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level,*,抗血管生成药物联合,TKI,治疗,晚期非小细胞肺癌的新进展,-A+T,模式指导晚期肺癌治疗临床应用,方勇,浙江大学医学院附属邵逸夫医院肿瘤内科,抗血管生成药物联合TKI治疗晚期非小细胞肺癌的新进展-,肿瘤抗血管生成联合,TKI,应用病例,肿瘤抗血管生成联合,TKI,治疗晚期,NSCLC,研究进展,A+T,模式的未来研究发展,主要内容,肿瘤抗血管生成联合TKI应用病例主要内容,患者病史（,1,）,男性，赵,，,53,岁,主诉：“诊断为肺癌近一年，化疗后再次进展”于,2016-3-30,再次入院,1,年余前因,“,咳嗽痰中带血,7,天,”,就诊于永康市第一人民医院,。,查头胸腹部,CT,提示（,2015-4-20,）：左肺下叶癌伴左肺门及纵隔多发淋巴结增大，右侧肾上腺转移瘤考虑,。,颅脑,MRI,增强示“,右侧额叶低密度灶，转移瘤考虑,”。,2015-4,行肺部肿块穿刺活检，病理（,HZ2015036916,）：（左肺下叶）考虑腺癌，免疫组化结果：,P63(+),CgA,（,-,），,TTF-1,（,+,），,CK5/6,（,-,），,CK-7(+),NapsinA,（,+,），符合肺腺癌,.,分子病理：,EGFR,野生型,。,患者病史（1）男性，赵，53岁,并于,2015-05-02,至,2015-07-30,起永康市中医院予以紫杉醇,210mgd1+,顺铂针,40mgd1-3,静滴,q3w,化疗,5,周期。,2015-05-19,在浙江省人民医院行伽马刀治疗，具体方案：患者局麻下头架固定，头颅,MRI,定位，,MR,显示，经,TPS,规划，,50%,剂量曲线包绕，周边剂量,21Gy,，中心剂量,42Gy,，共,11,个靶点。,2015-08-31,起,予,“,贝伐单抗,400mg,静滴,d1+,奈达铂针,115mg/90mg,静脉滴注,d1+,培美曲塞二钠,(,普来乐,),针,0.8g,静脉滴注,d1,”,方案化疗,4,次,；,于,2015.12.17,予,“,贝伐珠单抗针,400mg,静滴,d1+,培美曲塞二钠针,0.8g,静脉滴注,d1,”维持,化疗,。,患者病史（,2,）,并于2015-05-02至2015-07-30起永康市中医院,上腹部,CT,（,2016-3-31,）,上腹部CT（2016-3-31）,What treatment strategy would you next recommend(pre-ASCO 2012)?,1.,免疫治疗,治疗策略您会如何推荐？,Q,：,3,.,放化疗,4,.,TKI,5,.,TKI+AVASTIN,What treatment strategy would,2016-3-31,2016-4-20,2016-5-9,2016-3-312016-4-202016-5-9,肿瘤抗血管生成联合,TKI,应用病例,肿瘤抗血管生成联合,TKI,治疗晚期,NSCLC,研究进展,A+T,模式的未来研究发展,主要内容,肿瘤抗血管生成联合TKI应用病例主要内容,EGFR突变阳性NSCLC的一线治疗,EGFR TKI,单药治疗,目前标准治疗,PFS:9.2-13.7,个月,EGFR TKI,研究,N,PFS(,月,),厄洛替尼,OPTIMAL,82,13.7,EURTAC,86,10.4,ENSURE,110,11.0,JO22903,102,11.8,吉非替尼,NEJ002,114,10.8,WJTOG3405,86,9.2,阿法替尼,LUX-Lung 3,230,11.1,LUX-Lung 6,364,11.0,Chen,et al.Ann Oncol 2013;,Costa,et al,Clin Cancer Res 2014;,Wu,et al.WCLC 2013(abst P1 11-021);,Goto,et al.Lung Cancer 2013;,Maemondo,et al.N Engl J Med 2010;,Mitsudomi,et al.Lancet Oncol 2010;,Sequist,et al.J Clin Oncol 2013;,Wu,et al.Lancet Oncol 2013.,KATO T,et al.2014 ASCO Abstract,8005.,EGFR突变阳性NSCLC的一线治疗EGFR TKI单药治疗,肿瘤异质性,TKI,治疗的轮回,跷跷板理论,肿瘤异质性TKI治疗的轮回跷跷板理论,晚期NSCLC的抗血管生成治疗：有望突破化疗瓶颈,单靶点：,靶向,VEGF,信号通路的单克隆抗体,Bevacizumab,（安维汀）：,VEGF-A,Ramucirumab,(,Cyramza,),：,VEGFR-2,多靶点：,靶向,VEGFR/PDGFR/FGFR,的多靶点小分子,TKI,Nintedanib,泛靶点,内皮抑素（恩度）,更安全不易耐药,适合长期维持治疗,Cancer Treat Rev,2014,40(4):548-57.,晚期NSCLC的抗血管生成治疗：有望突破化疗瓶颈单靶点：Ca,1.Sandler,et al.NEJM 2006;2.Reck,et al.JCO 2009;3.Lucio Crin,et al.Lancet Oncol 2010;4.Fabrice Barlesi,et al.JCO 2013;5.Caicun Z,et al.2013 WCLC MO06.13.;6.Martin Reck,et al.Lancet Oncol 2014;7.KATO T,et al.2014 ASCO Abstract 8005;8.Maurice Perol,et al.2014 ASCO Abstract LBA 8006.9.JCO(June 1 S),2005:7138;10.JCO,2010,28(15):7598;11。J Thorac Oncol.2011;6:11041109；12.,中华肿瘤杂志,2013,35(8):618-622.,2010,2006,E4599,bevacizumab+CP vs CP,1,2009,AVAiL,bevacizumab+CG vs CG,2,2014,LUME-Lung 1,nintedanib+doc vs doc,6,2013,SAiL,bevacizumab+chemo vs chemo,3,AVAPERL,bevacizumab+pem/cispem+bev,4,vs bev,4,BEYOND,bevacizumab+CP vs CP,5,JO25567,bevacizumab+erlotinib vs erlotinib,7,一线研究,二线研究,REVEL,ramucirumab+doc vs doc,8,抗血管生成治疗在晚期NSCLC的关键研究,2005,ENDO III,endostar+NP vs NP,9,ENDO IV,endostar+,chemo vs chemo,10,ENDO TC,endostar+TC vs TC,11,2011,ENDO 2nd,endostar+doc vs doc,12,一线,/,二线 研究,1.Sandler,et al.NEJM 2006;2,EGFR突变患者的预后能否进一步提高？,mPFS,：,6,个月,mPFS,：,11,个月,含铂双药化疗,EGFR TKI,治疗,Chen,et al.Ann Oncol 2013;Costa,et al,Clin Cancer Res 2014;Wu,et al.WCLC 2013(abst P1 11-021);Goto,et al.Lung Cancer 2013;,Maemondo,et al.N Engl J Med 2010;Mitsudomi,et al.Lancet Oncol 2010;Sequist,et al.J Clin Oncol 2013;Wu,et al.Lancet Oncol 2013.,联合抗血管生成治疗,mPFS,：,？,EGFR突变患者的预后能否进一步提高？mPFS：mPFS：含,贝伐珠单抗的多种作用对疗效提高,(,较传统治疗,),很重要,120,现有肿瘤脉管系统的,消退,13,新血管生长,13,8,抑制,一致提高缓解率,47,持续控制肿瘤生长,810,减少,腹水与积液,2,3,11,1420,存活脉管系统的,抗渗透性,1113,1,.,Baluk,et al.Curr Opin Genet Dev 2005;2.Willett,et al.Nat Med 2004;3.OConnor,et al.Clin Cancer Res 2009;4.Hurwitz,et al.NEJM 2004;5.Sandler,et al.NEJM 2006;,6.Escudier,etal.Lancet 2007;7.Miller,et al.NEJM 2007;8.Mabuchi,et al.Clin Cancer Res 2008;9.Wild,et 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