贝伐在卵巢癌研究(同名434)课件

Avastininovariancancer:clinicaltrialsAvastininovariancancer:cliAvastin在卵巢癌的相关研究

复发卵巢癌的II期临床试验BurgerRA,etal.JClinOncol2007CannistraSA,etal.JClinOncol2007GarciaAA,etal.JClinOncol2008初治卵巢癌的II期临床试验Michaetal.IntJGynecolCancer2007Pensonetal,JClinOncol2010初治卵巢癌的III期临床试验GOG-0218,ASCO2010ICON7/OVAR11,IGCS&ESMO2010进行中/完成的临床试验OCEANS(铂类敏感)AURELIA(铂类耐药)GOG-0213(铂类敏感)Avastin在卵巢癌的相关研究复发卵巢癌的II期临床GOG170D:Avastin单药治疗卵巢癌复发的II期临床试验–试验设计主要研究终点:6-monthPFS和ORR次要研究终点:安全性,OS,PFS第三研究终点:可能影响PFS的因素*1–2priorcytotoxicregimens(firstplatinum-based,withasecondplatinum-basedregimen

ifplatinum-freeinterval≥12months)Burger,etal.JCO2007PD既往治疗后进展卵巢癌*(n=62)Avastin15mg/kg

every3weeksGOG170D:Avastin单药治疗卵巢癌复发的IIGOG170D:Avastin单药治疗卵巢癌复发的II期临床试验–特性Characteristic(n=62)FIGOstage(%)IIB2IIIA2IIIB8IIIC77IV11Primarysite(%)EOC84PPC16No.ofpriorregimens(%)134266No.ofplatinumregimens(%)168232Platinum-freeinterval<6months(%)58EOC=epithelialovariancancer;PPC=primaryperitonealcancer

Burger,etal.JCO2007GOG170D:Avastin单药治疗卵巢癌复发的IIGOG170D:Avastin单药治疗卵巢癌复发的II期临床试验–疗效总结EfficacydataAvastin(n=62)ORR*,%(90%CI)21(13–31)Completeresponse,%(n)3(2)Stabledisease*‡,%(n)52(32)6-monthPFS,%(90%CI)40(30–54)MedianPFS(months)4.7MedianOS(months)16.9DatafortheprimaryefficacyendpointsareshowninboldBurger,etal.JCO2007疗效似乎更支持其他的单药治疗方案*AssessedusingRECISTcriteria‡14of32patientswithstablediseasehadPFS>6monthsGOG170D:Avastin单药治疗卵巢癌复发的IIGOG170D:Avastin单药治疗卵巢癌复发的II期临床试验–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=venousthromboembolicevents

Burger,etal.JCO2007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1/2级不良事件

为疼痛，

体质改变，肝损，

贫血，蛋白尿和生殖泌尿系统疾病GOG170D:Avastin单药治疗卵巢癌复发的IIGOG170D:Avastin单药治疗卵巢癌复发的II期临床试验–总结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Avastin15mg/kgq3w对于既往接受过1~2次化疗方案的卵巢癌患者耐受性良好

副反应都在预料之中，且大多比较轻微，容易控制许多患者接受了>30个周期的治疗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.JCO2007GOG170D:Avastin单药治疗卵巢癌复发的IIAvastin联合治疗铂类敏感/耐药卵巢癌的II期临床试验nPriorregimensPlatinumsensitivePlatinumresistantStudytherapyOR(%)MedianPFS(months)MedianOS(months)Single-agentAvastinBurger2007162≤2Avastin214.717Cannistra20072442–3Avastin164.4Smerdel2009338Median5Avastin305.98.6Avastin-basedcombinationregimensGarcia2008470≤3Avastin+cyclophosphamide247.2(TTP)16.9McGonigle2008522≤2Avastin+topotecan22Kikuchi2009622>1Avastin+PLD36NRNRMuggia2009721≤3Avastin+PLDNimeiri2008813≤2Avastin+erlotinib154.111RepresentativehistoricaltrialsPlatinum-sensitive9–111–2Platinum±paclitaxel,gemcitabineorPLD31–475.8–13.017.3–29.0Platinum-resistant12–141–2Topotecan,gemcitabineorPLD6–293.1–4.69.5–13.51.Burger,etal.JCO2007;2.Cannistra,etal.JCO2007;3.Smerdal,etal.ESMO2009;4.Garcia,etal.JCO2008

5.McGonigle,etal.ASCO2008;6.Kikuchi,etal.ASCO2009;7.Muggia,etal.ASCO2009;8.Nimeiri,etal.GynecolOncol2008

9.Parmar,etal.Lancet2003;10.Pfisterer,etal.JCO2006;11.Pujade-Lauraine,etal.ASCO2009;12.Mutch,etal.JCO2007

13.Ferrandina,etal.JCO2007;14.Gordon,etal.JCO2001CP=carboplatin/paclitaxel;PLD=pegylatedliposomaldoxorubicin;NR=notreported;NRe=notreachedAvastin联合治疗铂类敏感/耐药卵巢癌的II期临床试

Avastin+CPAvastin维持一线治疗卵巢癌的II期临床试验–试验设计主要研究终点:毒性,RR和PFS*Eligiblepatientshadepithelialovarian,primaryperitoneal,fallopiantubeorpapillaryserousmülleriancarcinoma‡Avastinwasnotadministeredwiththefirstcycleofcarboplatin/paclitaxelPenson,etal.JCO2010新诊断的

≥IC期卵巢癌*(n=62)Carboplatin(AUC5)/paclitaxel175mg/m2

q3wx6–8+Avastin15mg/kgq3w‡Avastin15mg/kgq3w

for12monthsAvastin+CPAvastin维持一线治疗卵巢Avastin+CPAvastin维持一线治疗卵巢癌的II期临床试验–特性Characteristic(n=62)Medianage,years(range)58(18–77)Performancestatus(%) 168 232FIGOstage(%)Early10III69IV21Primarysite(%)Ovary73Primaryperitoneal16Fallopiantube8Uterinepapillaryserous5Cytoreduction(%)Optimal79Suboptimal21Penson,etal.JCO2010Avastin+CPAvastin维持一线治疗卵巢癌Avastin+CPAvastin维持一线治疗卵巢癌的II期临床试验

–疗效总结Efficacydata(n=62)ORR(RECIST),%(95%CI)75(62–85)Completeresponse23(13–36)Partialresponse52(38–65)Stabledisease(RECIST),%(95%CI)25(15–37)MedianPFS,months(95%CI)29.8(17.3–NR)MedianOS(months)NREfficacycomparesfavourablytodataforcarboplatin/paclitaxelinthissettingNR=notreachedDatafortheprimaryefficacyendpointsareshowninboldPenson,etal.JCO2010Avastin+CPAvastin维持一线治疗卵巢癌Avastin+CPAvastin维持一线治疗卵巢癌的II期临床试验

–化疗的安全性3/4级不良事件的种类和发生率与已知的Avastin和CP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Avastin+CPAvastin维持一线治疗卵巢癌的II期临床试验

–与单药治疗安全性一致Avastin维持治疗耐受性良好高血压肌肉骨骼疼痛血小板减少蛋白尿代谢疾病中性粒细胞减少6543210发声困难Penson,etal.JCO2010Patients(%)3级4级Avastin+CPAvastin维持一线治疗卵巢癌Avastin运用于卵巢癌中胃肠道穿孔的发生率

StudyPriorregimens,median(range)Events,n(%)Micha,etal.200/20(0)Penson,etal.301/62(1.6)Burger,etal.(GOG-170D)42(1–2)0/62(0)Muggia,etal.52(NA)0/24(0)Kikuchi,etal.6NA(>1)1/22(4.6)Garcia,etal.72(1–3)4/70(5.7)Nimeiri,etal.82(1–3)2/13(15.4)Cannistra,etal.92(2–3)5/44(11.4)Bidus,etal.10NA(3–6)0/3(0)Wright,etal.115(NA)4/62(6.5)Smerdel,etal.125(NA)2/38(5.3)Monk,etal.135(2–10)1/32(3.1)Wright,etal.147(2–15)2/23(8.7)Total22/475

(4.6)NA=notavailable1.Han,etal.GynecolOncol2007;2.Micha,etal.IntJGynecolCancer2007;3.Penson,etal.JCO2010

4.Burger,etal.JCO2005;5.Muggia,etal.ASCO2009;6.Kikuchi,etal.ASCO2009;7.Garcia,etal.JCO2008

8.Nimeiri,etal.GynecolOncol2008;9.Cannistra,etal.JCO2006;10.Bidus,etal.GynecolOncol2006;11.Wright,etal.JCO2006

12.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Avastin后胃肠道穿孔的发生率增加1Avastin运用于卵巢癌中胃肠道穿孔的发生率StudyPAvastin运用于卵巢癌:可能增加胃肠道穿孔风险的因素卵巢癌中的肠道问题相对比较常见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1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：卵巢癌细胞侵犯肠道浆膜引起坏死以及潜在的穿孔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Avastin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.GynecolOncol2007Avastin运用于卵巢癌:可能增加胃肠道穿孔风险的因素1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Avastin运用于卵巢癌: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近期关于既往多次化疗后的卵巢癌患者不建议使用Avastin为卵巢癌中三个关键的III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卵巢癌中三个关键的III期临床研究一线晚期卵巢癌一线卵巢癌复GOG-0218:随机双盲III期研究StratificationvariablesGOGperformancestatusstage/debulkingstatusBevacizumab15mg/kgq3w15monthsPaclitaxel(P)175mg/m2Carboplatin(C)AUC6Carboplatin(C)AUC6Paclitaxel(P)175mg/m2Carboplatin(C)AUC6Paclitaxel(P)175mg/m2Placeboq3wPlaceboq3wFront-line:epithelialOV,PPorFTcancer StageIIIoptimal (macroscopic) StageIII suboptimal StageIVN=1,873IIIIIIArm1:1:1Burger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;365(26):2473-83.OV=ovarian;PP=primaryperitoneal

FT=fallopiantube;Bev=bevacizumabBev15mg/kgR

A

N

D

O

M

I

S

EGOG-0218:随机双盲III期研究StratifiGOG-0218:主要入组条件Burger,etal.NEJM2011病理诊断明确为EOV,PP,orFTcancer最大减瘤术后:stageIIIoptimal(肉眼残余肿瘤

≤1

cm)orsuboptimal(>1cm),orstageIV既往未化疗术后1–12周GOGPS0–2既往无明显血管事件

既往无需要肠外营养支持的肠梗阻签署知情同意书GOG-0218:主要入组条件Burger,etal.入组条件改变Burger,etal.NEJM2011

Stuart,etal.IntJGynecolCancer2011最初入组条件:只接受次优化减瘤术后患者(>1cm)修改后入组条件:接受优化减瘤术后患者入组(≤1cm)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因此患者群预后较差入组条件改变Burger,etal.NEJM2011统计分析Burger,etal.NEJM2011Primaryanalysis:ComparisonofPFS(investigator-assessed)ineachbevacizumabarmvscontrol疾病进展决定于RECISTorCA-125onlyPlannedsamplesizeof1800basedon:90%powertodetectaPFShazardratio(HR)≤0.77Secondaryanalyses:Overallsurvival(OS),safety,qualityoflifeandcorrelativelaboratorystudiesPrimaryendpointchangedfromOStoPFS;unblindingtotreatmentassignmentallowedattimeofprogression统计分析Burger,etal.NEJM2011PrGOG-0218:三组基线水平平衡Characteristic,%ArmI

CP+Pl

(n=625)ArmII

CP+B15→Pl

(n=625)ArmIII

CP+B15→B15

(n=623)Ageinyears,median(range)60(25–86)60(24–88)60(22–89)GOGPS0/1/2,%50/44/750/43/649/43/8Stage/residualsize% IIIoptimal(macroscopic) IIIsuboptimal IV354125334126353927Histology% Serous Endometrioid Clearcell Mucinous

87321

8424<1

84431Tumourgrade,% 1/2/3* Notspecified/pending5/15/66144/12/70143/15/6914*Grade3includesallclearcelltumoursPercentagesmaynottotal100%duetoroundingorcategorisationBurger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;365(26):2473-83.GOG-0218:三组基线水平平衡Characterist23*OnepatientineachgroupreceivedBev/placeboincycle1Percentagesmaynottotal100%duetoroundingorcategorisationCharacteristicArmICP+Pl

(n=625)ArmIICP+Bev→Pl

(n=625)ArmIIICP+B15B15

(n=623)Median(range)numberBev/placebocycles11(0–22*)12(0–22*)14(0–21)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) Cycles1–657(9)73(12)59(9) Cycle≥712(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疗的患者

在单接受化疗组更多Burger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;365(26):2473-83.23*OnepatientineachgrouprGOG-0218:持续bevacizumab治疗较标准化化疗明显延长PFSAvastinSummaryofProductCharacteristicsRoche,dataonfile0 6 12 18 24 30 36 42 48Time(months)1.00.20PFSestimateI

CP+PlPl

(n=625)MedianPFS(months)10.6StratifiedanalysisHR

(95%CI)pvalueone-sided(logrank)II

CP+BevPl

(n=625)11.60.89(0.78–1.02)0.0437aIII

CP+Bev

Bev

(n=623)14.70.70(0.61–0.81)<0.0001a*pvalueboundary=0.0116+Bev(ArmII)Chemo(ArmI)+BevcontinuedBev(ArmIII)GOG-0218:持续bevacizumab治疗较标准GOG-0218:CA-125检测的频率可能影响PFSMonthsCP+Pl/B15(6cycles)MaintenancePl/B15(16cycles)Imaging*CA-125Exam0 3 6 9 12 15 每项检测间隔相同:2年内每3个月评估一次之后3年内每6个月评估一次之后每年一次Post-treatmentfollow-up*ConventionalCTorMRIBurger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;365(26):2473-83.GOG-0218:CA-125检测的频率可能影响PFSMMRCOV05/EORTC55955:根据CA-125水平决定继续治疗导致下一步化疗提前

Rustin,etal.Lancet2010延误治疗完全切除术后卵巢癌患者接受一线铂类为基础化疗后，并具有正常水平CA-125注册每3个月检测CA-125水平早期治疗当CA-125>2x正常上限随机化MRCOV05/EORTC55955:根据CA-12Proportionalivewhohave

notstartedfurtherchemotherapyTimesincerandomisation(months) Median(months)Early,basedonCA125levels>2xULN 0.8Delayed,basedonclinicalfeatures 5.6HR=0.29(95%CI:0.24–0.35),p<0.0001 0 3 6 9 12 15 18 21 241.00.750.500.250NumberatriskEarly 265 23 16 14 11 11 10 10 9Delayed 264 177 116 91 69 56 49 42 33MRCOV05/EORTC55955:根据CA-125水平决定继续治疗导致下一步化疗提前

Rustin,etal.Lancet2010Proportionalivewhohave

notNumberatriskEarly 265 247 211 165 131 94 72 39 27 22 15Delayed 264 236 203 167 129 103 69 46 31 25 16ProportionsurvivingTimesincerandomisation(months) 0 6 12 18 24 30 36 42 48 54 601.00.750.500.250MRCOV05/EORTC55955:根据CA-125水平决定下一步化疗并没有提高生存Rustin,etal.Lancet2010 Median(months)Early,basedonCA125levels>2xULN 25.7Delayed,basedonclinicalfeatures 27.1HR=0.98(95%CI:0.80–1.20),p=0.85NumberatriskProportionsurviGOG-0218:CA-125截尾数据分析显示继续使用bevacizumab较化疗相比明显延长患者PFS0 6 12 18 24 30 36 42 481.00.20*pvalueboundary=0.0116Timesincerandomisation(months)PFSestimateCP+B15B15CP+PlI

CP+PlPl(n=625)III

CP+B15B15(n=623)MedianPFS(months)12.018.2StratifiedanalysisHR

(95%CI)0.62(0.52–0.75)pvalueone-sided(logrank)<0.0001*AvastinSummaryofProductCharacteristics;Roche,dataonfileGOG-0218:CA-125截尾数据分析显示继续使用be什么是生存分析中的截尾数据？生存分析中主要的数据为生存时间,通过下列参数定义–起始事件，例如，手术或药物治疗的开始–终点事件，例如，死亡–两个事件之间的时间间隔即“生存时间”生存时间与其它数值资料间主要的区别：–并非所有患者的生存时间都能获得。尚未发生事件者即为“截尾”。生存分析“截尾”数据来自于在截尾日期时因下列原因尚未出现事件的患者–当前已知患者尚存活–末次联系时已知患者尚存活（失访，早期或随机截尾）什么是生存分析中的截尾数据？生存分析中主要的数据为生存时间,截尾数据对生存的影响

在特定时间点t，截尾并不会影响生存概率过多的早期截尾（由于失访）可能会对分析造成影响截尾数据对生存的影响DatainpurplerepresentcomparisonofarmIIvsarmIDataingreyrepresentcomparisonofarmIIIvsarmIBurger,etal.NEJM2011GOG-0218:subgroupanalysesofPFSRiskfactorTotalno.ofpatientsHazardratioforAvastin(95%CI)CancerstageandresiduallesionsizeIII,macroscopic≤1cmArmIIvsArmIArmIIIvsArmI4234340.7800.618III,>1cmArmIIvsArmIArmIIIvsArmI5104960.9810.763IVArmIIvsArmIArmIIIvsArmI3173180.9230.698HistologictypeSerousArmIIvsArmIArmIIIvsArmI1,0661,0680.9130.701NonserousArmIIvsArmIArmIIIvsArmI1841800.8930.713Tumourgrade1or2ArmIIvsArmIArmIIIvsArmI2322351.0390.5783ArmIIvsArmIArmIIIvsArmI8478420.8910.7000.330.500.671.001.502.003.00AvastinbetterControlbetterDatainpurplerepresentcompaBurger,etal.NEJM2011GOG-0218:subgroupanalysesofPFS(cont’d)RiskfactorTotalno.ofpatientsHazardratioforAvastin(95%CI)GOGperformancestatusscore0ArmIIvsArmIArmIIIvsArmI6266160.8770.7101or2ArmIIvsArmIArmIIIvsArmI6246320.9610.690Age<60yearsArmIIvsArmIArmIIIvsArmI6166300.9760.68060–69yearsArmIIvsArmIArmIIIvsArmI4144080.8920.763

≥70yearsArmIIvsArmIArmIIIvsArmI2202100.8410.6780.330.500.671.001.502.003.00AvastinbetterControlbetterDatainpurplerepresentcomparisonofarmIIvsarmIDataingreyrepresentcomparisonofarmIIIvsarmIBurger,etal.NEJM2011GOG-02AvastinSummaryofProductCharacteristicsGOG-0218:independentreviewconfirmsthePFSbenefitIRC-assessedPFSanalysisInvestigator-assessedcensoredPFSanalysis

CP+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(0.50–0.77)0.62(0.52–0.75)AvastinSummaryofProductChaRochedataonfileGOG-0218:finalOSresultsCP+Pl(n=625)CP+Av15Pl(n=625)CP+Av15Av15(n=623)Deaths,n(%)299(47.8%)309(49.4%)270(43.3%)Medianoverallsurvival(months)40.638.843.8Hazardratio(95%CI)1.065(0.908–1.249)0.879(0.745–1.038)p0.21970.0641RochedataonfileGOG-0218:fiATE=arterialthromboembolicevent;VTE=venousthromboembolicevent

RPLS=reversibleposteriorleucoencephalopathysyndrome;aPerforation/fistula/necrosis/leakBurgeretal.NEJM2011治疗第二个周期至治疗结束后30天内的不良事件100806040200Patients(%)GIevents(grade≥2)Hypertension(grade≥2)Proteinuria(grade≥3)Pain(grade≥2)Neutropenia(grade≥4)VTE(allgrades)ATE(allgrades)WoundhealingcomplicationsCNSbleeding(allgrades)Non-CNAbleeding(grade≥3)RPLS(allgrades)ArmI(CP+Pl→Pl;n=601)ArmII(CP+Av15→Pl;n=607)ArmIII(CP+Av15→Av15;n=608)P<0.05Febrileneutropenia(allgrades)ATE=arterialthromboembolicGOG-0218:不同治疗时期的不良事件Selectedadverseevents,

No.ofpatientsArmICP+PlaPlaArmIICP+BevPlaArmIIICP+BevBev(n=601)(n=607)(n=608)Cycles,n290629112891TreatmentphaseaCytotoxic(cycles2–6)Cytotoxic(cycles2–6)Cytotoxic(cycles2–6)GIeventsb(grade≥2) 6 16 15Hypertension(grade≥2) 21 64 60Proteinuria(grade≥3) 2 4 0Pain(grade≥2) 127 117 112Neutropenia(grade≥4) 345 382 385Febrileneutropenia(allgrades) 21 30 26VTE(allgrades) 26 27 27ATE(allgrades) 4 1 3Wound-healingcomplications(allgrades)111413CNSbleeding(allgrades) 0 0 0Non-CNSbleeding(grade≥3) 3 8 10RPLS(allgrades) 0 1 0

aOnsetwithin30daysoflasttreatment.bPerforation/fistula/necrosis/leak.Burgeretal.ESMO2010GOG-0218:不同治疗时期的不良事件SelectedGOG-0218:不同治疗时期的不良事件Selectedadverseevents,

No.ofpatientsArmICP+PlaPlaArmIICP+BevPlaArmIIICP+BevBev(n=601)(n=483)(n=607)(n=457)(n=608)(n=464)Cycles,n290640592911420428914677TreatmentphaseaCytotoxic(cycles2–6)Continued(cycles7–22)Cytotoxic(cycles2–6)Continued(cycles7–22)Cytotoxic(cycles2–6)Continued(cycles7–22)GIeventsb(grade≥2) 6 1 16 1 15 1Hypertension(grade≥2) 21 22 64 36 60 79Proteinuria(grade≥3) 2 2 4 0 0 10Pain(grade≥2) 127 123 117 135 112 174Neutropenia(grade≥4) 345 2 382 2 385 0Febrileneutropenia(allgrades) 21 0 30 0 26 0VTE(allgrades) 26 9 27 5 27 14ATE(allgrades) 4 1 1 3 3 1Wound-healingcomplications(allgrades)116148135CNSbleeding(allgrades) 0 0 0 0 0 2Non-CNSbleeding(grade≥3) 3 2 8 0 10 3RPLS(allgrades) 0 0 1 0 0 1

aOnsetwithin30daysoflasttreatment.bPerforation/fistula/necrosis/leak.Burgeretal.ESMO2010GOG-0218:不同治疗时期的不良事件Selecteda20.1%Platinumsensitive:recurring>6monthsafterlastplatinumPlatinumresistant:recurring≤6monthsafterlastplatinumPatientswithrecurrencesGOG-0218:一线是否使用Avastin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%Internalconfidentialdata20.1%Platinumsensitive:recurQForm=StudyFollow-upForm;FUAT=Follow-UpAdditionalTreatmentsForm.RochedataonfileGOG-0218:后续治疗CP+PlPl

(n=625)CP+Av15Pl

(n=625)CP+Av15Av15

(n=623)Useofanynonprotocoltherapy(QForm)78%79%73%Chemotherapy74%74%70%Useofanyantiangiogenictreatments(FUAT)31%30%17%Avastin28%28%15%QForm=StudyFollow-upForm;FGOG-0218:总结GOG-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

CP+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)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CP+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GOG-0218:总结GOG-0218肯定了bevaciR

A

N

D

O

M

I

S

EICON7:一项随机开放的III期临床试验变量分层:疾病分期以及减瘤术范围:I–III期

残余病灶≤1cmvsI–III期

残余病灶>1cmvsIV期以及不可切除的III期病灶术后治疗开始时间:≤vs>术后4周GCIGgroup(*alsochoiceofAUCdose5[AGO,NSGO,GINECO]or6)Paclitaxel175mg/m2CarboplatinAUC5or6*CarboplatinAUC5or6*Paclitaxel175mg/m21:1StageI–IIa(grade3orclearcell)orStageIIb–IV(allgrades/histologictypes)SurgicallydebulkedhistologicallyconfirmedOC,PP,FTC(n=1,528)Bevacizumab7.5mg/kgq3w12monthsControlTreatment(CP+BB7.5)Perren,etal..NEnglJMed.2011Dec29;365(26):2484-96.R

A

N

D

O

M

I

S

EICON7:一项随机开放ICON7:入组患者必须接受最大减瘤术后

病理证实为卵巢上皮癌，原发性腹膜癌或者输卵管癌

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FIGO分期I–IIA高风险:3级或透明细胞型(10%)IIB–IV:任何分级和组织类型活检明确的无手术计划的不可手术切除III/IV期患者

ECOGPS0–2Perren,etal..NEnglJMed.2011Dec29;365(26):2484-96ICON7:入组患者必须接受最大减瘤术后病理证实为卵巢上ICON7:研究终点

–

根据RECIST评估PFS主要研究终点:PFS疾病进展根据RECIST评估标准

CA-125单独升高不作为疾病进展的依据1,528patientsrandomisedover2years(684events)→5%significancelevel,90%powertodetect:PFSHRof0.78increaseofmedianPFSfrom18to23months次要研究终点:OS(due2013),biologicPFS，responsetotherapy,toxicity,QolPerren,etal.ESMO2010ICON7:研究终点–根据RECIST评估PFS主要研CharacteristicCP(n=764)CP+B7.5B7.5(n=764)Medianage(range)57(18–81)57(24–82)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)10

ICON7:特征基线水平平衡Perren,etal.ESMO2010CharacteristicCP(n=764)CP+BCharacteristic,n(%)CP(n=764)CP+B7.5B7.5(n=764)FIGOstage,n(%)I/IIAIIB–IIIBIIIC/IV75(10)160(21)529(69)67(9)155(20)542(71)Debulkingsurgeryresidualtumor≤1cmresidualtumor>1cmNosurgery552(74)195(26)17(2)559(74)192(26)13(2)FIGOstageandresiduum*StageI–III(≤1cm)StageI–III(>1cm)StageIII(inoperable)/IV508(66)150(20)106(14)518(68)140(18)106(14)Intenttostartchemotherapy*≤4weeksfromsurgery>4weeksfromsurgery328(43)436(57)326(43)438(57)

*StratificationvariableICON7:特征基线水平平衡Perren,etal.ESMO2010Characteristic,n(%)CP(n=76417.319.0CPCP+B7.5B7.5ICON7:连续使用bevacizumab较单用基础化疗相比显著提高PFSNumberatriskCP 764 723 693 556 464 307 216 143 91 50 25CP+B7.5 764 748 715 647 585 399 263 144 73 36 190 3 6 9 12 15 18 21 24 27 30Time(months)Proportionalivewithoutprogression1.000.750.500.250CPCP+B7.5B7.5Events,n(%)392(51)367(48)Median,months17.319.0Log-ranktestp=0.0041HR(95%CI)0.81(0.70–0.94)Perren,etal.ESMO201017.319.0CPCP+B7.5B7.5ICONICON7:连续使用bevacizumab较单用基础化疗相比显著提高PFS–updatedanalysisKristensen,etal.ASCO2011CPCP+B7.5B7.5ProportionalivewithoutprogressionNumberatriskCP 764 693 474 350 221 114 39 5 0CP+B7.5 764 716 599 430 229 107 27 1 0CPCP+B7.5Events,n(%)464(61)470(62)Median,months17.419.8Log-ranktestp=0.039HR(95%CI)0.87(0.77–0.99)1.00.20Time(months)0 6 12 18 24 30 36 42 48ICON7:连续使用bevacizumab较单用基础化疗相比0.20.10–0.1–0.2Treatmentdifference(research–control)Time(months)KMdifferenceSmootheddifference0 3 6 9 12 15 18 21 24 27 30

MonthsPFStreatmentdifference(PFSestimate:control/research)63.7%(92.1/95.8)1215.1%(64.6/79.7)187.6%(47.3/54.9)24–2.5%(39.8/37.3)Perren,etal.NEJM2011AbsolutedifferenceinPFSCPCP+Av7.5Av7.5Restrictedmeanestimatedat36months(months)20.321.8Difference(95%CI)1.5(0.2–2.9)15.1%0.2Treatmentdifference(reseaICON7:在所有患者亚组中，连续的bevacizumab治疗都可以提供PFS获益CP+B7.5B7.5betterCPbetterPerren,etal.ESMO2010ICON7:在所有患者亚组中，连续的bevacizumabICON7:高风险亚组的PFS分析

NumberatriskCP 234 205 98 36 14 2CP+B7.5B7.5 231 213 159 56 10 11.000.750.500.250ProportionalivewithoutprogressionTime(months)0 3 6 9 12 15 18 21 24 27 30CP

(n=234)CP+B7.5B7.5(n=231)Events,n(%)173(74)158(68)Median,months10.515.9Log-ranktestp<0.001HR(95%CI)0.68(0.55–0.85)CPCP+B7.5B7.5OperatedFIGOIIIwithresiduals>1cmandFIGOIV:≈30%oftotalpopulationPerren,etal.ESMO2010ICON7:高风险亚组的PFS分析NumberatrICON7:关于总体OS数据的中期分析结果Kristensen,etal.ASCO2011*BasedonimmatureOSdata(378of715requiredevents,53%)asrequired

byregulatoryauthoritiesNumberatriskCP 764 724 672 623 421 212 71 6 0CP+B7.5 764 737 702 657 459 228 69 4 01.000.750.500.250Time(months)0 6 12 18 24 30 36 42 48ProportionvalueCPCP+B7.5Events,n(%)200(26)178(23)Median,monthsNotyetreachedLog-ranktestP=0.11HR(95%CI)0.85(0.69–1.04)1-yearOSrate(%)9295ICON7:关于总体OS数据的中期分析结果KristensICON7:关于高风险组OS数据的中期分析结果High-risksubgroupCP(n=234)CP+B7.5(n=231)Events,n(%)109(47)79(34)Median,months28.836.6Log-ranktestP=0.002HR(95%CI)0.64(048–0.85)1-yearOSrate(%)8692NumberatriskCP 234 219 194 166 107 46 15 CP+B7.5 231 222 208 186 134 65 13 1.000.750.500.250Time(months)0 6 12 18 24 30 36 42 48ProportionvalueKristensen,etal.ASCO2011OperatedFIGOIIIwithresiduals>1cmandFIGOIV:≈30%oftotalpopulationICON7:关于高风险组OS数据的中期分析结果High-riICON7:与bevacizumab相关的各级不良事件ATE=arterialthromboembolism;CHF=congestiveheartfailure

RPLS=reversibleposteriorleucoencephalopathysyndrome

VTE=venousthromboembolismCP(n=753)CP+B7.5B7.5(n=745)Perren,etal.ESMO2010Patients(%)403020100ICON7:与bevacizumab相关的各级不良事件ATEICON7:

≥3级的与bevacizumab相关的不良事件CP(n=753)CP+B7.5B7.5(n=745)*Grade≥2Perren,etal.ESMO2010Patients(%)403020100ICON7:≥3级的与bevacizumab相关的不良ICON7:总结ICON7的数据进一步证实了GOG-0218的结论：卵巢癌患者一线接受bevacizumab联合化疗后续bevacizumab单药治疗明显提高患者PFS1–3Bevacizumab治疗通常合并可控制的副反应，

目前无新的安全顾虑产生1ICON7中高风险亚组分析结果进一步支持bevacizumab运用于III/IV期肿瘤残存的患者2

CP+bevacizumabcontinuedsingle-agentbevacizumab

应该成为进展期卵巢癌一线治疗的标准方案1.Burger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;365(26):2473-832.Perren,etal..NEnglJMed.2011Dec29;365(26):2484-963.AvastinSummaryofProductCharacteristicsICON7:总结ICON7的数据进一步证实了GOG-02关于bevacizumab一线治疗的两个III期研究比较:

试验设计

1.Burger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;365(26):2473-832.Perren,etal.NEnglJMed.2011Dec29;365(26):2484-96Bevacizumab15mg/kgq3w15monthsPaclitaxel175mg/m2CarboplatinAUC6CarboplatinAUC6Paclitaxel175mg/m2CarboplatinAUC6Paclitaxel175mg/m2Placeboq3wPlaceboq3wFront-line:epithelialOV,PPorFTcancer StageIIIoptimal (macroscopic) StageIIIsuboptimal StageIVN=1,8731:1:1Bev15mg/kg