胃癌靶向治疗课件.ppt

1、胃癌靶向治疗分子靶向治疗分子靶向治疗困惑的临床困惑的临床n 理解分子靶点理解分子靶点n 理解疗效与特异性毒性反应理解疗效与特异性毒性反应n 药物机理与临床研究结果的解读药物机理与临床研究结果的解读n 分子靶向治疗药物的应用实践分子靶向治疗药物的应用实践n 做到真正的做到真正的translational researchtranslational researchn指导临床研究设计指导临床研究设计n指导临床指南指导临床指南胃癌靶向治疗近十年的晚期胃癌临床研究近十年的晚期胃癌临床研究nMAGIC in NEJM(Cunningham,2006)nTAX 325 in JCO（Eric Van Cu

2、tsem,2006）nREAL-2 in NEJM(Cunningham,2008)nML-17032 in Ann Oncology（Kang,2009）nFLAGS in ASCO GI（Ajani,2009）nToGA in ASCO(Eric Van Cutsem&Bang,2009)nAVAGAST in ASCO(Kang,2010)nGRANIT-1(Eric Van Cutsem,2012）nREAL-3(Waddell,2012)n胃癌靶向治疗目前正在研究中的胃癌治疗靶点与靶向药物目前正在研究中的胃癌治疗靶点与靶向药物Wong H,Yau T.The Oncologist 2

3、012;17:346-358.西妥昔单抗西妥昔单抗帕尼单抗帕尼单抗曲妥珠单抗曲妥珠单抗贝伐珠单抗贝伐珠单抗FigitumumabGDC-0449拉帕替尼拉帕替尼厄洛替尼厄洛替尼吉非替尼吉非替尼索拉非尼索拉非尼舒尼替尼舒尼替尼依维莫司依维莫司细胞生存/增殖GSK089RasRafMEKERKP13KAktmTORSmoGli-1Ptch-1PTENHhIGF-1RPDGFRVEGFRHER-2HER-1VEGFMet胃癌靶向治疗 合理治疗靶点的标准合理治疗靶点的标准n与肿瘤的恶性表型相关与肿瘤的恶性表型相关n重要脏器与组织中很少表达重要脏器与组织中很少表达n分子特性与生物学行为相关分子特性与生物

4、学行为相关n能在临床较易获得的样本中重复检测能在临床较易获得的样本中重复检测n与临床预后相关与临床预后相关n当该靶点被阻断、干扰或抑制时，对高度表达该靶点当该靶点被阻断、干扰或抑制时，对高度表达该靶点的患者应有一定的临床反应，对不表达该靶点者，应的患者应有一定的临床反应，对不表达该靶点者，应无或产生较少临床反应无或产生较少临床反应胃癌靶向治疗胃癌的分子靶点寻找胃癌的分子靶点寻找nKRAS MT10%nBRAF MT5%nEGFR MT 5%nC-met 扩增扩增40%)nHER-2 过表达过表达10-25%胃癌靶向治疗单药应用疗效有限单药应用疗效有限（Phase 2）Phase IIStudy

5、RegimenNResponse(%)TTP/OSBang 2007Sunitinib383%NSMuro 2008RAD001240%NSGold 2008Cetuximab552%1.8 mos/4 mosHecht 2008Lapatinib210%-Lqbal 2007477%2 mos/5mos胃癌靶向治疗靶向化疗：成绩较好（靶向化疗：成绩较好（Phase 2）Phase II StudyRegimenNRR(%)TTP/OSLordick et al.20064Cetuximab+FUFOX2856%8.1/28.2mosDi Fabio et al.20062Cetuximab+

6、FOLFIRI2752%Pinto et al.20063Cetuximab+FOLFIRI2556%8/16 mosJhawer 2009Bev+Modified DCF3664%12 mos/16mosShah et al.20061Bev+Cisplatin+Irinotecan3465%8.3/12.3MosEnzinger et al.2008Bev+Irino/Docet/Cisplatin2268%NS1.Shah et al.J Clin Oncol,2006;24;6201;2.DL Fabio et al.ESMO,2006,Abstract 1077PD;3.Pinto

7、et al.Ann Oncol 2007;4.Lordick et al.Ann Oncol 2008胃癌靶向治疗铂类药物铂类药物替换替换氟尿嘧啶类氟尿嘧啶类药物替换药物替换分子靶向分子靶向药物药物添加药物添加药物替换药物替换药物基于优效性检验的基于优效性检验的胃癌一线化疗方案胃癌一线化疗方案晚期胃癌药物治疗的优化策略序贯治疗序贯治疗诱导化疗诱导化疗/维持化疗维持化疗其他策略其他策略目目标标：延：延长长生存生存胃癌靶向治疗ToGA（XP/FPH）AVAGAST（XPBV）07/23/2007胃癌靶向治疗胃癌胃癌 EGFREGFR 表达表达 包括包括EGFEGF家族在内的各类生长因子及其受体在胃

8、癌中呈过家族在内的各类生长因子及其受体在胃癌中呈过度表达度表达 (Gastric Cancer 2004;7:61-77)(Gastric Cancer 2004;7:61-77)免疫组化染色提示胃癌组织中免疫组化染色提示胃癌组织中EGFREGFR表达率为表达率为59,559,5 8686%(JCO2006;(JCO2006;24:4922-4927;ASCO2007#4526)24:4922-4927;ASCO2007#4526)RT-PCRRT-PCR检测提示胃癌组织中检测提示胃癌组织中EGFREGFR基因扩增率约基因扩增率约 6262%(World J(World J Gastroent

9、erol 2007;13:3605-3609)Gastroenterol 2007;13:3605-3609)EGFREGFR表达升高与以下临床病理因素相关表达升高与以下临床病理因素相关:进展期胃癌淋巴结转移进展期胃癌淋巴结转移 生存期缩短生存期缩短 (EJC 2001;37:S9-S15)(EJC 2001;37:S9-S15)胃癌靶向治疗EGF receptor signaling pathway:A rationale for personalized therapySurvival(anti-apoptosis)Gene transcriptionCell-cycle progress

10、ionMYCMYCCyclin D1FOSJUNPPCyclin D1AngiogenesisInvasion andmetastasisChemotherapy/radiotherapy resistanceProliferation/maturationMAPKMEKRASRAFSOSGRB2PTENAKTSTATP13KpYpYLigand:AREG/EREGTarget for EGFR-ERBITUXEGFR-TKTarget for EGFT-TK inhibitorpYYarden Y,Sliwkowski MX.Nat Rev Mol Cell Biol 2001;2:1271

11、37;Chakravarti A,et al.Cancer Res 2002;62:43074315;Baselga J.Eur J Cancer 2001;37(Suppl.4):S16S22;Kawanaka H,et al.Life Sci 2001;69:30193033胃癌靶向治疗EGFR TKI in GC(Phase 2)GastricCase Number Response(%)Dragovich(erlotinib)250Doi(Gefitinib)751GE JunctionFerry(Gefitinib)2711Janmaat(Gefitinib)260Tew(Erlot

12、inib)170Dragovich(Erlotinib)439Doi 2036,Proc ASCO 22,2003;Ferry Clin Can Res,132:5669,2007,Jarmaat,JCO,24,200807/23/2007胃癌靶向治疗西妥昔单抗一线治疗胃癌的尝试西妥昔单抗一线治疗胃癌的尝试方案方案病例数病例数RR(%)PFS(mo)OS(mo)作者作者FOLFIRI+Erbitux38448.016.0Pinto,Ann Onc.2007FUFOX+Erbitux46657.69.5Lordick,ASCO 2007Iri/5-FU/FA+Erbitux49428.516.6

13、Kanzler,ASCO 2009Irino/Oxa+Erbitux31426.29.5Woell,ASCO 2009Docetaxel+Erbitux3441Pinto,ASCO GI 2008Cispl.+Cape+Erbi47485.2Zhang,ASCO GI 2009Cis+5-FU+Erbitux35691114.5Yeh,ASCO 2009XELOX+Erbitux44526.611.7Kim,ASCO GI 2009FOLFOX-6+Erbitux38505.59.9Han,Br.J.Cancer 2009胃癌靶向治疗年龄年龄18岁，岁，KPS评分评分60分分病理学和病理学和/

14、或细胞学证实为胃腺癌，预计生存期或细胞学证实为胃腺癌，预计生存期3月月局部晚期或转移性癌，无法手术切除局部晚期或转移性癌，无法手术切除一线治疗患者，接受辅助治疗至少间隔一线治疗患者，接受辅助治疗至少间隔6月以上月以上血常规检查正常：血常规检查正常：WBC3.0109/L，中性粒细胞，中性粒细胞 1.5109/L，PLT80109/LECOG 评分为评分为 2无严重心、肺、肝、肾功能障碍，未伴发急性感染无严重心、肺、肝、肾功能障碍，未伴发急性感染西妥昔单抗西妥昔单抗+FOLFOX4一线治疗一线治疗晚期胃癌临床观察晚期胃癌临床观察Shi M,Zhang J,et al,Hepatogastroen

15、terology,Shi M,Zhang J,et al,Hepatogastroenterology,20112011胃癌靶向治疗临床疗效评价临床疗效评价 例数例数 百分比（百分比（%）CR 0 0 PD 4 16.0 SD 12 48.0 PR 9 36.0 ORR=9/25=36.0%DCR=20/24=84.0%Shi M,Zhang J,et al,Hepatogastroenterology,Shi M,Zhang J,et al,Hepatogastroenterology,20112011胃癌靶向治疗治疗前后治疗前后CT病例病例1：胃癌肝转移：胃癌肝转移Shi M,Zhang

16、J,et al,Hepatogastroenterology,Shi M,Zhang J,et al,Hepatogastroenterology,20112011胃癌靶向治疗治疗前后治疗前后CT病例病例2：胃癌肝多发转移：胃癌肝多发转移Shi M,Zhang J,et al,Hepatogastroenterology,Shi M,Zhang J,et al,Hepatogastroenterology,20112011胃癌靶向治疗治疗前后治疗前后CT病例病例3：胃癌肝多发转移：胃癌肝多发转移Shi M,Zhang J,et al,Hepatogastroenterology,Shi M,Z

17、hang J,et al,Hepatogastroenterology,20112011胃癌靶向治疗PFS&OSmPFS=6.5个月个月mOS=10.6个月个月Shi M,Zhang J,et al,Hepatogastroenterology,Shi M,Zhang J,et al,Hepatogastroenterology,20112011胃癌靶向治疗KRAS recently identified as predictive marker for response to KRAS recently identified as predictive marker for response

18、 to EGFR-inhibitor therapy in mCRC.EGFR-inhibitor therapy in mCRC.Incidence of KRAS mutations in gastric cancer?Incidence of KRAS mutations in gastric cancer?Current assumption:Current assumption:KRASKRAS尚不能作为胃癌尚不能作为胃癌EGFREGFR靶向抑制治疗的疗靶向抑制治疗的疗效预测标志物效预测标志物胃癌靶向治疗Cisplatin Cisplatin 80mg/m80mg/m2 2 d1 d

19、1Capecitabine Capecitabine 1000mg/m1000mg/m2 2 twice daily;d1-14 twice daily;d1-14q3wq3wR RA AN ND DO OM M Until radiographically documented PD or unacceptable toxicity Primary endpoint:PFS time (as assessed by Independent Review Committee)Cisplatin Cisplatin 80mg/m80mg/m2 2 d1 d1Capecitabine Capeci

20、tabine 1000mg/m1000mg/m2 2 twice daily;d1-twice daily;d1-1414q3wq3wCetuximab Cetuximab 400mg/m400mg/m2 2 loading dose,loading dose,then 250mg/mthen 250mg/m2 2 per week per week胃癌靶向治疗30%鼠源蛋白鼠源蛋白嵌合嵌合5%鼠源蛋白鼠源蛋白人源化人源化100%鼠源蛋白鼠源蛋白全鼠源全鼠源100%人蛋白人蛋白全人源化全人源化cetuximabnimotuzumabpanitumumab-momab-ximab-mumab-z

21、umab鼠源鼠源嵌合嵌合全人源化全人源化人源化人源化HAMA反应发生率降低胃癌靶向治疗进行亲和力设计，实现最适亲和力进行亲和力设计，实现最适亲和力 胃癌靶向治疗胃癌靶向治疗胃癌靶向治疗胃癌靶向治疗胃癌靶向治疗皮疹与疗效相关？皮疹与疗效相关？胃癌靶向治疗ToGA研究中研究中HER-2检测情况检测情况n HER2 with IHC&FISHn Resultsn 2484 个进展期胃癌蜡块个进展期胃癌蜡块n 544 HER2+(21,9%)n IHC-FISH一致率一致率 87,3n 与胃癌临床病理因素的关系与胃癌临床病理因素的关系LocationCardia 32,2%Non cardia 19,

22、9%P=0.02typeIntestinal:32,5%Diffuse:6%P=0.001胃癌靶向治疗HER-2 在胃癌表达Ann Oncol,2008,19:1523外科杂志外科杂志1996,1:25宫立群宫立群133中国中国18,1IHC胃癌靶向治疗ToGA 研究设计研究设计HER2-HER2-阳性阳性晚期胃癌患者晚期胃癌患者 (n=584)(n=584)5-FU 5-FU 或或 卡培他滨卡培他滨a a +顺铂顺铂(n=290)(n=290)R Ra a由研究者的判别来选择由研究者的判别来选择GEJ,GEJ,胃食管连接部胃食管连接部5-FU 5-FU 或或 卡培他滨卡培他滨a a +顺铂顺

23、铂+赫赛汀赫赛汀(n=294)(n=294)l 分层因素分层因素局部晚期或转移性局部晚期或转移性 胃体部胃体部 vs vs 胃食管连接部胃食管连接部可测量可测量 vs vs 不可测量不可测量ECOG ECOG 评分评分 0-1 vs 20-1 vs 2卡培他滨卡培他滨 vs 5-FUvs 5-FU全球、多中心、随机、开放全球、多中心、随机、开放IIIIII期临床研究期临床研究1 1Bang et al;Abstract 4556,ASCO 2009Bang et al;Abstract 4556,ASCO 2009 3807 3807 位患者接受筛选位患者接受筛选1 1 810 HER2-81

24、0 HER2-阳性阳性(22.1%)(22.1%)胃癌靶向治疗患者的人口统计学以及基线特征患者的人口统计学以及基线特征特征特征F+Cn=290n=290F+C+赫赛汀赫赛汀n=294n=294性别性别,%,%男性男性/女性女性75/2575/2577/2377/23中位年龄中位年龄 (年龄范围年龄范围)岁岁59.0(21-82)59.0(21-82)61.0(23-83)61.0(23-83)中位体重中位体重 (体重范围体重范围)公斤公斤60.3(28-105)60.3(28-105)61.5(35-110)61.5(35-110)地区地区,n(%),n(%)亚洲亚洲美洲美洲欧洲欧洲其他其他1

25、66(56)166(56)26(9)26(9)95(32)95(32)9(3)9(3)158(53)158(53)27(9)27(9)99(33)99(33)14(5)14(5)胃癌的类型胃癌的类型(中心实验室评估结果中心实验室评估结果)肠型肠型弥漫型弥漫型混合型混合型74.274.2a a8.78.7a a17.117.1a a76.876.8b b8.98.9b b14.314.3b b曾行胃部切除术曾行胃部切除术21.421.424.124.1入组最多的为韩国，日本，中国和俄罗斯F,氟尿嘧啶;C,顺铂 an=287;bn=293胃癌靶向治疗Primary end point:OSPrim

26、ary end point:OSTime(months)2942902772662462232091851731431471171139090647147563243243016211413712665401000No.at risk11.113.80.00.10.20.30.40.50.60.70.80.91.00246810 12 14 16 18 20 22 24 26 28 30 32 34 36EventFC+T TFCEventsEvents167167182182HRHR0.740.7495%CI95%CI0.60,0.910.60,0.91p valuep value0.004

27、60.0046MedianMedianOSOS13.813.811.111.1T,trastuzumab胃癌靶向治疗Secondary end point:PFSSecondary end point:PFS0246810 12 14 16 18 20 22 24 26 28 30 32 34Event2942902582382011821419995626033411728721513393826261614020005.56.7No.at risk0.00.10.20.30.40.50.60.70.80.91.0Time(months)FC+T TFCEventsEvents2262262

28、35235HRHR0.710.7195%CI95%CI0.59,0.850.59,0.85p valuep value0.00020.0002MedianMedianPFSPFS6.76.75.55.5胃癌靶向治疗Secondary end point:Secondary end point:tumor response ratetumor response rate2.4%2.4%5.4%5.4%32.1%32.1%41.8%41.8%34.5%34.5%47.3%47.3%Intent to treatORR=CR+PRCR,complete response;PR,partial res

29、ponsep=0.0599p=0.0599p=0.0145p=0.0145F+C+trastuzumabF+Cp=0.0017p=0.0017Patients(%)CRPRORR胃癌靶向治疗Cross-trial Comparation of 1st Tx of GC张俊张俊,中国医学论坛报中国医学论坛报,20090723,20090723胃癌靶向治疗nThe response rate of Herceptin+CT in HER-2 positive patients was 47.3%,which means the other half of the patients were no

30、response to Herceptin treatmentnThe underlying mechanism is still unclearComments(Response rate)胃癌靶向治疗TITLE胃癌靶向治疗n 标本储藏条件对标本储藏条件对IHC 和和 FISH结果的影响结果的影响n胃癌的异质性胃癌的异质性n胃癌细胞胃癌细胞HER-2染色特征与乳腺癌的差异染色特征与乳腺癌的差异Comments(Standard techniques for HER-2 detection)胃癌靶向治疗Comments(Predictive marker)nHER-2 与胃癌预后不良相关，与胃

31、癌预后不良相关，HER-2作为作为Herceptin治疗胃癌的疗效预测标志物的价值？治疗胃癌的疗效预测标志物的价值？nHER-2/neu 信号通路内的其他接头蛋白或转录信号通路内的其他接头蛋白或转录因子作为潜在疗效预测标志物的价值？因子作为潜在疗效预测标志物的价值？nEGFR 单抗治疗中单抗治疗中KRAS 的故事的故事胃癌靶向治疗113OS in OS in IHC2+/FISH+or IHC3+IHC2+/FISH+or IHC3+(exploratory analysis)(exploratory analysis)1.00.80.60.40.20.03634323028262422201

32、81614121086420Time(months)11.816.0FC+T TFCEventsEvents120120136136HRHR0.650.6595%CI95%CI0.51,0.830.51,0.83MedianMedianOSOS16.016.011.811.8Event0.10.30.50.70.9218 19840531242011228 218196 170170 141142 11212296100758453653951281000No.at risk39202813胃癌靶向治疗研究设计研究设计:开放、单组、开放、单组、II期研究期研究主要终点主要终点:ORR次要终点次

33、要终点:PFS,中国晚期胃癌患者中国晚期胃癌患者HER2阳性率阳性率,OS,安全性安全性 HER2+晚期胃癌晚期胃癌之前未接受治疗之前未接受治疗 曲妥珠单抗曲妥珠单抗8mg/kg 首剂首剂,然后然后 6mg/kg 每每3周周卡培他滨卡培他滨1000 mg/m2 BID D1-14 每每3周周奥沙利铂奥沙利铂130 mg/m130 mg/m2 2,D1,D1 每每3 3周周曲妥珠单抗曲妥珠单抗6mg/kg 每每3周周卡培他滨卡培他滨1000 mg/m2 BID D1-14 每每3周周直到进展直到进展6 cycles第一阶段第一阶段CGOG1001（ML25578）:曲妥珠单抗联合曲妥珠单抗联合X

34、ELOX方案方案用于用于HER2阳性晚期胃癌的一线治疗阳性晚期胃癌的一线治疗HER2+晚期胃癌晚期胃癌之前未接受治疗之前未接受治疗曲妥珠单抗曲妥珠单抗8mg/kg 首剂首剂,然后然后 6mg/kg 每每3周周卡培他滨卡培他滨1000 mg/m2 BID D1-14 每每3周周奥沙利铂奥沙利铂130 mg/m2,D1 130 mg/m2,D1 每每3 3周周曲妥珠单抗曲妥珠单抗6mg/kg 每每3周周卡培他滨卡培他滨1000 mg/m2 BID D1-14 每每3周周直到进展直到进展6 cycles第二阶段第二阶段如果如果16例患者例患者中有中有7例以上例以上患者缓解，研患者缓解，研究进入第二阶

35、究进入第二阶段段全部全部 N=51胃癌靶向治疗43mTORl mTORmTOR是细胞代谢、生长、增殖是细胞代谢、生长、增殖和血管生成的核心调控者和血管生成的核心调控者1,21,2l mTORmTOR是肿瘤生长开关是肿瘤生长开关1,21,2 胰岛素样生长因子胰岛素样生长因子-1-1（IGF-1IGF-1）等激活等激活mTORmTOR通路通路 mTORmTOR激活以下基因突变激活以下基因突变:PTEN,:PTEN,TSC2,NF1TSC2,NF1和和VHLVHL丢失丢失l 抑制抑制mTORmTOR能抑制肿瘤的生长和能抑制肿瘤的生长和增殖增殖2 21.Yao JC,et al.Best Prac C

36、lin Endocrinol Metab.2007;21:163-172.2.von Wichert G,et al.Cancer Res.2000;60:4573-4581.mTOR:哺乳动物雷帕霉素靶蛋白哺乳动物雷帕霉素靶蛋白胃癌靶向治疗GRANITE-1研究研究N=656靶向组靶向组(439):BSC+Everolimus Everolimus对照组对照组(217):BSC+安慰剂安慰剂R 2012 ASCO GIProbability of overall survival(%)100806040200024681012Time(months)14Censoring TimesEver

37、olimus+BSC(n/N=352/439)Placebo+BSC(n/N=180/217)Kaplan-Meier medians Everolimus+BSC:5.39 months Placebo+BSC:4.34 monthsHazard ratio:0.90(95%CI,0.75-1.08)Log-rank P value=0.1244No.of patients still at riskTime(months)EverolimusPlacebo16182022240246810121416182022242171721178260352816128410439355253195

38、139875230136310胃癌靶向治疗Everolimus用于胃癌的思考用于胃癌的思考l 单药用于二线单药用于二线/三线并未显著延长三线并未显著延长OS mOS HR 0.90（N.S.）l mPFS 1.44 1.68 mos，HR 0.66，P 0.001l 疾病控制率疾病控制率 22%43%l III期研究未能重复期研究未能重复II期数据期数据(n=53)OS 10.1 mos，PFS 2.7 mos，DCR 56%胃癌靶向治疗胃癌靶向治疗AVAGAST:A Randomized Double-Blind Placebo-Controlled Phase III StudyStart

39、ing dose of bev/placebo:30 minutes,subsequent doses:15 minutesStarting dose of bev/placebo:30 minutes,subsequent doses:15 minutesCapecitabineCapecitabine*/Cisplatin(XP)/Cisplatin(XP)+Placebo q3w+Placebo q3wCapecitabineCapecitabine*/Cisplatin(XP)/Cisplatin(XP)+Bevacizumab q3w+Bevacizumab q3wLocally a

40、dvancedLocally advanced or metastatic or metastatic gastric cancergastric cancerR R*5-FU also allowed 5-FU also allowed if cape contraindicatedif cape contraindicatedCape 1000Cape 1000 mg/mmg/m2 2 oral bid,oral bid,d114,1-week rest d114,1-week restCisplatin 80Cisplatin 80 mg/mmg/m2 2 d1 d1Bevacizuma

41、b 7.5 mg/kg d1Bevacizumab 7.5 mg/kg d1Maximum of 6 cycles of cisplatinMaximum of 6 cycles of cisplatinCape and bevacizumab/placebo until PDCape and bevacizumab/placebo until PDStratification factors:Stratification factors:1.Geographic region1.Geographic region2.Fluoropirimidine backbone2.Fluoropirim

42、idine backbone3.Disease status3.Disease status胃癌靶向治疗病例特征病例特征 (I)(I)Number of patients N=774(%)XP+PlaceboN=387XP+BevN=387GenderMale258(67)257(66)Age,yearsMedian(range)59(2282)58(2281)ECOG PS012 367(95)20(5)365(94)22*(6)RegionAsiaEuropePan-America188(49)124(32)75(19)188(49)125(32)74(19)Fluoropyrimidin

43、eCapecitabine5-FU365(94)22(6)364(94)23(6)Disease statusLocally advancedMetastatic9(2)378(98)20(5)367(95)*1 additional patient had an ECOG PS of 41 additional patient had an ECOG PS of 4胃癌靶向治疗病例特征病例特征 (II)(II)Number of patients N=774(%)XP+PlaceboN=387XP+BevN=387Primary siteStomachGEJ338(87)49(13)333(

44、86)54(14)Histologic typeIntestinalDiffuseMixed135(35)206(53)26(7)155(40)176(46)35(9)Disease measurabilityMeasurableEvaluable297(77)90(23)311(80)76(20)Metastatic sites,n0128(2)131(34)247(64)8(2)131(34)247(64)Prior gastrectomyYes107(28)110(28)Liver metastasisYes126(33)130(34)胃癌靶向治疗总生存总生存38738738738734

45、3343355355271271291291204204232232146146178178989810410415151919XP+PlaceboXP+PlaceboXP+BevXP+BevNumber at riskNumber at risk545450500 00 0XP+PlaceboXP+PlaceboXP+BevXP+BevHR=0.87HR=0.8795%CI 95%CI 0.731.03 0.731.03 p=0.1002p=0.1002Survival rateSurvival rate3 39 915151818212124240 00.00.00.10.10.20.20

46、.30.30.40.40.50.50.60.60.70.70.80.80.90.91.01.06 61212Study monthStudy month10.110.112.112.1胃癌靶向治疗无进展生存无进展生存387387387387279279306306145145201201868612312355557171323238383 33 3151511110 00 0XP+PlaceboXP+PlaceboXP+BevXP+BevNumber at riskNumber at riskXP+PlaceboXP+PlaceboXP+BevXP+BevHR=0.80HR=0.8095%C

47、I 95%CI 0.680.93 0.680.93 p=0.0037p=0.0037Progression-free survival rateProgression-free survival rate0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91.01.03 39 915151818212124240 06 612125.35.36.76.7Study monthStudy month胃癌靶向治疗最佳总体反应率最佳总体反应率XP+PlaceboN=387XP+BevN=387Patients with measur

48、able disease297311Overall response111(37%)143(46%)95%CI31.943.140.351.7Difference9%95%CI0.616.6P value(2)0.0315Complete response3(1%)5(2%)Partial response108(36%)138(44%)Stable disease90(30%)93(30%)Progressive disease63(21%)44(14%)Not assessable33(11%)31(10%)胃癌靶向治疗总生存总生存:亚组分析亚组分析Pan-AmericaPan-Ameri

49、ca 2 2NoNoDisease statusDisease statusECOG performanceECOG performancePrior gastrectomyPrior gastrectomyRegionRegionSite of primary Site of primary diseasediseaseNo.of metastatic sites at No.of metastatic sites at baselinebaselineDisease Disease measurability measurability Histologic type Histologic

50、 type AllAllLocally advancedLocally advanced*MetastatMetastaticic0 0YesYesEuropeEuropeAllAll 1 1AsiaAsiaStomachStomachGE junctionGE junction 1 1MeasurableMeasurableNon-measurableNon-measurableIntestinIntestinalalDiffuseDiffuseMixeMixed dSubgroupSubgroupCategoryCategory2 2Hazard RatioHazard Ratio0 01