贝伐在卵巢癌研究

Avastininovariancancer:clinicaltrialsAvastin在卵巢癌的相关研究•复发卵巢癌的II期临床试验–BurgerRA,etal.JClinOncol2007–CannistraSA,etal.JClinOncol2007–GarciaAA,etal.JClinOncol2008•初治卵巢癌的II期临床试验–Michaetal.IntJGynecolCancer2007–Pensonetal,JClinOncol2010•初治卵巢癌的III期临床试验–GOG-0218,ASCO2010–ICON7/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)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-basedregimenifplatinum-freeinterval≥12months)Burger,etal.JCO2007PD既往治疗后进展卵巢癌*(n=62)Avastin15mg/kgevery3weeksGOG170D: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-freeinterval6months(%)58EOC=epithelialovariancancer;PPC=primaryperitonealcancerBurger,etal.JCO2007GOG170D: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‡14of32patientswithstablediseasehadPFS6monthsGOG170D: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=venousthromboemboliceventsBurger,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.JCO2007Avastin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≤2Avastin214.717Cannistra20072442–3Avastin164.4Smerdel2009338Median5Avastin305.98.6Avastin-basedcombinationregimensGarcia2008470≤3Avastin+cyclophosphamide247.2(TTP)16.9McGonigle2008522≤2Avastin+topotecan22Kikuchi20096221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.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/m2q3wx6–8+Avastin15mg/kgq3w‡Avastin15mg/kgq3wfor12monthsAvastin+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(%)168232FIGOstage(%)Early10III69IV21Primarysite(%)Ovary73Primaryperitoneal16Fallopiantube8Uterinepapillaryserous5Cytoreduction(%)Optimal79Suboptimal21Penson,etal.JCO2010Avastin+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Patients(%)16141210864203级4级*AllallergicreactionsweretopaclitaxelPenson,etal.JCO2010Avastin+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6543210Penson,etal.JCO2010Patients(%)3级4级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.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Avastin后胃肠道穿孔的发生率增加1Avasti