,0.2,0.0,处危险,阿法替尼,2041691431157549301030,Cis/Pem 104623517962200,PFS (,月,),0369121518212427,阿法替尼,n=204,Cis/pem n=104,PFS,事件, n (%),130 (64),61 (59),中位,PFS (,月,),13.6,6.9,HR(95% CI),0.47,(0.340.65)P2,b,起始剂量调整为,30mg QD,且治疗,8,周后如果没有出现以下情况则剂量递增至,45mg QD:,队列,A,中,30,例在,1,个月的时间内没有出现,1,级毒性；队列,B,中既往未接受治疗患者,队列,B:,HER2,突变或,HER2,扩增,a,目标,n=25 (,仍在入组,),研究,1017,：,Dacomitinib (PF-00299804),一线治疗,EGFR,活化突变的晚期,NSCLC,外显子,19,与外显子,21,突变的,EGFR,突变肺癌患者的疗效瀑布图,(N=45),自基线变化,(%),20,0,10,10,20,30,40,50,60,70,80,90,110,PR,外显子,19,外显子,21,100,RR=76%,外显子,19,与外显子,21,突变的,EGFR,突变肺癌患者的,PFS,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,月,处危险患者数,中位,PFS: 18.2,个月,(95% CI:12.8, 23.8),4,个月,PFS,：,95.5% (95% CI: 83.2, 98.9),1,年,PFS,：,76.5% (95% CI: 60.6, 86.6),PFS,0510152025303540,45393124167410,LUX Lung 7,晚期,NSCLC,腺癌,EGFR,突变,+,一线治疗,PS 0-1,阿法替尼,40mg qd,吉非替尼,250mg qd,1,1,N= 264,随,机,ARCHER 1050,晚期,NSCLC,腺癌,EGFR,外显子,19/21,突变,一线治疗,PS 0-1,随,机,Dacomitinib,45mg qd,吉非替尼,250mg qd,1,1,N= 440,分层,-,种族,-,外显子,19 v 21,第二代,TKI,与吉非替尼的头对头对比研究,第二代的,EGFR-TKI,是否优于第一代的,TKI,，有待于临床研究的验证。,总结,肺癌应根据基因组变异的检测结果而进行个体化治疗,EGFR,突变患者应接受,TKI,一线治疗，吉非替尼是唯一拥有一线,EGFR,突变适应症的,TKI,哪个,TKI,更好有待后续更多临床研究的验证,谢 谢！,