分子靶向治疗(消化道肿瘤).ppt.ppt

复旦大学附属肿瘤医院李进,消化道肿瘤的分子靶向治疗,alkylate,anthracycline,platinum,targetmolecular,taxol,1960s,1970s,1980s,1990s,2000s,肿瘤的药物治疗变迁,肿瘤发生的分子机制,？,血管内皮细胞,proliferation,migration,angiogenesis:,tubuleformation,pdgf-b,vegf,vegfr-2,pdgfr-b,paracrinestimulation,differentiation,mitochondria,apoptosis,肿瘤细胞,pdgf,vegf,egf,proliferation,survival,mitochondria,egf,hif-2,细胞核,vhl,autocrineloop,apoptosis,raf,细胞核,wilhelmsetal.clincancerres.2004;64:7099-7109.,分子靶向治疗主要途径,单克隆抗体,西妥昔贝伐帕尼尼妥珠曲妥珠,小分子靶向药物,吉菲替尼埃罗替尼舒尼替尼索拉菲尼zd2171zd6474,egfr信号传导通路,西妥昔一线联合化疗,crystal研究:研究设计,分层因素:种族ecogps患者群：随即分组的患者n=1217安全性评价人群n=1202itt人群:n=1198,mfolfiri,西妥昔单抗+mfolfiri,随机,egfr表达的mcrc,2007.ascoannualmeeting.abstractno.4000,pfs:针对itt人群的独立评估,progression-freesurvivaltime(months),pfsestimate,1.0,hr=0.851;95%ci=0.726-0.998,stratifiedlog-rankp-value=0.0479,8.9mo,8.0mo,1-yearpfsrate23%vs34%,2007.ascoannualmeeting.abstractno.4000,西妥昔二线联合化疗,epic的试验设计,cetuximab/irinotecan,irinotecan,以奥沙利铂为基础的一线治疗失败,survival,分层因素:研究中心ecogps(0-1,2),主要终点:总生存(os)次要终点:pfs,rr,dcr,safety,qol样本量:221个中心，1298例患者,n=648,n=650,abstract#40032007ascoannualmeeting,有效率和疾病控制率,p-value=0.0001,p-value=0.0001,abstract#40032007ascoannualmeeting,proportionprogressionfree,0.0,0.2,0.4,0.6,0.8,1.0,0,3,6,9,12,15,18,4.0mo,2.6mo,months,hr=0.69295%ci=0.6170.776,西妥昔单抗+伊立替康;n=648,伊立替康单用;n=650,p-value=0.0001,epic研究pfs,abstract#40032007ascoannualmeeting,奥沙利铂治疗失败后mcrc二线治疗,abstract#40032007ascoannualmeeting,西妥昔三线联合化疗,bond试验,随机入组,西妥昔起始剂量400mg/m22-h滴注250mg/m21-h滴注1/周+伊立替康*n=218,西妥昔起始剂量400mg/m22-h滴注250mg/m21-h滴注1/周n=111,329例egfr表达阳性的病人,伊立替康用药后三个月内复发,病情进展,西妥昔+i伊立替康*n=56,cunninghametal.nengljmed2004;351:337-345,*伊立替康剂量同以往相同,有效率,cunninghametal.nengljmed2004;351:337-345.,西妥昔+伊立替康(n=218)西妥昔(n=111),23*,11*,32*,56*,*p=0.0074;*p0.001;intenttotreat,化疗后的西妥昔的效能,cunninghametal.nengljmed2004;351:337-345,vegf/vegfr系统,tki=tyrosinekinaseinhibitors,steward.horizonsincancertherapeutics.2004;5(2):11-21,贝伐一线联合化疗,贝伐的iii期临床,*thirdarmwasdiscontinuedafterapredeterminedinterimsafetyanalysisdemonstratedthesafetyoftherapywith5-fu/lv/cpt-11+bevacizumab.patientsreceivingbevacizumabcouldcontinuetherapypastdiseaseprogressionincombinationwithsecond-linetherapy.ifl=bolus5-fu/lv/irinotecanhurwitzetal.procamsocclinoncol.2003;22.abstract3646.avastin(bevacizumab)pi.,初治大肠癌(n=923),pd,ifl+安慰剂(n=411),pd,fl+贝伐*(5mg/kg,q2w)(n=110),pd,ifl+贝伐(5mg/kg,q2w)(n=402),主要终点:生存,随机入组,有效率,hurwitzetal.procamsocclinoncol.2003;22.abstract3646andoralpresentation.avastinpi.,无进展生存,0.2,0,10,20,30,0,0.8,1.0,0.4,0.6,progression-freesurvival(mo),proportionprogression-free,treatmentgroup,ifl+placeboifl+bevacizumab,hurwitzetal.procamsocclinoncol.2003;22.abstract3646andoralpresentation.avastinpi.,hr=0.54,p0.00001mpfs:6.210.6mo,生存,hr=0.66,p=0.00004中位生存:15.6vs20.3mo,durationofsurvival(mo),proportionsurviving,0.2,20,0,10,30,40,0,0.8,1.0,0.4,0.6,治疗组,ifl+安慰剂ifl+贝伐,hurwitzetal.procamsocclinoncol.2003;22.abstract3646andoralpresentation.avastinpi.,贝伐二线联合化疗,iii期临床:e3200,二线治疗晚期大肠癌(n=880),folfox-4,贝伐单药*(10mg/kg,q2w),folfox-4+贝伐(10mg/kg,q2w),pd,pd,pd,主要终点:生存时间次要终点:orr,*armstoppedtoenrolment.pi=b.giantonio.,randomization,rr,9.2%,21.8%,无进展生存,probabilityofbeingprogression-free,1.00.20,progression-freesurvival(months),02468101214161820,cens,fail,median,total,273,228,45,7.2,273,241,32,4.8,229,215,14,2.7,a:folfox4+avastin,b:folfox4,c:avastin,hr=0.64avsb:p10,000,chowlq,etal.jclinoncol.2007;25:884-896.,pdgfr-apdgfr-bcsf1rkitflt3,有效抑制vegfr,pdgfr,kit和flt3这些靶点肿瘤增殖和血管生成gist,肾细胞癌等,inarecentstudywithsunitinib,mttpwasonly2.2and2.5monthsrespectivelyinthepriorbevacizumabandbevacizumab-navecohortsandostimewas7.1monthsand10.2monthsrespectivelyab1.inbondtrial,cetuximabmonotherapyprovidedtheheavilytreatedpatientswithamttpof1.5months,阿帕替尼,全新的分子靶向药物恒瑞公司研制开发针对vegfr-2比ptk-787的结合能力强14倍对c-kit也有抑制作用,vegf家族及其受体,ellis.horizonsincancertherapeutics.2004;5(2):4-10,twomonthslater,治疗前,二个周期后,monotherapywithapatinibincrc,32casesofheavytreatedcr