贝伐在卵巢癌研究.ppt

Avastininovariancancer:clinicaltrialsAvastin在卵巢癌的相关研究在卵巢癌的相关研究复发卵巢癌的II期临床试验lBurgerRA,etal.JClinOncol2007lCannistraSA,etal.JClinOncol2007lGarciaAA,etal.JClinOncol2008初治卵巢癌的II期临床试验lMichaetal.IntJGynecolCancer2007lPensonetal,JClinOncol2010初治卵巢癌的III期临床试验lGOG-0218,ASCO2010lICON7/OVAR11,IGCS&ESMO2010进行中/完成的临床试验lOCEANS(铂类敏感)lAURELIA(铂类耐药)lGOG-0213(铂类敏感)GOG170D:Avastin单药治疗卵巢癌复发的单药治疗卵巢癌复发的II期临床试验期临床试验试验设计试验设计l主要研究终点:6-monthPFS和ORRl次要研究终点:安全性,OS,PFSl第三研究终点:可能影响PFS的因素*12priorcytotoxicregimens(firstplatinum-based,withasecondplatinum-basedregimenifplatinum-freeinterval12months)Burger,etal.JCO2007PD既往治疗后进展卵巢癌既往治疗后进展卵巢癌*(n=62)Avastin 15mg/kg every 3 weeksGOG170D:Avastin单药治疗卵巢癌复发的单药治疗卵巢癌复发的II期临床试验期临床试验特性特性Characteristic(n=62)FIGOstage(%)IIB2IIIA2IIIB8IIIC77IV11Primarysite(%)EOC84PPC16No.ofpriorregimens(%)134266No.ofplatinumregimens(%)168232Platinum-freeinterval6monthsGOG170D:Avastin单药治疗卵巢癌复发的单药治疗卵巢癌复发的II期临床试验期临床试验安全性安全性无胃肠道穿孔,瘘以及动脉栓塞发生无2级的出血事件发生GI=gastrointestinal;ATE=arterialthromboembolicevents;VTE=venousthromboemboliceventsBurger,etal.JCO2007没有发现新发或预期以外的毒性发生，没有发现新发或预期以外的毒性发生，3/4 不良事件的发生率与其他肿瘤类型一致不良事件的发生率与其他肿瘤类型一致高血压静脉血栓蛋白尿恶心呕吐肠梗阻便秘脱水过敏肺部疾病肾脏泌尿系统疾病体质改变凝血肝损疼痛其他出血Patients(%)1210864203级4级最常见的最常见的1/2级不良事件级不良事件 为疼痛，为疼痛，体质改变，肝损，体质改变，肝损，贫血，蛋白尿和生殖泌尿贫血，蛋白尿和生殖泌尿系统疾病系统疾病GOG170D:Avastin单药治疗卵巢癌复发的单药治疗卵巢癌复发的II期临床试验期临床试验总结总结l根据缓解率以及中位PFS的结果,Avastin确保了未来卵巢癌复发治疗的相关研究lAvastin15mg/kgq3w对于既往接受过12次化疗方案的卵巢癌患者耐受性良好l副反应都在预料之中，且大多比较轻微，容易控制l许多患者接受了30个周期的治疗l基于此次试验的结果，GOG开展了一项Avastin联合化疗的空白对照III期临床试验(GOG-0218)Burger,etal.JCO2007Avastin联合治疗铂类敏感联合治疗铂类敏感/耐药卵巢癌的耐药卵巢癌的II期临床试验期临床试验nPrior regimensPlatinum sensitivePlatinum resistantStudy therapyOR(%)Median PFS(months)Median OS(months)Single-agent AvastinBurger20071622Avastin214.717Cannistra200724423Avastin164.4Smerdel2009338Median5Avastin305.98.6Avastin-based combination regimensGarcia20084703Avastin+cyclophosphamide247.2(TTP)16.9McGonigle20085222Avastin+topotecan22Kikuchi20096221Avastin+PLD36NRNRMuggia20097213Avastin+PLDNimeiri20088132Avastin+erlotinib154.111Representative historical trialsPlatinum-sensitive91112Platinumpaclitaxel,gemcitabineorPLD31475.813.017.329.0Platinum-resistant121412Topotecan,gemcitabineorPLD6293.14.69.513.51.Burger,etal.JCO2007;2.Cannistra,etal.JCO2007;3.Smerdal,etal.ESMO2009;4.Garcia,etal.JCO20085.McGonigle,etal.ASCO2008;6.Kikuchi,etal.ASCO2009;7.Muggia,etal.ASCO2009;8.Nimeiri,etal.GynecolOncol20089.Parmar,etal.Lancet2003;10.Pfisterer,etal.JCO2006;11.Pujade-Lauraine,etal.ASCO2009;12.Mutch,etal.JCO200713.Ferrandina,etal.JCO2007;14.Gordon,etal.JCO2001CP=carboplatin/paclitaxel;PLD=pegylatedliposomaldoxorubicin;NR=notreported;NRe=notreachedAvastin+CPAvastin维持一线治疗卵巢癌的维持一线治疗卵巢癌的II期临床试验期临床试验试验设试验设计计l主要研究终点:毒性,RR和PFS*Eligiblepatientshadepithelialovarian,primaryperitoneal,fallopiantubeorpapillaryserousm lleriancarcinomaAvastinwasnotadministeredwiththefirstcycleofcarboplatin/paclitaxelPenson,etal.JCO2010新诊断的新诊断的 IC期卵巢癌期卵巢癌*(n=62)Carboplatin(AUC 5)/paclitaxel 175mg/m2q3w x68+Avastin 15mg/kg q3wAvastin 15mg/kg q3wfor 12 monthsAvastin+CPAvastin维持一线治疗卵巢癌的维持一线治疗卵巢癌的II期临床试验期临床试验特性特性Characteristic(n=62)Medianage,years(range)58(1877)Performancestatus(%)168232FIGOstage(%)Early10III69IV21Primarysite(%)Ovary73Primaryperitoneal16Fallopiantube8Uterinepapillaryserous5Cytoreduction(%)Optimal79Suboptimal21Penson,etal.JCO2010Avastin+CPAvastin维持一线治疗卵巢癌的维持一线治疗卵巢癌的II期临床试验期临床试验疗效总结疗效总结Efficacy data(n=62)ORR(RECIST),%(95%CI)75(6285)Completeresponse23(1336)Partialresponse52(3865)Stabledisease(RECIST),%(95%CI)25(1537)Median PFS,months(95%CI)29.8(17.3NR)MedianOS(months)NREfficacy compares favourably to data for carboplatin/paclitaxel in this settingNR=notreachedDatafortheprimaryefficacyendpointsareshowninboldPenson,etal.JCO2010Avastin+CPAvastin维持一线治疗卵巢癌的维持一线治疗卵巢癌的II期临床试验期临床试验化疗的安全性化疗的安全性3/4级不良事件的种类和发生率与已知的级不良事件的种类和发生率与已知的Avastin和和CP的相关耐受分析相一致的相关耐受分析相一致中性粒细胞减少代谢疾病高血压血小板减少神经病变过敏反应*肌肉骨骼疼痛血栓栓塞贫血呕吐胃肠道穿孔肝功能异常中性粒细胞减少性发热Patients(%)16141210864203级4级*AllallergicreactionsweretopaclitaxelPenson,etal.JCO2010Avastin+CPAvastin维持一线治疗卵巢癌的维持一线治疗卵巢癌的II期临床试验期临床试验与单药治疗安全性一致与单药治疗安全性一致Avastin 维持治疗耐受性良好维持治疗耐受性良好高血压高血压肌肉骨骼疼痛肌肉骨骼疼痛血血小板减少小板减少蛋白尿蛋白尿代谢疾病代谢疾病中性粒细胞减少中性粒细胞减少6543210发声困难发声困难Penson,etal.JCO2010Patients(%)Patients(%)3级4级Avastin运用于卵巢癌中胃肠道穿孔的发生率运用于卵巢癌中胃肠道穿孔的发生率StudyPrior regimens,median(range)Events,n(%)Micha,etal.200/20(0)Penson,etal.301/62(1.6)Burger,etal.(GOG-170D)42(12)0/62(0)Muggia,etal.52(NA)0/24(0)Kikuchi,etal.6NA(1)1/22(4.6)Garcia,etal.72(13)4/70(5.7)Nimeiri,etal.82(13)2/13(15.4)Cannistra,etal.92(23)5/44(11.4)Bidus,etal.10NA(36)0/3(0)Wright,etal.115(NA)4/62(6.5)Smerdel,etal.125(NA)2/38(5.3)Monk,etal.135(210)1/32(3.1)Wright,etal.147(215)2/23(8.7)Total22/475(4.6)NA=notavailable1.Han,etal.GynecolOncol2007;2.Micha,etal.IntJGynecolCancer2007;3.Penson,etal.JCO20104.Burger,etal.JCO2005;5.Muggia,etal.ASCO2009;6.Kikuchi,etal.ASCO2009;7.Garcia,etal.JCO20088.Nimeiri,etal.GynecolOncol2008;9.Cannistra,etal.JCO2006;10.Bidus,etal.GynecolOncol2006;11.Wright,etal.JCO200612.Smerdel,etal.ECCO-ESMO2009;13.Monk,etal.GynecolOncol2006;14.Wright,etal.Cancer2006分析结果提示既往多次治疗后的卵巢癌患者使用分析结果提示既往多次治疗后的卵巢癌患者使用Avastin后胃肠道穿孔的发生率增加后胃肠道穿孔的发生率增加 1Avastin运用于卵巢癌运用于卵巢癌:可能增加胃肠道穿孔风险的因素可能增加胃肠道穿孔风险的因素l卵巢癌中的肠道问题相对比较常见l数据显示既往多次化疗以及肠壁增厚或梗阻可能会增加胃肠道穿孔的风险1l卵巢癌多次化疗后接受Avastin治疗引起潜在胃肠道穿孔风险增高的原因可能是2：l卵巢癌细胞侵犯肠道浆膜引起坏死以及潜在的穿孔l卵巢癌患者往往发生腹腔扩散，肠梗阻风险仅次于肠道肿瘤以及术后肠粘连lAvastin可以通过栓塞或血管收缩限制血液流向内脏血管，因此可能导致肠梗阻和肠穿孔l卵巢癌患者发生胃肠道穿孔的明确原因尚未确定1.Cannistra,etal.JCO2007;2.Simpkins,etal.GynecolOncol2007近期关于既往多次化疗后的卵巢癌患者不建议使用近期关于既往多次化疗后的卵巢癌患者不建议使用Avastin为基础的治疗为基础的治疗Avastin运用于卵巢癌运用于卵巢癌:胃肠道穿孔总结胃肠道穿孔总结Avastin联合化疗(n=68)较单用化疗(n=195)相比，胃肠道穿孔和/或胃肠道瘘发生的风险并没有增加(RR=1.09)11.Sfakianos,etal.GynecolOncol2009卵巢癌中三个关键的卵巢癌中三个关键的III期临床研究期临床研究一线晚期卵巢癌一线卵巢癌复发铂类敏感卵巢癌GOG-0218:随机双盲随机双盲III期研究期研究lStratificationvariableslGOGperformancestatuslstage/debulkingstatusBevacizumab15mg/kgq3w15monthsPaclitaxel(P)175mg/m2Carboplatin(C)AUC6Carboplatin(C)AUC6Paclitaxel(P)175mg/m2Carboplatin(C)AUC6Paclitaxel(P)175mg/m2Placeboq3wPlaceboq3wFront-line:epithelialOV,PPorFTcancerStageIIIoptimal(macroscopic)StageIIIsuboptimalStageIVN=1,873IIIIIIArm1:1:1Burger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;365(26):2473-83.OV=ovarian;PP=primaryperitonealFT=fallopiantube;Bev=bevacizumabBev15mg/kgRANDOMISEGOG-0218:主要入组条件主要入组条件Burger,etal.NEJM2011l病理诊断明确为EOV,PP,orFTcancerl最大减瘤术后:stageIIIoptimal(肉眼残余肿瘤1cm)orsuboptimal(1cm),orstageIVl既往未化疗l术后112周lGOGPS02l既往无明显血管事件l既往无需要肠外营养支持的肠梗阻l签署知情同意书入组条件改变入组条件改变Burger,etal.NEJM2011Stuart,etal.IntJGynecolCancer2011l最初入组条件:只接受次优化减瘤术后患者(1cm)l修改后入组条件:接受优化减瘤术后患者入组(1cm)l需要注意的是，根据2010GCIG共识，研究中入组的所有患者接受的只是次优化减瘤术l因此患者群预后较差统计分析统计分析Burger,etal.NEJM2011Primaryanalysis:lComparisonofPFS(investigator-assessed)ineachbevacizumabarmvscontroll疾病进展决定于RECISTorCA-125onlylPlannedsamplesizeof1800basedon:l90%powertodetectaPFShazardratio(HR)0.77Secondaryanalyses:lOverallsurvival(OS),safety,qualityoflifeandcorrelativelaboratorystudieslPrimaryendpointchangedfromOStoPFS;unblindingtotreatmentassignmentallowedattimeofprogressionGOG-0218:三组基线水平平三组基线水平平衡衡Characteristic,%Arm I CP+Pl(n=625)Arm II CP+B15 Pl (n=625)Arm III CP+B15 B15(n=623)Ageinyears,median(range)60(2586)60(2488)60(2289)GOGPS0/1/2,%50/44/750/43/649/43/8Stage/residualsize%IIIoptimal(macroscopic)IIIsuboptimalIV354125334126353927Histology%SerousEndometrioidClearcellMucinous873218424184431Tumourgrade,%1/2/3*Notspecified/pending5/15/66144/12/70143/15/6914*Grade3includesallclearcelltumoursPercentagesmaynottotal100%duetoroundingorcategorisationBurger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;365(26):2473-83.2323*OnepatientineachgroupreceivedBev/placeboincycle1Percentagesmaynottotal100%duetoroundingorcategorisationCharacteristicArm ICP+Pl(n=625)Arm IICP+Bev Pl(n=625)Arm IIICP+B15 B15(n=623)Median(range)numberBev/placebocycles11(022*)12(022*)14(021)Ontreatmentattimeofanalysis,n(%)86(14)82(13)117(19)Completedregimen,n(%)100(16)104(17)148(24)Discontinuedstudytreatment,n(%)Diseaseprogression299(48)264(42)164(26)Adverseevents69(11)86(14)94(15)Cycles1657(9)73(12)59(9)Cycle712(2)13(2)35(6)Deaths8(1)7(1)13(2)Patientrefusal44(7)55(9)50(8)Other19(3)27(4)37(6)GOG-0218:因疾病进展而中断治因疾病进展而中断治疗的患者疗的患者在单接受化疗组更多在单接受化疗组更多Burger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;365(26):2473-83.GOG-0218:持续持续bevacizumab治疗较标准化化疗明显延长治疗较标准化化疗明显延长PFSAvastin Summary of Product CharacteristicsRoche,dataonfile0612182430364248Time(months)1.00.80.60.40.20PFS estimateICP+Pl Pl(n=625)Median PFS(months)10.6Stratified analysis HR(95%CI)p value one-sided(log rank)IICP+Bev Pl(n=625)11.60.89(0.781.02)0.0437aIII CP+Bev Bev(n=623)14.70.70(0.610.81)2x CA-125 2x 正常上限正常上限随机化随机化ProportionalivewhohavenotstartedfurtherchemotherapyTimesincerandomisation(months)Median(months)Early,basedonCA125levels2xULN0.8Delayed,basedonclinicalfeatures5.6HR=0.29(95%CI:0.240.35),p2xULN25.7Delayed,basedonclinicalfeatures27.1HR=0.98(95%CI:0.801.20),p=0.85GOG-0218:CA-125截尾数据截尾数据分析显示继续使用分析显示继续使用bevacizumab较化疗相比明显延长患者较化疗相比明显延长患者PFS06121824303642481.00.80.60.40.20*pvalueboundary=0.0116Timesincerandomisation(months)PFSestimateCP+B15B15CP+PlICP+Pl Pl(n=625)IIICP+B15 B15(n=623)Median PFS(months)12.018.2Stratified analysis HR(95%CI)0.62(0.520.75)p value one-sided(log rank)1cm Arm II vs Arm I Arm III vs Arm I 510 4960.9810.763 IV Arm II vs Arm I Arm III vs Arm I 317 3180.9230.698Histologic type Serous Arm II vs Arm I Arm III vs Arm I 1,0661,0680.9130.701 Nonserous Arm II vs Arm I Arm III vs Arm I 184 1800.8930.713Tumour grade 1 or 2 Arm II vs Arm I Arm III vs Arm I 232 2351.0390.578 3 Arm II vs Arm I Arm III vs Arm I 847 8420.8910.7000.330.500.671.001.502.003.00AvastinbetterControlbetterBurger,etal.NEJM2011GOG-0218:subgroupanalysesofPFS(contd)Risk factorTotal no.of patientsHazard ratio for Avastin(95%CI)GOG performance status score 0 Arm II vs Arm I Arm III vs Arm I 6266160.8770.710 1 or 2 Arm II vs Arm I Arm III vs Arm I 6246320.9610.690Age 60 years Arm II vs Arm I Arm III vs Arm I 6166300.9760.680 6069 years Arm II vs Arm I Arm III vs Arm I 4144080.8920.763 70 years Arm II vs Arm I Arm III vs Arm I 2202100.8410.6780.330.500.671.001.502.003.00AvastinbetterControlbetterDatainpurplerepresentcomparisonofarmIIvsarmIDataingreyrepresentcomparisonofarmIIIvsarmIAvastinSummaryofProductCharacteristicsGOG-0218:independentreviewconfirmsthePFSbenefitIRC-assessed PFS analysisInvestigator-assessed censored PFS analysisCP+Pl Pl(n=625)CP+Av15 Av15(n=623)CP+Pl Pl(n=625)CP+Av15 Av15(n=623)Median(months)13.119.11218.2PFS,months6.06.2Hazardratio,stratified(95%CI)0.62(0.500.77)0.62(0.520.75)RochedataonfileGOG-0218:finalOSresultsCP+Pl(n=625)CP+Av15 Pl(n=625)CP+Av15 Av15(n=623)Deaths,n(%)299(47.8%)309(49.4%)270(43.3%)Medianoverallsurvival(months)40.638.843.8Hazardratio(95%CI)1.065(0.9081.249)0.879(0.7451.038)p0.21970.0641ATE=arterialthromboembolicevent;VTE=venousthromboemboliceventRPLS=reversibleposteriorleucoencephalopathysyndrome;aPerforation/fistula/necrosis/leakBurgeretal.NEJM2011治疗第二个周期至治疗结束后治疗第二个周期至治疗结束后30天内的不良事件天内的不良事件100806040200Patients(%)GIevents(grade2)Hypertension(grade2)Proteinuria(grade3)Pain(grade2)Neutropenia(grade4)VTE(allgrades)ATE(allgrades)WoundhealingcomplicationsCNSbleeding(allgrades)Non-CNAbleeding(grade3)RPLS(allgrades)ArmI(CP+PlPl;n=601)ArmII(CP+Av15Pl;n=607)ArmIII(CP+Av15Av15;n=608)P6monthsafterlastplatinumPlatinumresistant:recurring6monthsafterlastplatinumPatients with recurrencesGOG-0218:一线是否使用一线是否使用Avastin对于患者复发时铂类敏感情况对于患者复发时铂类敏感情况Avastin与化疗相比铂类敏感患者比例高20.1%InternalconfidentialdataQForm=StudyFollow-upForm;FUAT=Follow-UpAdditionalTreatmentsForm.RochedataonfileGOG-0218:后续治疗后续治疗CP+Pl Pl(n=625)CP+Av15 Pl(n=625)CP+Av15 Av15(n=623)Useofanynonprotocoltherapy(QForm)78%79%73%Chemotherapy74%74%70%Useofanyantiangiogenictreatments(FUAT)31%30%17%Avastin28%28%15%GOG-0218:总结总结lGOG-0218肯定了bevacizumab用于晚期卵巢癌一线治疗时具有延长PFS的作用lCP+bevacizumabbevacizumab单药15mg/kg持续使用15个月(ArmIII)后患者PFS统计学上明显优于单用CP(ArmI)l不良反应通常都是可控制的，安全性结果与bevacizumab运用于其他类型肿瘤的试验结果相似lCP+bevacizumabbevacizumab单药15mg/kg持续使用15个月应该作为晚期卵巢癌一线治疗的标准方案RANDOMISEICON7:一项随机开放的一项随机开放的III期临床试验期临床试验l变量分层:l疾病分期以及减瘤术范围:IIII期残余病灶1cmvsIIII期残余病灶1cmvsIV期以及不可切除的III期病灶l术后治疗开始时间:vs术后4周lGCIGgroup(*alsochoiceofAUCdose5AGO,NSGO,GINECOor6)Paclitaxel175mg/m2CarboplatinAUC5or6*CarboplatinAUC5or6*Paclitaxel175mg/m21:1StageIIIa(grade3orclearcell)orStageIIbIV(allgrades/histologictypes)SurgicallydebulkedhistologicallyconfirmedOC,PP,FTC(n=1,528)Bevacizumab7.5mg/kgq3w12monthsControlTreatment(CP+BB7.5)Perren,etal.NEnglJMed.2011Dec29;365(26):2484-96.ICON7:入组患者必须接受最大减瘤术后入组患者必须接受最大减瘤术后l病理证实为卵巢上皮癌，原发性腹膜癌或者输卵管癌l患者接受最大减瘤术后并且疾病进展前无进一步外科切除计划lFIGO分期lIIIA高风险:3级或透明细胞型(10%)lIIBIV:任何分级和组织类型l活检明确的无手术计划的不可手术切除III/IV期患者lECOGPS02Perren,etal.NEnglJMed.2011Dec29;365(26):2484-96ICON7:研究终点研究终点根据根据RECIST评估评估PFSl主要研究终点:PFSl疾病进展根据RECIST评估标准lCA-125单独升高不作为疾病进展的依据l1,528patientsrandomisedover2years(684events)5%significancelevel,90%powertodetect:lPFSHRof0.78lincreaseofmedianPFSfrom18to23monthsl次要研究终点:OS(due2013),biologicPFS，responsetotherapy,toxicity,QolPerren,etal.ESMO2010CharacteristicCP(n=764)CP+B7.5 B7.5(n=764)Medianage(range)57(1881)57(2482)ECOGPS,n(%)012358(47)354(47)43(6)334(45)366(49)45(6)Originofcancer,n(%)OvaryFallopiantubePrimaryperitonealMultiplesites667(87)29(4)56(7)12(2)673(88)27(4)50(6)14(2)HistologySerousClearcellEndometrioidMucinousMixed/other529(69)60(8)57(7)15(2)103(13)525(69)67(9)60(8)19(2)93(12)Grade,n(%)123Unknown56(7)142(19)556(74)1041(5)175(23)538(71)10ICON7:特征基线水平平衡特征基线水平平衡Perren,etal.ESMO2010Characteristic,n(%)CP(n=764)CP+B7.5 B7.5(n=764)FIGOstage,n(%)I/IIAIIBIIIBIIIC/IV75(10)160(21)529(69)67(9)155(20)542(71)Debulkingsurgeryresidualtumor1cmresidualtumor1cmNosurgery552(74)195(26)17(2)559(74)192(26)13(2)FIGOstageandresiduum*StageIIII(1cm)StageIIII(1cm)StageIII(inoperable)/IV508(66)150(20)106(14)518(68)140(18)106(14)Intenttostartchemotherapy*4weeksfromsurgery4weeksfromsurgery328(43)436(57)326(43)438(57)*StratificationvariableICON7:特征基线水平平衡特征基线水平平衡Perren,etal.ESMO201017.319.0CPCP+B7.5B7.5ICON7:连续使用连续使用bevacizumab较单用基础化疗相比显较单用基础化疗相比显著提高著提高PFSNumberatriskCP764723693556464307216143915025CP+B7.5764748715647585399263144733619036912151821242730Time(months)Proportionalivewithoutprogression1.000.750.500.250CPCP+B7.5 B7.5 Events,n(%)392(51)367(48)Median,months17.319.0Log-rank testp=0.0041HR(95%CI)0.81(0.700.94)Perren,etal.ESMO2010ICON7:连续使用连续使用bevacizumab较单用基础化疗相比显著较单用基础化疗相比显著提高提高PFSupdatedanalysisKristensen,etal.ASCO2011CPCP+B7.5B7.5ProportionalivewithoutprogressionNumberatriskCP7646934743502211143950CP+B7.57647165994302291072710CPCP+B7.5Events,n(%)464(61)470(62)Median,months17.419.8Log-rank testp=0.039HR(95%CI)0.87(0.770.99)1.00.80.60.40.20Time(months)06121824303642480.20.100.10.2Treatmentdifference(researchcontrol)Time(months)KMdifferenceSmootheddifference036912151821242730MonthsPFS treatment difference(PFS estimate:control/research)63.7%(92.1/95.8)1215.1%(64.6/79.7)187.6%(47.3/54.9)242.5%(39.8/37.3)Perren,etal.NEJM2011AbsolutedifferenceinPFSCPCP+Av7.5 Av7.5Restrictedmeanestimatedat36months(months)20.321.8Difference(95%CI)1.5(0.22.9)15.1%ICON7:在所有患者亚组中，连续的在所有患者亚组中，连续的bevacizumab治疗治疗都可以提供都可以提供PFS获益获益CP+B7.5B7.5betterCPbetterPerren,etal.ESMO2010ICON7:高风险亚组的高风险亚组的PFS分析分析Num