胃癌靶向治疗课件

1、近十年的晚期胃癌临床研究MAGIC in NEJM (Cunningham,2006)TAX 325 in JCO （Eric Van Cutsem,2006） REAL-2 in NEJM (Cunningham,2008)ML-17032 in Ann Oncology（Kang,2009） FLAGS in ASCO GI（Ajani,2009）ToGA in ASCO (Eric Van Cutsem & Bang,2009)AVAGAST in ASCO (Kang, 2010)GRANIT-1 (Eric Van Cutsem , 2012）REAL-3 ( Waddell, 20

2、12)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 2012; 17:346-358.西妥昔单抗帕尼单抗曲妥珠单抗贝伐珠单抗FigitumumabGDC-0449拉帕替尼厄洛替尼吉非替尼索拉非尼舒尼替尼依维莫司细胞生存/增殖GSK089RasRafMEKERKP13KAktmTORSmoGli-1Ptch-1PTENHhIGF-1RPDGFRVEGFRHER-2HER-1VEGFMet 合理治疗靶点的标准与肿瘤的恶性表型相关重要脏器与组织中很少表达分子特性与生物学行为相关能在临床较易获得的样本中重复检测与临床预后相关当该靶点被阻断、干扰或抑制

3、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，应无或产生较少临床反应胃癌的分子靶点寻找KRAS MT10%BRAF MT5%EGFR MT 5%C-met 扩增40%)HER-2 过表达10-25%单药应用疗效有限（ Phase 2）Phase IIStudyRegimenNResponse(%)TTP/OSBang 2007Sunitinib383%NSMuro 2008RAD001240%NSGold 2008Cetuximab552%1.8 mos/4 mosHecht 2008Lapatinib210%-Lqbal 2007477%2 mos/5mos靶向化疗：成绩较

4、好（Phase 2）Phase II StudyRegimenNRR(%)TTP/OSLordick et al.20064Cetuximab +FUFOX2856%8.1/28.2mosDi Fabio et al.20062Cetuximab +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

5、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 et al. Ann Oncol 2007; 4.Lordick et al. Ann Oncol 2008铂类药物替换氟尿嘧啶类药物替换分子靶向药物添加药物替换药物基于优效性检验的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诱导化疗/维持化疗其他策略目标：延长生存ToGA（XP/FPH）AVAGAST（XPBV）07/23/

6、2007胃癌 EGFR 表达包括EGF家族在内的各类生长因子及其受体在胃癌中呈过度表达 (Gastric Cancer 2004; 7:61-77)免疫组化染色提示胃癌组织中EGFR表达率为59,5 86% (JCO2006; 24:4922-4927; ASCO2007 #4526)RT-PCR检测提示胃癌组织中EGFR基因扩增率约 62% (World J Gastroenterol 2007; 13:3605-3609) EGFR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 生存期缩短 (EJC 2001; 37:S9-S15)EGF receptor signaling pa

7、thway: A rationale for personalized therapySurvival (anti-apoptosis)Gene transcriptionCell-cycle progressionMYCMYCCyclin D1FOSJUNPPCyclin D1AngiogenesisInvasion andmetastasisChemotherapy/radiotherapy resistanceProliferation/maturationMAPKMEKRASRAFSOSGRB2PTENAKTSTATP13KpYpYLigand: AREG/EREGTarget for

8、 EGFR-ERBITUXEGFR-TKTarget for EGFT-TK inhibitorpYYarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol 2001;2:127137; 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;69:30193033EGFR TKI in GC (Phase 2)GastricCase Number

9、Response(%)Dragovich(erlotinib)250Doi (Gefitinib)751GE JunctionFerry (Gefitinib)2711Janmaat(Gefitinib)260Tew (Erlotinib)170Dragovich(Erlotinib)439Doi 2036, Proc ASCO 22,2003; Ferry Clin Can Res, 132:5669, 2007, Jarmaat, JCO,24,200807/23/2007西妥昔单抗一线治疗胃癌的尝试方案病例数RR (%)PFS (mo)OS (mo)作者FOLFIRI + Erbitux

10、38448.016.0Pinto, Ann Onc. 2007FUFOX + Erbitux46657.69.5Lordick, ASCO 2007Iri/5-FU/FA + Erbitux49428.516.6Kanzler, ASCO 2009Irino/Oxa + Erbitux31426.29.5Woell, ASCO 2009Docetaxel + Erbitux3441Pinto, ASCO GI 2008Cispl. + Cape + Erbi47485.2Zhang, ASCO GI 2009Cis + 5-FU + Erbitux35691114.5Yeh, ASCO 200

11、9XELOX + Erbitux44526.611.7Kim, ASCO GI 2009FOLFOX-6 + Erbitux38505.59.9Han, Br.J.Cancer 2009年龄18岁，KPS评分60分病理学和/或细胞学证实为胃腺癌，预计生存期3月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6月以上血常规检查正常：WBC3.0109/L，中性粒细胞 1.5109/L，PLT80109/LECOG 评分为 2无严重心、肺、肝、肾功能障碍，未伴发急性感染西妥昔单抗+FOLFOX4一线治疗晚期胃癌临床观察Shi M, Zhang J, et al, Hepatoga

12、stroenterology, 2011临床疗效评价 例数 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, 2011治疗前后CT病例1：胃癌肝转移Shi M, Zhang J, et al, Hepatogastroenterology, 2011治疗前后CT病例2：胃癌肝多发转移Shi M, Zhang J, et al, Hepatogastroenterology, 2011治疗前后CT病例3：

13、胃癌肝多发转移Shi M, Zhang J, et al, Hepatogastroenterology, 2011PFS & OSmPFS=6.5个月mOS=10.6个月Shi M, Zhang J, et al, Hepatogastroenterology, 2011胃癌 KRAS 突变率StudyNo. of examined samplesNo. (%) of samples with KRAS mutationsZhao et al., Int J Cancer 2004; 108:167948 (8.5%)Lee et al., Oncogene 2003; 22: 694260

14、 early GC 259 advanced GC1 in EGC (1.7%), 8 in AGC (3.1%)Kim et al., Hum Genet 2003; 114:118664 (6.1%)KRAS recently identified as predictive marker for response to EGFR-inhibitor therapy in mCRC. Incidence of KRAS mutations in gastric cancer? Current assumption: KRAS尚不能作为胃癌EGFR靶向抑制治疗的疗效预测标志物Cisplati

15、n 80mg/m2 d1Capecitabine 1000mg/m2 twice daily; d1-14q3wRANDOM Until radiographically documented PD or unacceptable toxicity Primary endpoint: PFS time (as assessed by Independent Review Committee)Cisplatin 80mg/m2 d1Capecitabine 1000mg/m2 twice daily; d1-14q3wCetuximab 400mg/m2 loading dose,then 25

16、0mg/m2 per weekEXPAND Phase IIIEGFR单克隆抗体的分类30% 鼠源蛋白嵌合5% 鼠源蛋白人源化100% 鼠源蛋白全鼠源100% 人蛋白全人源化cetuximabnimotuzumabpanitumumab -momab-ximab-mumab-zumab鼠源嵌合全人源化人源化HAMA反应发生率降低如何改进？进行亲和力设计，实现最适亲和力 TITLETITLETITLETITLE皮疹与疗效相关？ToGA研究中HER-2检测情况HER2 with IHC & FISHResults2484 个进展期胃癌蜡块544 HER2+(21,9%)IHC-FISH一致率 87

17、,3与胃癌临床病理因素的关系LocationCardia 32,2%Non cardia 19,9%P=0.02typeIntestinal:32,5%Diffuse: 6%P=0.001HER-2 在胃癌表达Ann Oncol, 2008,19:1523外科杂志1996,1:25宫立群133中国18,1IHCToGA 研究设计HER2-阳性晚期胃癌患者 (n=584)5-FU 或 卡培他滨a + 顺铂(n=290)Ra由研究者的判别来选择GEJ, 胃食管连接部5-FU 或 卡培他滨a + 顺铂+ 赫赛汀(n=294)分层因素局部晚期或转移性 胃体部 vs 胃食管连接部可测量 vs 不可测量E

18、COG 评分 0-1 vs 2卡培他滨 vs 5-FU全球、多中心、随机、开放III期临床研究1Bang et al; Abstract 4556, ASCO 2009 3807 位患者接受筛选1 810 HER2-阳性 (22.1%)患者的人口统计学以及基线特征特征F+Cn=290F+C + 赫赛汀n=294性别, %男性 / 女性75 / 2577 / 23中位年龄 (年龄范围) 岁59.0 (21-82)61.0 (23-83)中位体重 (体重范围) 公斤60.3 (28-105)61.5 (35-110)地区, n (%)亚洲美洲欧洲其他166 (56)26 (9)95 (32)9 (

19、3)158 (53)27 (9)99 (33)14 (5)胃癌的类型 (中心实验室评估结果)肠型弥漫型混合型74.2a8.7a17.1a76.8b8.9b14.3b曾行胃部切除术21.424.1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=293Primary end point: OSTime (months)2942902772662462232091851731431471171139090647147563243243016211413712665401000No. at risk11.113.80.00.10.20.30.40.50.60.7

20、0.80.91.0024681012141618202224262830323436EventFC + TFCEvents167182HR0.7495% CI0.60, 0.91p value0.0046MedianOS13.811.1T, trastuzumabSecondary end point: PFS0246810121416182022242628303234Event2942902582382011821419995626033411728721513393826261614020005.56.7No. at risk0.00.10.20.30.40.50.60.70.80.91

21、.0Time (months)FC + TFCEvents226235HR0.7195% CI0.59, 0.85p value0.0002MedianPFS6.75.5Secondary end point: tumor response rate2.4%5.4%32.1%41.8%34.5%47.3%Intent to treatORR= CR + PRCR, complete response; PR, partial responsep=0.0599p=0.0145F+C + trastuzumabF+Cp=0.0017Patients (%)CRPRORRCross-trial Co

22、mparation of 1st Tx of GC张俊,中国医学论坛报,20090723The response rate of Herceptin+CT in HER-2 positive patients was 47.3%, which means the other half of the patients were no response to Herceptin treatmentThe underlying mechanism is still unclearComments (Response rate)TITLE 标本储藏条件对IHC 和 FISH结果的影响胃癌的异质性胃癌细

23、胞HER-2染色特征与乳腺癌的差异Comments (Standard techniques for HER-2 detection)Comments (Predictive marker)HER-2 与胃癌预后不良相关，HER-2作为Herceptin治疗胃癌的疗效预测标志物的价值？HER-2/neu 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？EGFR 单抗治疗中KRAS 的故事113OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)1.00.80.60.40.20.0363432302826242220181614121

24、086420Time (months)11.816.0FC + TFCEvents120136HR0.6595% CI0.51, 0.83MedianOS16.011.8Event0.10.30.50.70.9218 19840531242011228 218196 170170 141142 11212296100758453653951281000No. at risk39202813研究设计: 开放、单组、II期研究主要终点: ORR次要终点: PFS, 中国晚期胃癌患者HER2阳性率, OS, 安全性 HER2+晚期胃癌之前未接受治疗 曲妥珠单抗8mg/kg 首剂, 然后 6mg/kg

25、 每3周卡培他滨1000 mg/m2 BID D1-14 每3周奥沙利铂130 mg/m2, D1 每3周曲妥珠单抗6mg/kg 每3周卡培他滨1000 mg/m2 BID D1-14 每3周直到进展6 cycles第一阶段CGOG1001（ML25578）: 曲妥珠单抗联合XELOX方案用于HER2阳性晚期胃癌的一线治疗HER2+晚期胃癌之前未接受治疗曲妥珠单抗8mg/kg 首剂, 然后 6mg/kg 每3周卡培他滨1000 mg/m2 BID D1-14 每3周奥沙利铂130 mg/m2, D1 每3周曲妥珠单抗6mg/kg 每3周卡培他滨1000 mg/m2 BID D1-14 每3周直

26、到进展6 cycles第二阶段如果16例患者中有7例以上患者缓解，研究进入第二阶段全部 N=5142mTORmTOR是细胞代谢、生长、增殖和血管生成的核心调控者1,2mTOR是肿瘤生长开关1,2胰岛素样生长因子-1（IGF-1）等激活mTOR通路 mTOR激活以下基因突变: PTEN, TSC2, NF1和VHL丢失抑制mTOR能抑制肿瘤的生长和增殖21. Yao JC, et al. Best Prac Clin Endocrinol Metab. 2007;21:163-172. 2. von Wichert G, et al. Cancer Res. 2000;60:4573-4581.

27、 mTOR: 哺乳动物雷帕霉素靶蛋白GRANITE-1研究N=656靶向组(439):BSC+ Everolimus对照组(217):BSC+安慰剂R 2012 ASCO GIProbability of overall survival (%)100806040200024681012Time (months)14Censoring TimesEverolimus + BSC (n/N = 352/439)Placebo + BSC (n/N = 180/217)Kaplan-Meier medians Everolimus + BSC: 5.39 months Placebo + BSC:

28、 4.34 monthsHazard ratio: 0.90 (95% CI, 0.75-1.08)Log-rank P value = 0.1244No. of patients still at riskTime (months)EverolimusPlacebo16182022240246810121416182022242171721178260352816128410439355253195139875230136310Everolimus用于胃癌的思考单药用于二线/三线并未显著延长OSmOS HR 0.90 （N.S.）mPFS 1.44 1.68 mos，HR 0.66， P 0

29、.001疾病控制率 22%43%III期研究未能重复II期数据 (n=53)OS 10.1 mos， PFS 2.7 mos， DCR 56%AVAGAST: A Randomized Double-Blind Placebo- Controlled Phase III StudyStarting dose of bev/placebo: 30 minutes, subsequent doses: 15 minutesCapecitabine*/Cisplatin (XP) + Placebo q3wCapecitabine*/Cisplatin (XP)+ Bevacizumab q3wLo

30、cally advanced or metastatic gastric cancerR*5-FU also allowed if cape contraindicatedCape 1000 mg/m2 oral bid, d114, 1-week restCisplatin 80 mg/m2 d1Bevacizumab 7.5 mg/kg d1Maximum of 6 cycles of cisplatinCape and bevacizumab/placebo until PDStratification factors:1. Geographic region2. Fluoropirim

31、idine backbone3. Disease status病例特征 (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)FluoropyrimidineCapeci

32、tabine5-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 4病例特征 (II)Number of patients N=774 (%)XP + PlaceboN=387XP + BevN=387Primary siteStomachGEJ338 (87)49 (13)333 (86)54 (14)Histologic typeIntestinalDiffuseMix

33、ed135 (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)总生存387387343355271291204232146178981041519XP + P

34、laceboXP + BevNumber at risk545000XP + PlaceboXP + BevHR = 0.8795% CI 0.731.03 p = 0.1002Survival rate391518212400.00.10.20.30.40.50.60.70.80.91.0612Study month10.112.1无进展生存387387279306145201861235571323833151100XP + PlaceboXP + BevNumber at riskXP + PlaceboXP + BevHR = 0.8095% CI 0.680.93 p = 0.003

35、7Progression-free survival rate0.00.10.20.30.40.50.60.70.80.91.0391518212406125.36.7Study month最佳总体反应率XP + PlaceboN=387XP + BevN=387Patients with measurable disease297311Overall response111 (37%)143 (46%)95% CI31.943.140.351.7Difference9%95% CI0.616.6P value (2)0.0315Complete response3 (1%)5 (2%)Par

36、tial response108 (36%)138 (44%)Stable disease90 (30%)93 (30%)Progressive disease63 (21%)44 (14%)Not assessable33 (11%)31 (10%)总生存: 亚组分析Pan-America2NoDisease statusECOG performancePrior gastrectomyRegionSite of primary diseaseNo. of metastatic sites at baselineDisease measurability Histologic type Al

37、lLocally advanced*Metastatic0YesEuropeAll1AsiaStomachGE junction1MeasurableNon-measurableIntestinalDiffuseMixedSubgroupCategory2Hazard Ratio01* 29 patients with locally advanced disease onlyHR0.970.850.63不同地理区域的患者特征% of patientsAsiaEuropePan-AmericaAge6572687765283223ECOG PS0197919623*94Primary site

38、Stomach947884GEJ62216Extent of diseaseMetastatic999592Locally advanced158Prior gastrectomyyes322327no687773Measurable lesionyes738877no271223Liver metastasisyes273742no736358*1 additional patient had an ECOG PS of 4不同地理区域患者接受二线治疗情况RegionPatients enteredPatients receiving second-line treatment%Asia37624866Europe2497831Pan-America1493221AVAGAST 分析东西方的胃癌因发病机制、遗