貝伐在卵巢癌研究培訓(xùn)課件

Avastin在卵巢癌的相關(guān)研究

復(fù)發(fā)卵巢癌的II期臨床試驗(yàn)BurgerRA,etal.JClinOncol2007CannistraSA,etal.JClinOncol2007GarciaAA,etal.JClinOncol2008初治卵巢癌的II期臨床試驗(yàn)Michaetal.IntJGynecolCancer2007Pensonetal,JClinOncol2010初治卵巢癌的III期臨床試驗(yàn)GOG-0218,ASCO2010ICON7/OVAR11,IGCS&ESMO2010進(jìn)行中/完成的臨床試驗(yàn)OCEANS(鉑類敏感)AURELIA(鉑類耐藥)GOG-0213(鉑類敏感)Avastin在卵巢癌的相關(guān)研究復(fù)發(fā)卵巢癌的II期臨床1GOG170D:Avastin單藥治療卵巢癌復(fù)發(fā)的II期臨床試驗(yàn)–試驗(yàn)設(shè)計(jì)主要研究終點(diǎn):6-monthPFS和ORR次要研究終點(diǎn):安全性,OS,PFS第三研究終點(diǎn):可能影響PFS的因素*1–2priorcytotoxicregimens(firstplatinum-based,withasecondplatinum-basedregimen

ifplatinum-freeinterval≥12months)Burger,etal.JCO2007PD既往治療后進(jìn)展卵巢癌*(n=62)Avastin15mg/kg

every3weeksGOG170D:Avastin單藥治療卵巢癌復(fù)發(fā)的II2GOG170D:Avastin單藥治療卵巢癌復(fù)發(fā)的II期臨床試驗(yàn)–特性Characteristic(n=62)FIGOstage(%)IIB2IIIA2IIIB8IIIC77IV11Primarysite(%)EOC84PPC16No.ofpriorregimens(%)134266No.ofplatinumregimens(%)168232Platinum-freeinterval<6months(%)58EOC=epithelialovariancancer;PPC=primaryperitonealcancer

Burger,etal.JCO2007GOG170D:Avastin單藥治療卵巢癌復(fù)發(fā)的II3GOG170D:Avastin單藥治療卵巢癌復(fù)發(fā)的II期臨床試驗(yàn)–療效總結(jié)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療效似乎更支持其他的單藥治療方案*AssessedusingRECISTcriteria?14of32patientswithstablediseasehadPFS>6monthsGOG170D:Avastin單藥治療卵巢癌復(fù)發(fā)的II4GOG170D:Avastin單藥治療卵巢癌復(fù)發(fā)的II期臨床試驗(yàn)–安全性無胃腸道穿孔,瘺以及動(dòng)脈栓塞發(fā)生無≥2級(jí)的出血事件發(fā)生GI=gastrointestinal;ATE=arterialthromboembolicevents;VTE=venousthromboembolicevents

Burger,etal.JCO2007沒有發(fā)現(xiàn)新發(fā)或預(yù)期以外的毒性發(fā)生，3/4不良事件的發(fā)生率與其他腫瘤類型一致高血壓靜脈血栓蛋白尿惡心嘔吐腸梗阻便秘脫水過敏肺部疾病腎臟泌尿系統(tǒng)疾病體質(zhì)改變凝血肝損疼痛其他出血Patients(%)1210864203級(jí)4級(jí)最常見的1/2級(jí)不良事件

為疼痛，

體質(zhì)改變，肝損，

貧血，蛋白尿和生殖泌尿系統(tǒng)疾病GOG170D:Avastin單藥治療卵巢癌復(fù)發(fā)的II5GOG170D:Avastin單藥治療卵巢癌復(fù)發(fā)的II期臨床試驗(yàn)–總結(jié)根據(jù)緩解率以及中位PFS的結(jié)果,Avastin確保了未來卵巢癌復(fù)發(fā)治療的相關(guān)研究Avastin15mg/kgq3w對(duì)于既往接受過1~2次化療方案的卵巢癌患者耐受性良好

副反應(yīng)都在預(yù)料之中，且大多比較輕微，容易控制許多患者接受了>30個(gè)周期的治療基于此次試驗(yàn)的結(jié)果，GOG開展了一項(xiàng)Avastin聯(lián)合化療的空白對(duì)照III期臨床試驗(yàn)(GOG-0218)Burger,etal.JCO2007GOG170D:Avastin單藥治療卵巢癌復(fù)發(fā)的II6Avastin聯(lián)合治療鉑類敏感/耐藥卵巢癌的II期臨床試驗(yàn)nPriorregimensPlatinumsensitivePlatinumresistantStudytherapyOR(%)MedianPFS(months)MedianOS(months)Single-agentAvastinBurger2007162≤2

Avastin214.717Cannistra20072442–3

Avastin164.4Smerdel2009338Median5

Avastin305.98.6Avastin-basedcombinationregimensGarcia2008470≤3

Avastin+cyclophosphamide247.2(TTP)16.9McGonigle2008522≤2

Avastin+topotecan22Kikuchi2009622>1

Avastin+PLD36NRNRMuggia2009721≤3

Avastin+PLDNimeiri2008813≤2

Avastin+erlotinib154.111RepresentativehistoricaltrialsPlatinum-sensitive9–111–2

Platinum±paclitaxel,gemcitabineorPLD31–475.8–13.017.3–29.0Platinum-resistant12–141–2

Topotecan,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聯(lián)合治療鉑類敏感/耐藥卵巢癌的II期臨床試7

Avastin+CPAvastin維持一線治療卵巢癌的II期臨床試驗(yàn)–試驗(yàn)設(shè)計(jì)主要研究終點(diǎn):毒性,RR和PFS*Eligiblepatientshadepithelialovarian,primaryperitoneal,fallopiantubeorpapillaryserousmülleriancarcinoma?Avastinwasnotadministeredwiththefirstcycleofcarboplatin/paclitaxelPenson,etal.JCO2010新診斷的

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

q3wx6–8+Avastin15mg/kgq3w?Avastin15mg/kgq3w

for12monthsAvastin+CPAvastin維持一線治療卵巢8Avastin+CPAvastin維持一線治療卵巢癌的II期臨床試驗(yàn)–特性Characteristic(n=62)Medianage,years(range)58(18–77)Performancestatus(%) 168 232FIGOstage(%)Early10III69IV21Primarysite(%)Ovary73Primaryperitoneal16Fallopiantube8Uterinepapillaryserous5Cytoreduction(%)Optimal79Suboptimal21Penson,etal.JCO2010Avastin+CPAvastin維持一線治療卵巢癌9Avastin+CPAvastin維持一線治療卵巢癌的II期臨床試驗(yàn)

–療效總結(jié)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維持一線治療卵巢癌10Avastin+CPAvastin維持一線治療卵巢癌的II期臨床試驗(yàn)

–化療的安全性3/4級(jí)不良事件的種類和發(fā)生率與已知的Avastin和CP的相關(guān)耐受分析相一致中性粒細(xì)胞減少代謝疾病高血壓血小板減少神經(jīng)病變過敏反應(yīng)*肌肉骨骼疼痛血栓栓塞貧血嘔吐胃腸道穿孔肝功能異常中性粒細(xì)胞減少性發(fā)熱Patients(%)16141210864203級(jí)4級(jí)*AllallergicreactionsweretopaclitaxelPenson,etal.JCO2010Avastin+CPAvastin維持一線治療卵巢癌11Avastin+CPAvastin維持一線治療卵巢癌的II期臨床試驗(yàn)

–與單藥治療安全性一致Avastin維持治療耐受性良好高血壓肌肉骨骼疼痛血小板減少蛋白尿代謝疾病中性粒細(xì)胞減少6543210發(fā)聲困難Penson,etal.JCO2010Patients(%)3級(jí)4級(jí)Avastin+CPAvastin維持一線治療卵巢癌12Avastin運(yùn)用于卵巢癌中胃腸道穿孔的發(fā)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分析結(jié)果提示既往多次治療后的卵巢癌患者使用Avastin后胃腸道穿孔的發(fā)生率增加1Avastin運(yùn)用于卵巢癌中胃腸道穿孔的發(fā)生率StudyP13Avastin運(yùn)用于卵巢癌:可能增加胃腸道穿孔風(fēng)險(xiǎn)的因素卵巢癌中的腸道問題相對(duì)比較常見數(shù)據(jù)顯示既往多次化療以及腸壁增厚或梗阻可能會(huì)增加胃腸道穿孔的風(fēng)險(xiǎn)1卵巢癌多次化療后接受Avastin治療引起潛在胃腸道穿孔風(fēng)險(xiǎn)增高的原因可能是2：卵巢癌細(xì)胞侵犯腸道漿膜引起壞死以及潛在的穿孔卵巢癌患者往往發(fā)生腹腔擴(kuò)散，腸梗阻風(fēng)險(xiǎn)僅次于腸道腫瘤以及術(shù)后腸粘連Avastin可以通過栓塞或血管收縮限制血液流向內(nèi)臟血管，因此可能導(dǎo)致腸梗阻和腸穿孔卵巢癌患者發(fā)生胃腸道穿孔的明確原因尚未確定1.Cannistra,etal.JCO2007;2.Simpkins,etal.GynecolOncol2007Avastin運(yùn)用于卵巢癌:可能增加胃腸道穿孔風(fēng)險(xiǎn)的因素114近期關(guān)于既往多次化療后的卵巢癌患者不建議使用Avastin為基礎(chǔ)的治療Avastin運(yùn)用于卵巢癌:胃腸道穿孔總結(jié)Avastin聯(lián)合化療(n=68)較單用化療(n=195)相比，胃腸道穿孔和/或胃腸道瘺發(fā)生的風(fēng)險(xiǎn)并沒有增加(RR=1.09)11.Sfakianos,etal.GynecolOncol2009近期關(guān)于既往多次化療后的卵巢癌患者不建議使用Avastin為15卵巢癌中三個(gè)關(guān)鍵的III期臨床研究一線晚期卵巢癌一線卵巢癌復(fù)發(fā)鉑類敏感卵巢癌卵巢癌中三個(gè)關(guān)鍵的III期臨床研究一線晚期卵巢癌一線卵巢癌復(fù)16GOG-0218:隨機(jī)雙盲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:隨機(jī)雙盲III期研究Stratifi17GOG-0218:主要入組條件Burger,etal.NEJM2011病理診斷明確為EOV,PP,orFTcancer最大減瘤術(shù)后:stageIIIoptimal(肉眼殘余腫瘤

≤1

cm)orsuboptimal(>1cm),orstageIV既往未化療術(shù)后1–12周GOGPS0–2既往無明顯血管事件

既往無需要腸外營(yíng)養(yǎng)支持的腸梗阻簽署知情同意書GOG-0218:主要入組條件Burger,etal.入組條件改變Burger,etal.NEJM2011

Stuart,etal.IntJGynecolCancer2011最初入組條件:只接受次優(yōu)化減瘤術(shù)后患者(>1cm)修改后入組條件:接受優(yōu)化減瘤術(shù)后患者入組(≤1cm)需要注意的是，根據(jù)2010GCIG共識(shí)，研究中入組的所有患者接受的只是次優(yōu)化減瘤術(shù)因此患者群預(yù)后較差入組條件改變Burger,etal.NEJM2011統(tǒng)計(jì)分析Burger,etal.NEJM2011Primaryanalysis:ComparisonofPFS(investigator-assessed)ineachbevacizumabarmvscontrol疾病進(jìn)展決定于RECISTorCA-125onlyPlannedsamplesizeof1800basedon:90%powertodetectaPFShazardratio(HR)≤0.77Secondaryanalyses:Overallsurvival(OS),safety,qualityoflifeandcorrelativelaboratorystudiesPrimaryendpointchangedfromOStoPFS;unblindingtotreatmentassignmentallowedattimeofprogression統(tǒng)計(jì)分析Burger,etal.NEJM2011PrGOG-0218:三組基線水平平衡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-0218:三組基線水平平衡Characterist2122*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:因疾病進(jìn)展而中斷治療的患者

在單接受化療組更多Burger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;365(26):2473-83.22*Onepatientineachgroupr22GOG-0218:持續(xù)bevacizumab治療較標(biāo)準(zhǔn)化化療明顯延長(zhǎng)PFSAvastinSummaryofProductCharacteristicsRoche,dataonfile0 6 12 18 24 30 36 42 48Time(months)1.00.80.60.40.20PFSestimateI

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)+Bev

continuedBev(ArmIII)GOG-0218:持續(xù)bevacizumab治療較標(biāo)準(zhǔn)23GOG-0218:CA-125檢測(cè)的頻率可能影響PFSMonthsCP+Pl/B15(6cycles)MaintenancePl/B15(16cycles)Imaging*CA-125Exam0 3 6 9 12 15 每項(xiàng)檢測(cè)間隔相同:2年內(nèi)每3個(gè)月評(píng)估一次之后3年內(nèi)每6個(gè)月評(píng)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檢測(cè)的頻率可能影響PFSM24MRCOV05/EORTC55955:根據(jù)CA-125水平?jīng)Q定繼續(xù)治療導(dǎo)致下一步化療提前

Rustin,etal.Lancet2010延誤治療完全切除術(shù)后卵巢癌患者接受一線鉑類為基礎(chǔ)化療后，并具有正常水平CA-125注冊(cè)每3個(gè)月檢測(cè)CA-125水平早期治療當(dāng)CA-125>2x正常上限隨機(jī)化MRCOV05/EORTC55955:根據(jù)CA-1225Proportionalivewhohave

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:根據(jù)CA-125水平?jīng)Q定繼續(xù)治療導(dǎo)致下一步化療提前

Rustin,etal.Lancet2010Proportionalivewhohave

not26NumberatriskEarly 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:根據(jù)CA-125水平?jīng)Q定下一步化療并沒有提高生存Rustin,etal.Lancet2010 Median(months)Early,basedonCA125levels>2xULN 25.7Delayed,basedonclinicalfeatures 27.1HR=0.98(95%CI:0.80–1.20),p=0.85NumberatriskProportionsurvi27GOG-0218:CA-125截尾數(shù)據(jù)分析顯示繼續(xù)使用bevacizumab較化療相比明顯延長(zhǎng)患者PFS0 6 12 18 24 30 36 42 481.00.80.60.40.20*pvalueboundary=0.0116Timesincerandomisation(months)PFSestimateCP+B15

B15CP+PlI

CP+PlPl(n=625)III

CP+B15

B15(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截尾數(shù)據(jù)分析顯示繼續(xù)使用be28什么是生存分析中的截尾數(shù)據(jù)？生存分析中主要的數(shù)據(jù)為生存時(shí)間,通過下列參數(shù)定義–起始事件，例如，手術(shù)或藥物治療的開始–終點(diǎn)事件，例如，死亡–兩個(gè)事件之間的時(shí)間間隔即“生存時(shí)間”生存時(shí)間與其它數(shù)值資料間主要的區(qū)別：–并非所有患者的生存時(shí)間都能獲得。尚未發(fā)生事件者即為“截尾”。生存分析“截尾”數(shù)據(jù)來自于在截尾日期時(shí)因下列原因尚未出現(xiàn)事件的患者–當(dāng)前已知患者尚存活–末次聯(lián)系時(shí)已知患者尚存活（失訪，早期或隨機(jī)截尾）什么是生存分析中的截尾數(shù)據(jù)？生存分析中主要的數(shù)據(jù)為生存時(shí)間,29截尾數(shù)據(jù)對(duì)生存的影響

在特定時(shí)間點(diǎn)t，截尾并不會(huì)影響生存概率過多的早期截尾（由于失訪）可能會(huì)對(duì)分析造成影響截尾數(shù)據(jù)對(duì)生存的影響30DatainpurplerepresentcomparisonofarmIIvsarmIDataingreyrepresentcomparisonofarmIIIvsarmIBurger,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+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(0.908–1.249)0.879(0.745–1.038)p0.21970.0641RochedataonfileGOG-0218:fiATE=arterialthromboembolicevent;VTE=venousthromboembolicevent

RPLS=reversibleposteriorleucoencephalopathysyndrome;aPerforation/fistula/necrosis/leakBurgeretal.NEJM2011治療第二個(gè)周期至治療結(jié)束后30天內(nèi)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:不同治療時(shí)期的不良事件Selectedadverseevents,

No.ofpatientsArmICP+Pla

PlaArmIICP+Bev

PlaArmIIICP+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:不同治療時(shí)期的不良事件Selected36GOG-0218:不同治療時(shí)期的不良事件Selectedadverseevents,

No.ofpatientsArmICP+Pla

PlaArmIICP+Bev

PlaArmIIICP+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:不同治療時(shí)期的不良事件Selecteda3720.1%Platinumsensitive:recurring>6monthsafterlastplatinumPlatinumresistant:recurring≤6monthsafterlastplatinumPatientswithrecurrencesGOG-0218:一線是否使用Avastin對(duì)于患者復(fù)發(fā)時(shí)鉑類敏感情況Avastin與化療相比鉑類敏感患者比例高20.1%Internalconfidentialdata20.1%Platinumsensitive:recur38QForm=StudyFollow-upForm;FUAT=Follow-UpAdditionalTreatmentsForm.RochedataonfileGOG-0218:后續(xù)治療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%QForm=StudyFollow-upForm;FGOG-0218:總結(jié)GOG-0218肯定了bevacizumab用于晚期卵巢癌一線治療時(shí)具有延長(zhǎng)PFS的作用

CP+bevacizumabbevacizumab單藥15mg/kg持續(xù)使用15個(gè)月(ArmIII)后患者PFS統(tǒng)計(jì)學(xué)上明顯優(yōu)于單用CP(ArmI)不良反應(yīng)通常都是可控制的，安全性結(jié)果與bevacizumab運(yùn)用于其他類型腫瘤的試驗(yàn)結(jié)果相似CP+bevacizumabbevacizumab單藥15mg/kg持續(xù)使用15個(gè)月應(yīng)該作為晚期卵巢癌一線治療的標(biāo)準(zhǔn)方案GOG-0218:總結(jié)GOG-0218肯定了bevaci40R

A

N

D

O

M

I

S

EICON7:一項(xiàng)隨機(jī)開放的III期臨床試驗(yàn)變量分層:疾病分期以及減瘤術(shù)范圍:I–III期

殘余病灶≤1cmvsI–III期

殘余病灶>1cmvsIV期以及不可切除的III期病灶術(shù)后治療開始時(shí)間:≤vs>術(shù)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

EICON7:一項(xiàng)隨機(jī)開放41ICON7:入組患者必須接受最大減瘤術(shù)后

病理證實(shí)為卵巢上皮癌，原發(fā)性腹膜癌或者輸卵管癌

患者接受最大減瘤術(shù)后并且疾病進(jìn)展前無進(jìn)一步外科切除計(jì)劃FIGO分期I–IIA高風(fēng)險(xiǎn):3級(jí)或透明細(xì)胞型(10%)IIB–IV:任何分級(jí)和組織類型活檢明確的無手術(shù)計(jì)劃的不可手術(shù)切除III/IV期患者

ECOGPS0–2Perren,etal..NEnglJMed.2011Dec29;365(26):2484-96ICON7:入組患者必須接受最大減瘤術(shù)后病理證實(shí)為卵巢上42ICON7:研究終點(diǎn)

–

根據(jù)RECIST評(píng)估PFS主要研究終點(diǎn):PFS疾病進(jìn)展根據(jù)RECIST評(píng)估標(biāo)準(zhǔn)

CA-125單獨(dú)升高不作為疾病進(jìn)展的依據(jù)1,528patientsrandomisedover2years(684events)→5%significancelevel,90%powertodetect:PFSHRof0.78increaseofmedianPFSfrom18to23months次要研究終點(diǎn):OS(due2013),biologicPFS，responsetotherapy,toxicity,QolPerren,etal.ESMO2010ICON7:研究終點(diǎn)–根據(jù)RECIST評(píng)估PFS主要研43CharacteristicCP(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:特征基線水平平衡Perren,etal.ESMO2010CharacteristicCP(n=764)CP+B44Characteristic,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:特征基線水平平衡Perren,etal.ESMO2010Characteristic,n(%)CP(n=7644517.319.0CPCP+B7.5

B7.5ICON7:連續(xù)使用bevacizumab較單用基礎(chǔ)化療相比顯著提高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+B7.5

B7.5Events,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+B7.5B7.5ICON46ICON7:連續(xù)使用bevacizumab較單用基礎(chǔ)化療相比顯著提高PFS–updatedanalysisKristensen,etal.ASCO2011CPCP+B7.5

B7.5ProportionalivewithoutprogressionNumberatriskCP 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)1.00.80.60.40.20Time(months)0 6 12 18 24 30 36 42 48ICON7:連續(xù)使用bevacizumab較單用基礎(chǔ)化療相比470.20.10–0.1–0.2Treatmentdifference(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+Av7.5

Av7.5Restrictedmeanestimatedat36months(months)20.321.8Difference(95%CI)1.5(0.2–2.9)15.1%0.2Treatmentdifference(reseaICON7:在所有患者亞組中，連續(xù)的bevacizumab治療都可以提供PFS獲益CP+B7.5B7.5betterCPbetterPerren,etal.ESMO2010ICON7:在所有患者亞組中，連續(xù)的bevacizumab49ICON7:高風(fēng)險(xiǎn)亞組的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+B7.5

B7.5(n=231)Events,n(%)173(74)158(68)Median,months10.515.9Log-ranktestp<0.001HR(95%CI)0.68(0.55–0.85)CPCP+B7.5

B7.5OperatedFIGOIIIwithresiduals>1cmandFIGOIV:≈30%oftotalpopulationPerren,etal.ESMO2010ICON7:高風(fēng)險(xiǎn)亞組的PFS分析Numberatr50ICON7:關(guān)于總體OS數(shù)據(jù)的中期分析結(jié)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:關(guān)于總體OS數(shù)據(jù)的中期分析結(jié)果Kristens51ICON7:關(guān)于高風(fēng)險(xiǎn)組OS數(shù)據(jù)的中期分析結(jié)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:關(guān)于高風(fēng)險(xiǎn)組OS數(shù)據(jù)的中期分析結(jié)果High-ri52ICON7:與bevacizumab相關(guān)的各級(jí)不良事件ATE=arterialthromboembolism;CHF=congestiveheartfailure

RPLS=reversibleposteriorleucoencephalopathysyndrome

VTE=venousthromboembolismCP(n=753)CP+B7.5

B7.5(n=745)Perren,etal.ESMO2010Patients(%)403020100ICON7:與bevacizumab相關(guān)的各級(jí)不良事件ATE53ICON7:

≥3級(jí)的與bevacizumab相關(guān)的不良事件CP(n=753)CP+B7.5

B7.5(n=745)*Grade≥2Perren,etal.ESMO2010Patients(%)403020100ICON7:≥3級(jí)的與bevacizumab相關(guān)的不良54ICON7:總結(jié)ICON7的數(shù)據(jù)進(jìn)一步證實(shí)了GOG-0218的結(jié)論：卵巢癌患者一線接受bevacizumab聯(lián)合化療后續(xù)bevacizumab單藥治療明顯提高患者PFS1–3Bevacizumab治療通常合并可控制的副反應(yīng)，

目前無新的安全顧慮產(chǎn)生1ICON7中高風(fēng)險(xiǎn)亞組分析結(jié)果進(jìn)一步支持bevacizumab運(yùn)用于III/IV期腫瘤殘存的患者2

CP+bevacizumabcontinuedsingle-agentbevacizumab

應(yīng)該成為進(jìn)展期卵巢癌一線治療的標(biāo)準(zhǔn)方案1.Burger,etal.GynecologicOncologyGroup.NEnglJMed.2011Dec29;3