阿法替尼专题知识宣讲.ppt

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,第四级,第五级,*,*,阿法替尼专题知识宣讲,阿法替尼,机理：,表皮生长因子受体（,EGFR,）和人表皮生长因子受体,2,（,HER2,）酪氨酸激酶的强效、不可逆的双重抑制剂。,阿法替尼可以与,EGFR,、,HER2,及,HER4,激酶区结合，不可逆地抑制酪氨酸激酶自动磷酸化，导致,ErbB,信号通路的下调。,适应症：,EGFR,阳性的转移性非小细胞肺癌；之前治疗过的转移的肺鳞癌。,用法：,口服，,40mg,，,1,次,/,天，进餐前至少,1,小时或后,2,小时服用。,价格：,每瓶规格,30mg/40mg/50mg30,片，月均约,20000RMB,。,阿法替尼之,EGFR,适应症：,EGFR,阳性的转移性非小细胞肺癌。,临床试验：,LUX-LUNG,临床试验系列（,LUX-Lung 1,-8,）。,LUX-Lung2,试验,患者,EGFR,突变,治疗线数,药物,疗效,结论,II,期,EGFR,突变的,IIB/IV,期,NSCLC,患者,突变阳性,一线或二线,阿法替尼单药,4,0mg,或,50mg,ORR,40,mg60%,50,mg61%,阿法替尼对,EGFR,突变的晚期,NSCLC,患者具有治疗疗效，尤其,DEL19,或,L858,突变,1.,不良反应：腹泻,、皮疹、指甲毒性、消化道毒性等。,LUX-Lung3试验,患者,EGFR,突变,治疗线数,药物,疗效,结论,III,期,EGFR,突变的,IIB/IV,期,NSCLC,患者,突变阳性,一线,试验组：阿法替尼单药,4,0mg,对照组：培美曲塞,+,铂类,ORR,56.1%:22.6,%,PFS 11.1:6.9,月,OS 28.2:28.2,月,与化疗相比，阿法替尼可以提高,EGFR,突变的,NSCLC,患者的,PFS,1.,试验还进行了,EGFR,突变的亚组分析，具有常规突变（,L858R/DEL19,）的患者比其他突变患者对阿法替尼的治疗生存优势更大。对于,DRL19,的患者,OS,也得到改善（,46.9:31.5,月）。,2.,不良反应：腹泻,、皮疹、指甲毒性、消化道毒性等。,LUX-Lung6,试验,患者,EGFR,突变,治疗线数,药物,疗效,结论,III,期,EGFR,突变的晚期非小细胞肺癌,突变阳性,一线,试验组：阿法替尼单药,4,0mg,试验组：吉西他滨,+,铂类,PFS,11.0,：,5.6,月,阿法替尼对,EGFR,突变的晚期,NSCLC,患者具有治疗疗效,突变亚型分析：,汇总,LUX236,的不常见突变的患者，分为三组，,18-21,外显子点突变的患者为,1,组，新出现的,T790M,或与其他突变共同存在的患者为,2,组，,20,外显子插入的患者为,3,组。,结论：,阿法替尼对某些亚型，尤其是,Gly719XaaLeu861Gln,and Ser768Ile,有疗效。对其他突变型活性少。在新发,T790M,突变的患者及,20,外显子插入突变的患者临床疗效较低。,LUX-Lung236,LUX-Lung1,试验,患者,EGFR,突变,治疗线数,药物,疗效,结论,IIB/III,期,化疗及吉非替尼或厄洛替尼治疗有效*后进展的晚期腺癌,不需要,三线或四线,试验组：阿法替尼单药,50mg,对照组：安慰剂,ORR,7%:0.5,%,PFS 3.3:1.1,月,OS 10.8:12.0,月,对于吉非替尼厄洛替尼治疗后进展的,NSCLC,患者具有一定疗效（,PFS,及,ORR,）,1.,试验中有效的定义是,TKI类抑制剂治疗时间,12,周。,2.,不良反应：腹泻,、皮疹、指甲毒性、消化道毒性等。严重的不良反应发而后发生率是,10%,。,LUX-Lung4,试验,患者,EGFR,突变,治疗线数,药物,疗效,结论,II,期,吉非替尼或厄洛替尼进展后的晚期非小细胞肺癌,72.6%,患者突变,二线及以上,阿法替尼单药,50mg,ORR 8.2%,PFS 4.4,月,OS 19.0,月,对于吉非替尼厄洛替尼治疗后进展的,NSCLC,患者具有一定疗效,1.,试验中,2,例患者获得性,T790M,：,L858R+T790M,DEL19+T790M,。使用阿法替尼后,SD,分别,9,个月和,1,个月。附加结论：对于一代获得性耐药的,NSCLC,有效。,2.,不良反应：腹泻,(100%),、皮疹,(91.9%),。,LUX-Lung7,试验,患者,EGFR,突变,治疗线数,药物,疗效,结论,II,期,EGFR,突变阳性的,IIIB,或,IV,期,NSCLC,突变阳性,一线,试验组：阿法替尼单药,4,0mg,对照组：吉非替尼,PFS 11.0:10.9,月,TTF 13.7:11.5,月,OS,未成熟,相比于吉非替尼，阿法替尼可明显提高,EGFR,突变的初治,NSCLC,预后。,Afatinib demonstrated significantly improved response rates vsgefitinib,Improved objective response and disease control rates vs gefitinib(ORR:70%vs 56%,P,=0.0083;DCR:91.3%vs 87.4%),Longer duration of response vs gefitinib(10.1 vs 8.4 months,respectively),Park K et al.Abstract LBA2 and oral presentation.European Society for Medical Oncology(ESMO)ASIA,Singapore,20th December 2015.,Objective response by independent review(secondary endpoint),P,=0.0083,Afatinib,Gefitinib,10,Afatinib demonstrated a 27%reduction in relative risk of death or progression compared to gefitinib,Park K et al.Abstract LBA2 and oral presentation.European Society for Medical Oncology(ESMO)ASIA,Singapore,20th December 2015.,Patients,twice as likely,to be alive and progression free at 2 years with afatinib vs gefitinib,(18%vs 8%,respectively),Progression-free survival by independent review(primary endpoint),Estimated PFS probability,0.2,0.4,0.6,0.8,1.0,0.0,Time of progression free survival(months),0,3,6,9,18,21,12,15,24,42,Hazard ratio 0.73,(95%CI,0.57-0.95),P,=0.0165,Afatinib,(n=160),Gefitinib,(n=159),18%,vs,8%,Median(months),11.0,10.9,27,30,33,36,39,27%,vs,15%,11,Patients remained on treatment significantly longer with afatinib than with gefitinib,TTF is the time from randomisation to,discontinuation for any reason,allowing continuation of treatment if physicians consider patients to be receiving clinical benefit,Park K et al.Abstract LBA2 and oral presentation.European Society for Medical Oncology(ESMO)ASIA,Singapore,20th December 2015.,27%significant reduction in relative risk of treatment failure vs gefitinib(,P,=0.0073),Overall survival data not yet mature,Estimated probability of being free of treatment failure,0.2,0.4,0.6,0.8,1.0,0.0,Time to treatment failure(months),0,3,6,9,18,21,12,15,24,42,Hazard ratio 0.73,(95%CI,0.58-0.92),P,=0.0073,Afatinib,(n=160),Gefitinib,(n=159),Median(months),13.7,11.5,27,30,33,36,39,Time to treatment failure(primary endpoint),12,Pattern of AEs consistent with the known profiles ofboth agents,ALT=alanine aminotransferase;AST=aspartate transaminase;ILD=interstitial lung disease.,Park K et al.Abstract LBA2 and oral presentation.European Society for Medical Oncology(ESMO)ASIA,Singapore,20th December 2015.,*Preferred terms of AEs.,4 cases of ILD with gefitinib,3 of them grade 3,no case of ILD with GIOTRIFR.1 case of grade 4 diarrhoea with GIOTRIF,1 case of grade 4 ALT with gefitinib.,Related Aes occuringin,10%patients,n(%),Afatinib,Gefitinib,All Grades,Grade 3,All Grades,Grade 3,Diarrhoea,144(90.0),19(11.9),97(61.0),2(1.3),Rash/Acne*,142(88.8),15(9.4),129(81.1),5(3.1),Stomatitis*,103(64.4),7(4.4),38(23.9),Paronychia*,89(55.6),3(1.9),27(17.0),1(0.6),Dry skin,52(32.5),59(37.1),Pruritus,37(23.1),36(22.6),Fatigue*,33(206),9(5.6),23(14.5),Decreased,appetite,26(16.3),1(0.6),19(11.9),Nausea,26(16.3),2(1.3),22(13.8),Alopecia,17(10.6),24(15.1),Vomiting,17(10.6),6(3.8),1(0.6),ALT increase,15(9.4),38(23.9),12(7.5),AST increase,10(6.3),33(20.8),4(2.5),13,LUX-Lung5,试验,患者,EGFR,突变,治疗线数,药物,疗效,结论,III,期,晚期,NSCLC,患者*,不要求,三线或四线,试验组：阿法替尼,4,0mg,+,紫杉醇,对照组：单药化疗,PFS,（,5.6,：,2.8,月）,ORR,（,32.1%,：,13.2%,）,OS,无差异,中位治疗时间延长（,133:52,天）,相比化疗，阿法替尼联合化疗对吉非替尼,/,厄洛替尼获得性耐药后和阿法替尼治疗初始获益后进展的患者能改善,PFS,和,ORR,。,1.,此实验分两阶段，一阶段是对,1,线化疗失败，及吉非替尼,/,厄洛替尼治疗初始疾病控制,(12,周,),后失败的患者进行阿法替尼单药（,50mg,）治疗。,1154,例接受阿法替尼治疗的患者中,223,例患者疗效,12,周，之后进展的患者再以,2:1,的比例分别分配至联合组和单药化疗组。,2.,两组,3/4,级的不良反应发生率：,48.5%,：,30.0%,。,LUX-Lung8,试验,患者,EGFR,突变,治疗线数,药物,疗效,结论,III,期,化疗后进展的,IIIB,或,IV,期,鳞癌患者,不要求,二线,试验组：阿法替尼单药,4,0mg,对照组：厄洛替尼,PFS 2.6,：,1.9,月,OS 7.9:6.8,月,DCR 51%,：,40%,ORR,无差异,阿法替尼对于鳞癌患者治疗具有临床受益,LUX-LUNG,系列试验汇总,LUX-LUNG2,LUX-LUNG4,LUX-LUNG6,LUX-LUNG1,LUX-LUNG3,阿法替尼一线治疗,EGFR,突变的NSCLC,，临床受益,阿法替尼治疗一代,TKI,耐药的,NSCLC,，临床受益,LUX-LUNG5,LUX-LUNG7,LUX-LUNG8,阿法替尼进展后的持续治疗价值、与化疗联合,阿法替尼与吉非替尼头对头试验一线治疗,EGFR,突变的,NSCLC,，数据不成熟,阿法替尼二线治疗鳞癌，新适应症,阿法替尼之,HER2,Refer,：,Julien Mazieres,Solange Peters,Benoit Lepage,，,et al.,L,ung Cancer That Harbors an HER2 Mutation,：,Epidemiologic Characteristics and Therapeutic Perspectives,。,L,ung Cancer That Harbors an HER2 Mutation,HER2,突变在约,2%,的,NSCLC,中出现。突变类型主要是,20,号外显子的插入。,16,例,HER2,突变的患者，接受了抗,HER2,的药物治疗。,ORR 50%,，,DCR 82%,，,PFS 5.1,个月。其中曲妥珠为基础的治疗,DCR93%,，,3,例接受阿法替尼患者均出现疾病控制,。其他的,HER2,靶向药物无疗效。,阿法替尼与,HER2,的临床前试验,临床前试验：,1.,在,HER2,扩增的细胞系（,H2170,Calu-3,）及,HER2,突变细胞系（,H1781,）中，阿法替尼可抑制,HER2,及,EGFR,的自磷酸化及其下游通路，抑制肿瘤生长。其他,HER2,或,EGFR,阴性的细胞系则未出现肿瘤抑制效应。,2.,在,H2170,及,H1781,肿瘤细胞形成的异体移植肿物上也展现出抑制效应。,阿法替尼与,HER2,个案报道,Refer,：,Clinical activity of afatinib(BIBW 2992)in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu,个案报道：,患者，女性，,71,岁，无吸烟史，初诊,III,期腺癌，,4,周期,GP,方案，疗效评价,PR,，,4,周期,GP,，,PD,。基因检测：,HER2 20,号外显子的突变，开始使用阿法替尼，,50mg/d,，,8,天后出现影像的,PR,，代谢的,CR,，维持,3,个月后出现肿瘤的再次生长。患者共使用阿法替尼,9,月，自服用后生存期达到,1,年。,阿法替尼与,HER2,在研临床试验,在研临床试验,阿法替尼与,HER2,扩增,1.,研究表明，,HER2,扩增在肺癌里并不是驱动因素，可能只是中间调节因素，且检测显示部分,HER2,蛋白扩增的患者其,her2,基因并没有拷贝数扩增。且以,HER2,扩增为基础筛查的肺癌患者采用抗,HER2,类药物治疗无效。所以，在肺癌中，以,HER2,突变为最佳适应症。,HER2,扩增的适应症未知。,2.,既往试验中有,HER2,高表达的肺癌患者对曲妥珠,/,拉帕替尼有效。,