肾癌靶向治疗_省肿瘤大会--吴晓安

肾癌分子靶向药物治疗进展,解放军第一七四医院吴晓安,肾癌的药物治疗发展史上的重大事件,1.SnowM,etal.Urology1982;20:177.2.RiniBI,etal.Lancet2009;373:1119-1132.,靶向治疗时代,细胞因子时代,LAK、CIK、DC,过继免疫治疗,2010-11-23,杨姓女患者,46岁,2008-3-27外院手术切除右肾,病理为右肾乳头状细胞癌,20096-9腹腔肿物切除,2009-9-10超声示肝尾状叶占6.45.5cm占位.2010-10-9在外院行生物化疗(CF+5FU,干扰素900万U,每周3次至2010-11-5结束),2010-11-23,2010-11-23,2010-11-28,2010-11-28,FDA批准用于mRCC的药物,靶向药物抑制正常细胞生长和肿瘤涉及的多重信号传导通路,RiniBIandSmallEJ.JClinOncol2005;23:10281043,adaptedwithpermission;DuensingAetal.CancerInvest2004;22:106116;MarmorMDetal.IntJRadOncolBiolPhys2004;58:903913.Pleaseseefullprescribinginformation.,肿瘤细胞膜,VEGFR,P13K,AKT,mTOR,VEGFR,Raf,Mek,Ras,Erk,肿瘤血管内皮细胞基膜,PDGFR,KIT,PDGFR,内皮细胞,VEGF-A,VEGFR=血管内皮生长因子受体;PDGFR=血小板衍生生长因子受体;KIT=干细胞因子受体,细胞核,转录因子,细胞黏附,细胞生存,细胞增殖,细胞凋亡,细胞分化,新生血管形成,舒尼替尼,舒尼替尼,贝伐单抗,替西罗莫司依维莫司,索拉非尼,索拉非尼,晚期肾癌的一线治疗,*1类证据.需选择患者.,一线治疗(透明细胞为主型)?,NCCN指南-晚期肾癌的治疗策略,IV期(转移性),减瘤性肾切除术（若不能手术，则一线治疗）,舒尼替尼,索坦较干扰素显著延长PFS,Szczylik,etal.ASCO2007Abstract5025.MotzerRJ,etal.JClinOncol2009;27:3584-3590.,进展风险46%,索坦一线治疗较IFN-显著降低死亡风险达18%全组人群,MotzerRJ,etal.JClinOncol2009;27:3584-3590.,晚期RCC：目前唯一突破2年OS的治疗,TotalDeathSunitinib190IFN-a200,最终总生存期（OS）,MotzerRJ,etal.JClinOncol2009,索坦一线治疗较IFN-显著降低死亡风险达35%,MotzerRJ,etal.JClinOncol2009;27:3584-3590.,35%,(排除未接受后续治疗患者),未接受后续治疗的患者的OS分析（提出后续治疗因素）,MotzerRJ,etal.JClinOncol2009,同一对照药物IFN-，不同靶向药物的ORR不同,B=贝伐单抗；SOR=索拉非尼；SUN=索坦,1.EscudierB,etal.JClinOncol2009;27(15S):Abs.5020.2.RiniB,etal.JClinOncol2009;27(15S):LBA5019.3.EscudierB,etal.JClinOncol2009;27:1280-1289.4.MotzerRJ,etal.JClinOncol2009;27:3584-3590.,同一对照药物IFN-，不同靶向药物的PFS不同,B=贝伐单抗；SOR=索拉非尼SUN=索坦；PAZ=帕唑帕尼,*P0.05其余各组间差异都达到了统计学显著性差异,1.EscudierB,etal.JClinOncol2009;27(15S):Abs.5020.2.RiniB,etal.JClinOncol2009;27(15S):LBA5019.3.EscudierB,etal.JClinOncol2009;27:1280-1289.4.MotzerRJ,etal.JClinOncol2009;27:3584-3590.5.StembergCN,etal.JClinOncol2010;28:1061-1068.,同一对照药物IFN-，不同靶向药物的OS不同,1.EscudierB,etal.JClinOncol2009;27(15S):Abs.5020.2.RiniB,etal.JClinOncol2009;27(15S):LBA5019.3.MotzerRJ,etal.JClinOncol2009;27:3584-3590.,B=贝伐单抗；SUN=索坦；*P0.05,索坦是迄今首个证实单药治疗mRCC患者总生存期可超过2年的靶向药物,Sunitinib较IFN-显著改善患者生活质量,CellaD,etal.JClinOncol2008;27:3763-69,31.030.530.029.529.028.528.027.527.026.5,Sunitinib(Slope=0.140;P=0.003),IFN-(Slope=0.041;P=0.567),EstimatedmeanFKSI-DRSscore,1234567891011,Time(months),患者自觉症状改善Sunitinib显著优于IFN-,FKSI-DRS（生活质量主要研究终点）,FACT-G量表、EQ-5D指数、EQ-VAS评分和FKSI-15评分在两组间的差异均表明Suntinib治疗有利(P1.5xULNHb10mg/dL全身治疗距诊断时间1年KPS602处脏器转移(N=626),替西罗莫斯25mgIVweekly(n=209),IFN-逐渐增量至18MUSCTIW(n=207),替西罗莫斯15mgIVweekly+IFN-6MUSCTIW(n=210),HudesG,etal.NEnglJMed.2007;356:2271-2281.,HudesG,etal.NEnglJMed.2007;356:2271-2281.,OS*,PFS*,*Kaplan-Meierestimates.,替西罗莫斯vsIFN-OS，PFS,ProbabilityofSurvival,Months,0.00,0.25,0.50,0.75,1.00,0,5,10,15,20,25,30,Interferon,替西罗莫斯,Combination,ProbabilityofPFS,Months,0.00,0.25,0.50,0.75,1.00,0,5,10,15,20,25,30,Interferon,替西罗莫斯,Combination,贝伐单抗,AVOREN:贝伐单抗+IFN-vsIFN-（III期试验）,终点主要：OS次要：PFS,TTP,TTF,复发率,安全性,IFN-+Bevacizumab10mg/kgIVQ2W直至进展(n=327),IFN-9MUSCTIW(Max52weeks;允许减量)+安慰剂(n=322),入选标准肾癌切除术后的晚期患者分层国家MSKCCriskgroup(N=649),1:1,EscudierB,etal.Lancet.2007;370:2103-2111.,AVOREN中的PFS（根据MSKCC危险因素分层）,RiskfactorsassociatedwithshortersurvivalarelowHb,highcorrectedcalcium,highLDH,poorperformancestatus,andanintervalof1yrfromdiagnosistotreatment.*MotzerR,etal.JClinOncol.2002;20:289-296.,Pazopanib（VS安慰剂-III期临床）,研究设计,Pazopanib800mgqd(n=290),MatchingPlacebo(n=145),Optiontoreceivepazopanibviaanopen-labelstudyatprogression.,StratificationECOGPS0vs1PriornephrectomyRx-naive(n=233)vs1cytokinefailure(n=202),PatientswithadvancedRCC(N=435),Randomization2:1,Pazopanibvs安慰剂-总体人群PFS,1.0,0.0,0.2,0.4,0.6,0.8,0,5,10,15,20,Months,ProportionProgression-Free,PatientsatriskPazopanib29015976296Placebo14538142,HazardRatio=0.4695%CI(0.34,0.62)Pvalue0.0000001MedianPFSPazopanib:9.2moPlacebo:4.2mo,PazopanibPlacebo,1.0,0.0,0.2,0.4,0.6,0.8,0,5,10,15,20,Months,ProportionProgression-Free,PatientsatriskPazopanib1553439111Placebo782272,HazardRatio=0.4095%CI(0.27,0.60)Pvalue0.0000001MedianPFSPazopanib:11.1moPlacebo:2.8mo,PazopanibPlacebo,Pazopanibvs安慰剂-初治患者PFS,1.0,0.0,0.2,0.4,0.6,0.8,0,5,10,15,20,Months,ProportionProgression-Free,PatientsatriskPazopanib1357537185Placebo67167,HazardRatio=0.5495%CI(0.35,0.84)Pvalue0.001MedianPFSPazopanib:7.4moPlacebo:4.2mo,PazopanibPlacebo,Pazopanibvs安慰剂-细胞因子失败的PFS,总体人群的OS（初步结果）,OBrien-Flemingboundaryforfutility/superiority:P=0.201/0.004(1-sided),1.0,0.0,0.2,0.4,0.6,0.8,0,5,10,15,20,Months,ProportionSurviving,PatientsatriskPazopanib290254214115201PlacebHazardRatio=0.7395%CI(0.47,1.12)Pvalue=0.02(1-sided)MedianOSPazopanib:21.1moPlacebo:18.7mo,PazopanibPlacebo,25,48%ofplacebopatientsreceivedpazopanibafterPD,一线治疗小结,*Independentcentralreview.,转移性肾癌一线治疗的临床试验,一线方案中的PFS（根据危险因素分层）,1.MotzerRJ,etal.NEnglJMed.2007;356:115-124.2.SzczylikC,etal.ASCO2007.Abstract5025.3.HudesG,etal.NEnglJMed.2007;356:2271-2281.4.EscudierB,etal.Lancet.2007;370:2103-2111.5.RiniBI,etal.ASCOGU2008.Abstract350.,一线治疗MRCC的临床试验（已有的和进行中的）,1.MotzerRJ,etal.NEnglJMed.2007;356:115-124.2.SzczylikC,etal.ASCO2007.Abstract5025.3.EscudierB,etal.Lancet.2007;370:2103-2111.4.HudesG,etal.NEnglJMed.2007;356:2271-2281.5.ClinicalT.NCT00631371.6.ClinicalT.NCT00719264.7.ClinicalT.NCT00720941.8.ClinicalT.NCT00378703.,晚期肾癌-一线治疗,1类证据推荐：索坦Temsirolimus（高危）Bevacizumab+IFNPazopanib（新增）2A类证据推荐：HighdoseIL-2索拉菲尼,首选推荐,晚期肾癌的二线治疗,索拉非尼,细胞因子治疗失败后（TARGET试验）索拉非尼vs细胞因子（III期试验）,随机，双盲，多中心治疗终点：PD或毒性过大主要终点:OS次要终点:PFS,Placebo(n=452),Sorafenib400mgBID(n=451),入选标准透明细胞型既往接受过细胞因子治疗MSKCC预测分值(中低)(N=903),EscudierB,etal.NEnglJMed.2007;356:125-134.,20,ProbabilityofPFS(%),0,25,50,75,100,TimeFromRandomization(Mos),0,4,10,2,6,8,12,14,16,*Investigatorassessment.,EscudierB,etal.NEnglJMed.2007;356:125-134.,索拉非尼治疗细胞因子失败-PFS,Sorafenib(n=451)Placebo(n=452)HR(S/P)Censoredobservation,MedianPFS,*Mos5.502.800.44,BukowskiRM,etal.ASCO2007.Abstract5023.,TARGET试验初次OS分析:（未考虑交叉治疗）,TARGET试验调整OS分析：（去除交叉治疗的因素）,100,75,50,25,0,20,24,28,32,36,16,0,4,8,12,Sorafenib:17.8mos,Placebo:15.2mos,HR(sorafenib/placebo):0.88,95%CI:0.74-104,P=.146*,OS(%),TimeFromRandomization(Mos),Sorafenib:17.8mos,Placebo:14.3mos,HR(sorafenib/placebo):0.78,95%CI:0.62-0.97,P=.0287,索拉非尼治疗细胞因子失败-OS,两组平均治疗时间Placeboexposure:12.0wksSorafenibexposure:40.1wks,561events.*Nonsignificant;OBrien-Flemingthresholdforstatisticalsignificance:=0.037,40,100,75,50,25,0,20,24,28,32,36,16,0,4,8,12,OS(%),TimeFromRandomization(Mos),40,CensoredatJune30,2005,approxstartofcrossover.Statisticallysignificant;OBrien-Flemingthresholdforstatisticalsignificance:=0.037,依维莫斯（RAD001,Everolimus）,应用VEGFR抑制剂后进展的患者EverolimusVS安慰剂（III期试验）,N=410（2006年9月2007年10月）第2次中期总结:2007年10月15日,191例患者无进展独立数据监测委员会建议终止试验,随机2:1,分层既往用过12种VEGFR抑制剂治疗MSKCCriskgroup好(29%)中(56%)差(15%)(N=410),Everolimus+BestSupportiveCare(n=272),Placebo+BestSupportiveCare(n=138),MotzerRJ,etal.Lancet.2008;372:449-456.,100,80,60,40,20,0,0,2,4,6,8,10,12,PFS(%),Months,Everolimusvs安慰剂-PFS,MotzerRJ,etal.Lancet.2008;372:449-456.,MedianPFSEverolimus(n=272):4.0mosPlacebo(n=138):1.9mosHR:0.3095%CI:0.22-0.40LogrankP.0001,MotzerRJ,etal.Lancet.2008;372:449-456.,Everolimusvs安慰剂（优势治疗人群）,CentralreviewInvestigatorreviewMSKCCriskFavorableIntermediatePoorPrevioustreatmentSorafenibonlySunitinibonlyBothAge65yrs65yrsSexMaleFemaleRegionUSandCanadaEuropeJapanandAustralia,HR,PValue,N,.0001.0001.0001.0001.009.0001.0001.0001.0001.0001.0001.002.0001.0001.001,0,Infavorofeverolimus,0.300.310.350.250.390.290.300.280.320.290.290.360.240.370.10,410410118231611191841072591513179313025129,Infavorofplacebo,0.2,0.4,0.6,0.8,1.0,1.2,1.4,舒尼替尼（贝伐单抗失败）,贝伐单抗失败的MRCC应用舒尼替尼(II期试验):最好疗效,*AssessedwithRECIST.,RiniBI,etal.JClinOncol.2008;26:3743-3748.,阿昔替尼,Axitinib（索拉非尼失败）,RiniB,etal.ASCO2007.Abstract5032.,索拉非尼失败的MRCCAxitinib的应用:最好疗效,*1/14patientswhohadprevioussorafenibandsunitinibtreatmenthadaPR.9/14patientswhohadprevioussorafenibandsunitinibtreatmenthadtumorshrinkage.,二线治疗小结,2009年肾透明细胞癌的治疗原则（国外推荐）,AdaptedfromAtkinsM,etal.ASCO2009andBukowskiR,etal.ASCO2009.Abstract5023.,晚期肾癌二线治疗的药物推荐变化,低剂量IL-2+IFN-被从二线治疗去掉,新增Pazopanib一类证据,新增RAD001(依维莫司)一类证据,MotzerRJ,etal.JClinOncol2006;24:16-24,MotzerRJ,etal.JUrol2007;178:1883-7,#主要终点,索坦用于细胞因子失败的二线治疗依然有效,ORR仍可达33%以上,晚期肾癌二线治疗索坦仍是选择,正在研发的新药,在研的治疗肾细胞癌的抗血管生成药物,VEGFRTKIsCediranibVandetanibPazopanibAxitinibDASTMotesanibTelatinibBrivanib,IntegrininhibitorsVolociximabVitaxinCNT-095CilengitideE7820ATN-161AMG-386(angiopoietin),VEGFtargetedBevacizumabAfliberceptPTC299INGN241VEGFRtargetedIMC-1121BCDP791OthersCP-868596(PDGFR),AngioceptABT-869OSI-930CEP-11981CHIR-258XL880XL820XL647,索坦一线治疗中国mRCC的多中心、单臂、开放、IV期临床研究中期分析,研究设计,开放、单臂、多中心(11家三甲医院)、IV期临床研究评价索坦一线治疗中国mRCC患者的疗效及安全性主要终点：无进展生存期(PFS)次要终点：客观缓解率(ORR)总生存期(OS),一年生存率安全性指标,入选标准,18岁ECOG0-1经病理组织学检查，确诊具有透明细胞成分的转移性肾细胞癌，且无法手术治疗转移性肾癌，一线治疗有可测量病灶血常规、肝肾功能、凝血功能等基本正常心脏超声：LVEF正常值低限(LLN)签署知情同意书,排除标准,无透明细胞成分的肾细胞癌既往接受针对转移性肾癌的治疗既往辅助治疗结束至入组的时间少于6m入组前4周内接受大手术或放疗中枢神经系统