贝伐珠单抗抗血管机制ppt教材课件

Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,贝伐珠单抗抗血管机制,贝伐珠单抗抗血管机制,1,内容,抗血管生成是治疗肿瘤的关键因素,贝伐珠单抗精准地靶向于,VEGF,，通过多种作用控制肿瘤,贝伐珠单抗持续应用，持续抑制血管生成，维持肿瘤控制,2,内容抗血管生成是治疗肿瘤的关键因素2,抗血管生成是治疗肿瘤的关键因素,抗血管生成是治疗肿瘤的关键因素,在多个肿瘤类型中，血管生成是肿瘤发生发展的关键驱动因素,1,肿瘤直径,2mm,时，其存活与生长需要独立的血液供应,14,肿瘤血管生成，为肿瘤细胞提供血氧，使肿瘤不断发展、转移,1. Folkman. In: Kufe, Pollock, Weichselbaum, eds. Cancer Medicine(Holland). 6th ed. Hamilton, Ontario: BC Decker; 2000; 2. Bergers, Benjamin. Nat Rev Cancer 2003; 3.Folkman. NEJM 1971; 4. Folkman. J Natl Cancer Inst 1990,肿瘤,血管,4,在多个肿瘤类型中，血管生成是肿瘤发生发展的关键驱动因素1肿瘤,影响临床疗效的重要原因之一是肿瘤组织血管异常,肿瘤内血管系统结构异常,1. Jain, et al. Nat Med 2001; 2. Carmeliet, et al. Nat Rev,Drug Discov 2011,肿瘤内血管壁,的,细胞功能,异常,1,2,有效药物无法到达肿瘤组织,Week 11,Week 13,Week 16,A,正常血管,B,异常血管,影响临床疗效的重要原因之一是肿瘤组织血管异常肿瘤内血管系统结,5,血管生成的关键调节因素是,VEGF,和其受体的相互作用,1,5,，,高,VEGF,水平与不佳的临床预后相关,6,19,1. Ferrara. Endocr Rev 2004; 2. Hicklin, Ellis. JCO 2005; 3. Baka, et al. Expert Opin Ther Targets 2006; 4. Morabito, et al. Oncologist 2006; 5. de Vries, et al. Science 1992; 6.Bergers, Benjamin. Nat Rev Cancer 2003; 7. Jain. Science 2005; 8. Gerber, Ferrara. Cancer Res 2005; 9. Jain. Nat Med 2001; 10. Inoue, et al. Cancer Cell 2002; 11. Margolin. Curr Oncol Rep 2002; 12. Hu, et al. Am J Pathol 2002,，,1.Hicklin, Ellis. JCO 2005; 2. Ferrara. Endocr Rev 2004; 3.,Ferrara, et al. Nat Rev Drug Discov 2004; 4. Margolin. Curr Oncol Rep 2002; 5.,Kaya, et al. Respir Med 2004; 6.,Des Guetz, et al. Br J Cancer 2006; 7.,O,Byrne, et al. Br J Cancer 2000; 8.,Yuan, et al. Int J Cancer(Pred Oncol) 2000; 9.,Imoto, et al. J Thorac Cardiovasc Surg 1998; 10.,Galizia, et al. Clin Cancer Res 2004; 11. Ishigami, et al. Br J Cancer 1998; 12.,Escudier, et al. Lancet 2007; 13. Hu, et al. Am J Pathol 2002; 14. Ferrara, Davis-Smyth. Endocr Rev 1997,VEGF,VEGF,受体,促进现有内皮细胞的存活,1,2,68,有助于血管异常化,1,2,6,7,9,刺激新血管生长,1,2,68,10,增加血管通透性,11,12,抗血管生成的关键，在于抑制,VEGF,通路,6,血管生成的关键调节因素是VEGF和其受体的相互作用15，,内容,抗血管生成是治疗肿瘤的关键因素,贝伐珠单抗精准地靶向于,VEGF,，通过多种作用控制肿瘤,贝伐珠单抗持续应用，持续抑制血管生成，维持肿瘤控制,7,内容抗血管生成是治疗肿瘤的关键因素7,Mabuchi, et al.,持续应用贝伐珠单抗治疗直至进展的患者,新血管的生长13,8,JCO 2010; 21.,Curr Opin Genet Dev 2005; 2.,Clin Cancer Res 2008; 9.,Ann Oncol 2009; 24.,Rini, et al.,J Natl Cancer Inst 1990,Bergers, Benjamin.,Watanabe, et al.,Nat Med 2003; 6.,Imoto, et al.,肿瘤内血管系统结构异常,JHepatol 2008; 20.,Respir Med 2004; 6.,Nature 1993; 3.,Respirology 2009; 16.,Sandler, et al.,Melnyk, et al.,贝伐珠单抗精准靶向,VEGF,，抑制血管生成，持续控制肿瘤,1,2,贝伐珠单抗,VEGF,受体,VEGF,贝伐珠单抗阻止,VEGF,与受体的结合,1,2,贝伐珠单抗的清除半衰期长（约,20,天），有助于持续控制肿瘤,3,8,Mabuchi, et al.贝伐珠单抗精准靶向VEGF，抑,对比较传统治疗，贝伐珠单抗的多种作用能提高疗效,120,1. Baluk, et al. Curr Opin Genet Dev 2005; 2. Willett, et al. Nat Med 2004; 3. O,Connor, 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 al. Int J Cancer 2004; 10. Gerber, Ferrara. Cancer Res 2005; 11.Prager, et al. Mol Oncol 2010; 12. Yanagisawa, et al. Anti-Cancer Drugs 2010; 13. Dickson, et al. Clin Cancer Res 2007; 14. Hu, et al. Am J Pathol 2002;,15. Ribeiro, et al. Respirology 2009; 16.Watanabe, et al. Hum Gene Ther 2009; 17. Mesiano, et al. Am J Pathol 1998; 18. Bellati, et al. Invest New Drugs 2010; 19. Huynh, et al. JHepatol 2008; 20. Ninomiya, et al. J Surg Res2009,现有肿瘤血管系统的,退化,13,抑制,新血管的生长,13,8,改善现存血管系统的,抗通透性,1113,9,对比较传统治疗，贝伐珠单抗的多种作用能提高疗效1201.,Clin Cancer Res 2007; 14.,Diaz Jr， Nature 11219， 3.,应用VEGF 抑制剂（1天）,Clin Cancer Res 2009; 4.,Clin Cancer Res 2010;16:3887900, Figures 2A and B,Prager, et al.,持续应用贝伐珠单抗治疗直至进展的患者,Mesiano, et al.,1, Hurwitz, et al.,Invest New Drugs 2010; 19.,Hurwitz, et al.,Curr Opin Genet Dev 2005; 2.,贝伐珠单抗精准地靶向于VEGF，通过多种作用控制肿瘤,Nature 1993; 4.,Br J Cancer 2000; 8.,Cancer Res 2005,Cancer Res 2005,2013 ASCO Abstract 3502.,现有,肿瘤,血,管系统的,退化,Clin Cancer Res 2007; 14.现有肿瘤血,贝伐珠单抗导致现有肿瘤血管系统的退化,12,1. Baluk, et al. Curr Opin Genet Dev 2005; 2. Hu, et al. Am J Pathol 2002,11,无贝伐珠单抗,有贝伐珠单抗,贝伐珠单抗导致现有肿瘤血管系统的退化121. Baluk,11,临床前证据,1:,治疗开始时加入抗,VEGF,抗体的非常重要,1,抗,VEGF,治疗后，给药,48,小时内，血管和肿瘤体积,明显降低,1,1. O,Connor, et al. Clin Cancer Res 2009,对照,抗,VEGF,Figure reprinted with permission from O,Connor JP, et al. Clin Cancer Res 2009;15:667482, Figure 1B,人结直肠癌移植瘤模型中，进行抗,VEGF,抗体,G6-31,治疗，采用,微型计算机血管造影,评估体外肿瘤血管系统,12,临床前证据 1: 治疗开始时加入抗VEGF抗体的非常重要1,临床前证据,2:,降低,MVD,1,在带有人结肠腺癌,(LS174T),的免疫缺陷小鼠,(SCID),中，研究贝伐珠单抗,*,对,MVD,的作用,1,受试动物接受,0.2mL(492,g/mL),贝伐珠单抗或生理盐水,i.p.,或,i.v.,推注；,在治疗后,6,小时到,11,天的不同时间点进行评估,与对照组相比，抗,VEGF,治疗显著降低,LS174T,肿瘤的血管通透性及血管体积,(p30%,实线表示显著减少,(p0.05),Figure reprinted by permission from Macmillan Publishers Ltd: Willett, et al. Nat Med;10(2):1457, copyright 2004,贝伐珠单抗对血流,(A),与血管体积,(B),的作用,治疗前,治疗前,血管体积,(mL/100g,组织,),血流,(mL/min/100g,组织,),患者,14,I期临床研究证据: 减少肿瘤血流与体积11. Willet,抑制新,生,血管,抑制新生血管,贝伐珠单抗抑制新血管生长,12,，,持续控制肿瘤生长,3,7,1. Baluk, et al. Curr Opin Genet Dev 2005;,2.,Mabuchi, et al. Clin Cancer Res 2008,，,3Blazer, et al. JCO 2008,;,4,.,Baluk, et al. Curr Opin Genet Dev 2005; 5. Gerber, Ferrara. Cancer Res 2005; 6. Wild, et al. Int J Cancer 2004; 7. Mabuchi, et al. Clin Cancer Res 2008,无贝伐珠单抗,有贝伐珠单抗,16,贝伐珠单抗抑制新血管生长12，持续控制肿瘤生长371.,应用,VEGF,抑制剂（,1,天）,应用,VEGF,抑制剂（,2,天）,应用,VEGF,抑制剂（,7,天）,基 线,持续使用,VEGF,抑制剂，能持续控制肿瘤血管,应用VEGF 抑制剂（1天）应用VEGF抑制剂（2天）应用V,17,改善现存血管系统的通透性,改善现存血管系统的通透性,降低现存血管通透性，进行,抗肿瘤作用,1,2,血管直径降低,4,组织间隙,液压下降,13,1. Willett, et al. Nat Med 2004; 2. Gerber, Ferrara. Cancer Res 2005; 3.,Tobelem. Targ Oncol 2007;,4. Yuan, et al. PNAS USA 1996; 5. Dickson, et al. Clin Cancer Res 2007; 6. Prager, et al. Mol Oncol 2010,血管通透性,降低,16,有效药物到达,肿瘤组织,19,降低现存血管通透性，进行抗肿瘤作用1,2血管直径降低4组织间,临床前证据,1:,接受贝伐珠单抗治疗后，,血管,通,透性下降,1,，超过,50%,1. Prager, et al. Mol Oncol 2010,VEGF+,贝伐珠单抗,渗透率,(%),暴露于肿瘤,VEGF,中的人脐静脉内皮细胞，接受贝伐珠单抗治疗后，渗透率显著下降,*p0.05,存在,乳腺癌细胞株,(MDA-MB231),的,VEGF,时，贝伐珠单抗降低血管渗,通,性,1,20,临床前证据 1:接受贝伐珠单抗治疗后，血管通透性下降1，超,对比较传统治疗，贝伐珠单抗的多种作用都有助于疗效的提高,120,1. Baluk, et al. Curr Opin Genet Dev 2005; 2. Willett, et al. Nat Med 2004; 3. O,Connor, 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 al. Int J Cancer 2004; 10. Gerber, Ferrara. Cancer Res 2005; 11.Prager, et al. Mol Oncol 2010; 12. Yanagisawa, et al. Anti-Cancer Drugs 2010; 13. Dickson, et al. Clin Cancer Res 2007; 14. Hu, et al. Am J Pathol 2002;,15. Ribeiro, et al. Respirology 2009; 16.Watanabe, et al. Hum Gene Ther 2009; 17. Mesiano, et al. Am J Pathol 1998; 18. Bellati, et al. Invest New Drugs 2010; 19. Huynh, et al. JHepatol 2008; 20. Ninomiya, et al. J Surg Res2009,现有肿瘤血管系统的,退化,13,抑制,新血管的生长,13,8,一致提高缓解率,47,持续控制肿瘤生长,810,减少,腹水和积液,2,3,11,1420,对现存血管系统的,抗通透性,1113,肿瘤组织血管结构正常,肿瘤组织血管功能正常,21,对比较传统治疗，贝伐珠单抗的多种作用都有助于疗效的提高12,Mesiano, et al.,Hu, et al.,Dickson, et al.,In: Kufe, Pollock, Weichselbaum, eds.,J Clin Invest 2006; 6.,持续控制肿瘤生长810,Clin Cancer Res 2008,Melnyk, et al.,Grothey, et al.,Clin Lung Cancer 2011; 16.,Endocr Rev 1997,Baluk, et al.,JHepatol 2008; 20.,肿瘤发展过程中，VEGF持续表达，甚至在出现次要通路时2,3,6,7,NEJM 2006; 17.,Hu, et al.,Clin Cancer Res 2008，3Blazer, et al.,Clin Cancer Res 2004; 5.,Curr Opin Genet Dev 2005; 2.,Saltz, et al.,Figure reprinted with permission from OConnor JP, et al.,内容,抗血管生成是治疗肿瘤的关键因素,贝伐珠单抗精准地靶向于,VEGF,，通过多种作用控制肿瘤,贝伐珠单抗持续应用，持续抑制血管生成，维持肿瘤控制,22,Mesiano, et al.内容抗血管生成是治疗肿瘤的关键,持续使用,贝伐珠单抗,抑制,血管生成,，,持续,控制,肿瘤,13,一线并持续抑制,VEGF,是转移性肿瘤患者的重要治疗策略,16,1. Mabuchi, et al. Clin Cancer Res 2008; 2. Bagri, et al. Clin Cancer Res 2010; 3. Grothey, et al. JCO 2008; 4. Galizia, et al. Clin Cancer Res 2004; 5. Mancuso, et al. J Clin Invest 2006; 6. Vosseler, et al. Cancer Res 2005,贝伐珠单抗一线,治疗,：,获得肿瘤控制,贝伐珠单抗持续,应用,：,维持肿瘤控制,23,持续使用贝伐珠单抗抑制血管生成，持续控制肿瘤13一线并持续,VEGF,在,肿瘤,发生,和发展,的,过程中持续表达,15,肿瘤发展过程中，,VEGF,持续表达，甚至在出现次要通路时,2,3,6,7,VEGF,VEGF,bFGF,TGF-1,VEGF,bFGF,TGF-1,PLGF,VEGF,bFGF,TGF-1,PLGF,PD-ECGF,VEGF,bFGF,TGF-1,PLGF,PD-ECGF,Pleiotrophin,VEGF,持续表达,3,1. Bergers, Benjamin. Nat Rev Cancer 2003; 2. Kim, et al. Nature 1993; 3. Folkman. In: DeVita, Hellman, Rosenberg, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7,th,ed. Philadelphia, PA: Lippincott Williams 6,. Mesiano, et al. Am J Pathol 1998; 7. Melnyk, et al. J Urol 1999 8,. Folkman. In: DeVita, Hellman, Rosenberg, eds. Cancer: Principles and Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams ,9,. Mukhopadhyay, Datta. Semin Cancer Biol 2004,24,VEGF在肿瘤发生和发展的过程中持续表达15肿瘤发展过程中,不同于直接作用于肿瘤组织的药物，贝伐珠单抗作用于肿瘤微环境，很少出现获得性耐药,1,1,。,Robert S Kerbel, carcinogenesis vol.21 No.3 pp505-515.2000,；,2.Luis A. Diaz Jr,，,Nature 11219,，,3. Sandra Misale, Nature 11156,；,4,Wilkins; 2005;,5,. Mukhopadhyay, Datta. Semin Cancer Biol 2004,作用于肿瘤细胞：,基因不稳定，持续使用,EGFR,抑制剂,5-6,月后使,KRAS,状态发生改变,2,、,3,生长因子,EGFR,RAS,RAF,MEK,ERK,PI3K,AKT,mTOR,VEGF,遗传学稳定,8,、,9,其他,血管内皮细胞,VEGF,贝伐珠单抗,作用于肿瘤微环境：,VEGF,基因稳定,4,、,5,25,不同于直接作用于肿瘤组织的药物，贝伐珠单抗作用于肿瘤微环境，,临床前证据,:,使用贝伐珠单抗持续抑制血管生成，肿瘤得到长期控制,1,与对照组相比，使用抗,VEGF,治疗持续时间,长，,肿瘤抑制,和,生存期,的显著延长,26,1. Bagri, et al. Clin Cancer Res 2010,Figures reprinted with permission from Bagri A, et al. Clin Cancer Res 2010;16:3887900, Figures 2A and B,小鼠人结肠癌移植瘤模型,1,临床前证据:使用贝伐珠单抗持续抑制血管生成，肿瘤得到长期控,26,临床证据：,持续使用,贝伐珠单抗,，获得显著,临床疗效,1,2,NO16966,研究中，中位,PFS,的显著延长主要见于贝伐珠单抗持续,应用,直至疾病进展的患者,1,2,1. Saltz, et al. ASCO GI 2007(Abstract); 2. Saltz, et al. JCO 2008,总体人群,(PFS,获益较少,),1,持续应用贝伐珠单抗治疗直至进展的患者,(PFS,显著获益,),1,月,月,PFS (%),PFS (%),27,临床证据：持续使用贝伐珠单抗，获得显著临床疗效1,2NO1,随机,III,期研究显示，一线贝伐珠单抗联合化疗后维持治疗显著改善,PFS1/PFS2/TT2PD/OS,1,1. Koopman M,et al. 2013 ASCO Abstract 3502.,0,6,12,18,24,30,36,0.0,0.2,0.4,0.6,0.8,1.0,时间,(,月,),PFS2,率,观察,(n=279),：中位,10.5,个月,维持,(n=279),：中位,11.8,个月,分层,HR=0.81; 95CI=0.67-0.98,P=0.028,调整,HR=0.77; P=0.007,10.5,个月,11.8,个月,0,6,12,18,24,30,36,0.0,0.2,0.4,0.6,0.8,1.0,时间,(,月,),OS,观察,(n=279),：中位,18.2,个月,维持,(n=279),：中位,21.7,个月,分层,HR=0.87; 95%CI=0.71-1.06,P=0.156,调整,HR=0.80; P=0.035,(,初步生存分析,),18.2,个月,21.7,个月,CAIRO-3,研究,1,28,随机III期研究显示，一线贝伐珠单抗联合化疗后维持治疗显著改,Yuan, et al.,Galizia, et al.,Hu, et al.,Hum Gene Ther 2009; 17.,Clin Cancer Res 2010; 3.,*临床前疗效评估采用的是贝伐珠单抗的小鼠替代品微血管密度,安维汀+化疗 (n=409),JCO 2011; 25.,Nat Rev Drug Discov 2004; 4.,Baluk, et al.,Am J Pathol 2002; 15.,OConnor, et al.,Cancer Res 2005; 11.,NEJM 2006; 17.,Int J Cancer 2004; 10.,Cancer Res 1997; 8.,Nat Rev Cancer 2003; 3.,其中，VEGF是肿瘤血管生成的早期、持续性启动因子25,Lancet 2007; 13.,Cancer Res 2005; 9.,观察性研究和随机,III,期研究均证明，进展后使用,贝伐珠单抗治疗,仍有显著生存获益,1,-3,在一项非随机、观察性研究,（,BRiTE,）,中，贝伐珠单抗联合化疗治疗,mCRC,，与疾病进展即停用贝伐珠单抗,的患者,相比，进展后继续贝伐珠单抗治疗者的中位,OS,更长,（,分别为,31.8,个月和,19.9,个月，,HR=0.48, p0.001,）,1,1. Grothey, et al. JCO 2008; 2. Grothey, et al. ASCO 2007(Abstract and poster),；,3,。,Bennouna J, et al. Lancet Oncol 2012; doi:10.1016/S1470-2045(12)70516-8.,期望得到目前正在进行的前瞻性,III,期临床研究的确认,PD=,疾病进展,贝伐珠单抗持续应用至进展,及进展后继续应用,BRiTE,OS,估计,(%),月,时间,(,月,),1.0,0.8,0.6,0.4,0.2,0,9.8,11.2,总生存率,HR=0.81 P=0.0062,安维汀,+,化疗,(n=409),化疗,(n=410),0,12,24,36,48,死亡风险,19%,TLM,研究,3,29,Yuan, et al.观察性研究和随机III期研究均证明，,Endocr Rev 1997,Philadelphia, PA: Lippincott Williams 5.,Clin Cancer Res 2009,抗血管生成是治疗肿瘤的关键因素,de Vries, et al.,Nat Rev Cancer 2003; 3.,Miller, etal.,Willett, et al.,Hamilton, Ontario: BC Decker; 2000; 2.,Hum Gene Ther 2009; 17.,抗血管生成是治疗肿瘤的关键因素,Nat Med 2001; 10.,Nat Med 2004; 2.,Nature 1993; 4.,Clin Cancer Res 2004; 5.,Clin Cancer Res 2004; 5.,Copyright 2009 National Academy of Sciences, USA,NEJM 2006 4.,Willett, et al.,Respir Med 2004; 6.,贝伐珠单抗抑制血管，控制肿瘤得到广泛应证,1, Hurwitz, et al. NEJM 2004; 2. Saltz, et al. JCO 2008; 3. Sandler, et al. NEJM 2006 4. Reck, et al. JCO 2009; 5. Gray, et al. JCO 2009; 6. Avastin SmPC 7. Escudier, et al. Lancet 2007; 8. Rini, et al. JCO 2008,9. Friedman et al. J Clin Oncol 2009; 10. Burger et al ASCO 2010: 11. Perren et al., ESMO 2010,12. Koopman M,et al. 2013 ASCO Abstract 3502. 13,. Published online November 16, 2012,14.,Lopez-Chavez, et al. J Thorac Oncol 2012; 15. Gridelli, et al. Clin Lung Cancer 2011; 16.,; 17. ; 18.,Burger, et al. NEJM 2011,mCRC,mNSCLC,mBC,mRCC,AVF2107g1,OS:+4.7,月,HR=0.66p0.001,NO 16966,PFS: HR=0.83p=0.0023,E4599,3,OS:+3.9,月,HR=0.79p=0.003,E2100,5,PFS:+5.3,月,HR=0.48p0.0001,AVOREN,7,PFS:+4.8,月,HR=0.63p=0.0001,AVAiL,4,PFS: HR=0.75,p=0.003,AVADO,6,PFS: HR=0.67p=0.0002,CALGB 90206,8,PFS: HR=0.71p0.0001,BRAIN,9,6,月,PFS: 50%,vs. 15% in,historical controls,rGBM,OC,GOG 218,10,PFS:+6.2,月,HR=0.64p0.0001,ICON-7,11,PFS: HR=0.79p=0.001,OCEANS,PFS: HR=0.484p0.0001,TANIA,16,:,主要研究终点：,PFS,AVA,L,L,15,主要研究终点：,OS,MITO-16,17,主要研究终点：,PFS,MO28347,主要研究终点：,OS,TML(ML18147),13,PFS: 5.7 vs 4.1,月,OS,：,11.2 vs 9.8,月,HR=0.81 P=0.0062,跨线研究,持续治疗,GOG-0218,18,PFS:14.1 vs,11.2 vs 10.3,(HR 0.7/0.9;,p:0.0001/0.08),CAIRO-3,12,月,HR=0.77; P=0.007,OS: 21.7 vs 18.2,月,HR=0.80; P=0.035,ECOG,：,4599,14,PFS:,10.3 vs 6.5,月,HR: 0.64, p0.001,OS:,20.9 vs 10.2,月,HR,：,0.75,，,p=0.03,Endocr Rev 1997贝伐珠单抗抑制血管，控制肿瘤得,30,总结,1. Folkman. In: Kufe, Pollock, Weichselbaum, eds. Cancer Medicine(Holland). 6th ed. Hamilton, Ontario: BC Decker; 2000; 2. Bergers, Benjamin. Nat Rev Cancer 2003; 3. Kim, et al. Nature 1993; 4. Folkman. In: DeVita, Hellman, Rosenberg, eds. Cancer: Principles 10. O,Connor, et al. Clin Cancer Res 2009; 11. Mabuchi, et al. Clin Cancer Res 2008; 12. Prager, et al. Mol Oncol 2010; 13. Yanagisawa, et al. Anti-Cancer Drugs 2010; 14.Dickson, et al. Clin Cancer Res 2007; 15. Hurwitz, et al. NEJM 2004; 16. Sandler, et al. NEJM 2006; 17. Escudier, et al. Lancet 2007; 18. Grothey, et al. JCO 2008; 19. Miller, etal. NEJM 2007; 20. Tebbutt, et al. JCO 2010; 21. Sobrero, et al. Oncology 2009; 22. Fuchs, et al. JCO 2007; 23. Van Cutsem, et al. Ann Oncol 2009; 24. Robert, et al. JCO 2011; 25. Gray, et al. JCO 2009; 26. Bekaii-Saab, et al. ASCO 2010(Abstract); 27. Bagri, et al. Clin Cancer Res 2010; 28. Saltz, et al. ASCO GI 2007(Abstract); 29. Saltz, et al. JCO 2008,血管生成均是肿瘤发展的关键驱动因素,1,，改善肿瘤微环境是治疗肿瘤的关键因素。其中，,VEGF,是肿瘤血管生成的早期、持续性启动因子,25,贝伐珠单抗精准靶向,VEGF,联合传统治疗,6,1524,，抑制血管生成，从而持续控制肿瘤,6,7,使现有肿瘤血管退化,810,抑制新血管生长,811,降低现存血管通透性,1214,贝伐珠单抗持续并跨线应用，能持续抑制血管生成，维持肿瘤控制,11,1517,25,2729,，并且在各种肿瘤治疗中有广泛应用,31,总结1. Folkman. In: Kufe, Polloc,In: Kufe, Pollock, Weichselbaum, eds.,Nature 1993; 3.,Expert Opin Ther Targets 2006; 4.,Clin Lung Cancer 2011; 16.,应用VEGF 抑制剂（1天）,Prager, et al.,Cancer Cell 2002; 11.,Expert Opin Ther Targets 2006; 4.,贝伐珠单抗持续并跨线应用，能持续抑制血管生成，维持肿瘤控制11,1517,25,2729 ，并且在各种肿瘤治疗中有广泛应用,Ninomiya, et al.,Cancer: Principles & Practice of Oncology.,Clin Cancer Res 2008; 12.,Clin Cancer Res 2007; 15.,Respir Med 2004; 6.,Baluk, et al.,Lancet 2007; 7.,Cancer: Principles & Practice of Oncology.,临床证据：持续使用贝伐珠单抗，获得显著临床疗效1,2,Diaz Jr， Nature 11219， 3.,刺激新血管生长1,2,68,10,Mol Oncol 2010; 12.,J Surg Res2009,Mol Oncol 2010; 13.,Mabuchi, et al.,Ribeiro, et al.,JHepatol 2008; 20.,Ferrara, Davis-Smyth.,血管体积 (mL/100g 组织),Nat Rev Cancer 2003; 3.,Cancer Res 2005; 3.,Figure reprinted with permission from OConnor JP, et al.,Ferrara, et al.,Invest New Drugs 2010; 19.,Melnyk, et al.,NEJM 2006; 6.,JHepatol 2008; 20.,JHepatol 2008; 20.,Curr Opin Genet Dev 2005; 2.,在治疗后6小时到11天的不同时间点进行评估,Lancet Oncol 2012; doi:10.,Cancer Res 2005; 11.,Reck, et al.,JCO 2008; 3.,Dickson, et al.,87; 95%CI=0.,持续使用贝伐珠单抗抑制血管生成，持续控制肿瘤13,贝伐珠单抗精准靶向VEGF，抑制血管生成，持续控制肿瘤1,2,Cancer Cell 2002; 6.,Clin Cancer Res 2010,NEJM 2004; 5.,Semin Cancer Biol 2004, ESMO 2010,Gerber, Ferrara.,Diaz Jr， Nature 11219， 3.,安维汀+化疗 (n=409),NEJM 2006; 17.,J Surg Res2009,Nat Med 2001; 10.,临床前证据 2: 降低MVD1,Int J Cancer 2004; 10.,Watanabe, et al.,Ferrara, et al.,贝伐珠单抗持续应用至进展,J Surg Res2009,Sandler, et al.,Escudier, etal.,Cancer: Principles and Practice of Oncology.,Escudier, etal.,Invest New Drugs 2010; 19.,临床前证据:使用贝伐珠单抗持续抑制血管生成，肿瘤得到长期控制1,Endocr Rev 2004; 3.,Figure reprinted with permission from OConnor JP, et al.,Respirology 2009; 16., ESMO 2010,Lancet 2007; 8.,OConnor, et al.,Bergers, Benjamin.,Cancer Medicine(Holland).,Respir Med 2004; 6.,谢谢观看！,In: Kufe, Pollock, Weichselbau,32,