胃癌靶向治疗

张俊上海交通大学医学院附属瑞金医院外科,胃癌分子靶向治疗的若干热点问题,分子靶向治疗困惑的临床,理解分子靶点 理解疗效与特异性毒性反应 药物机理与临床研究结果的解读 分子靶向治疗药物的应用实践 做到真正的translational research指导临床研究设计指导临床指南,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, 2012),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.,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 MT40%)HER-2 过表达10-25%,单药应用疗效有限（ Phase 2）,靶向化疗：成绩较好（Phase 2）,1.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）,07/23/2007,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 pathway: A rationale for personalized therapy,Yarden 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;69:30193033,EGFR TKI in GC (Phase 2),Doi 2036, Proc ASCO 22,2003; Ferry Clin Can Res, 132:5669, 2007, Jarmaat, JCO,24,2008,07/23/2007,西妥昔单抗一线治疗胃癌的尝试,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, Hepatogastroenterology, 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：胃癌肝多发转移,Shi M, Zhang J, et al, Hepatogastroenterology, 2011,PFS & OS,mPFS=6.5个月,mOS=10.6个月,Shi M, Zhang J, et al, Hepatogastroenterology, 2011,胃癌 KRAS 突变率,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,Cisplatin 80mg/m2 d1Capecitabine 1000mg/m2 twice daily; d1-14q3w,RANDOM,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 250mg/m2 per week,EXPAND Phase III,EGFR单克隆抗体的分类,-momab,-ximab,-mumab,-zumab,鼠源,嵌合,全人源化,人源化,如何改进？,进行亲和力设计，实现最适亲和力,TITLE,TITLE,TITLE,TITLE,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 87,3与胃癌临床病理因素的关系,HER-2 在胃癌表达,Ann Oncol, 2008,19:1523外科杂志1996,1:25,宫立群133中国18,1IHC,ToGA 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),R,a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ECOG 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,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,Primary end point: OS,Time (months),294290,277266,246223,209185,173143,147117,11390,9064,7147,5632,4324,3016,2114,137,126,65,40,10,00,No. at risk,11.1,13.8,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,Event,FC + T,FC,Events167182,HR0.74,95% CI0.60, 0.91,p value0.0046,MedianOS13.811.1,T, trastuzumab,Secondary end point: PFS,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,Event,294290,258238,201182,14199,9562,6033,4117,287,215,133,93,82,62,61,61,40,20,00,5.5,6.7,No. at risk,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,Time (months),FC + T,FC,Events226235,HR0.71,95% CI0.59, 0.85,p value0.0002,MedianPFS6.75.5,Secondary end point: tumor response rate,2.4%,5.4%,32.1%,41.8%,34.5%,47.3%,Intent to treat,ORR= CR + PRCR, complete response; PR, partial response,p=0.0599,p=0.0145,F+C + trastuzumab,F+C,p=0.0017,Patients (%),CR,PR,ORR,Cross-trial Comparation of 1st Tx of GC,张俊,中国医学论坛报,20090723,The 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 unclear,Comments (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,113,OS in IHC2+/FISH+ or IHC3+ (exploratory analysis),1.0,0.8,0.6,0.4,0.2,0.0,36,34,32,30,28,26,24,22,20,18,16,14,12,10,8,6,4,2,0,Time (months),11.8,16.0,FC + T,FC,Events120136,HR0.65,95% CI0.51, 0.83,MedianOS16.011.8,Event,0.1,0.3,0.5,0.7,0.9,218 198,40,53,124,2011,228 218,196 170,170 141,142 112,12296,10075,8453,6539,5128,10,00,No. at risk,3920,2813,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 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=51,44,mTOR,mTOR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2,1. 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.,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 GI,Everolimus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 0.001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 Study,Starting dose of bev/placebo: 30 minutes, subsequent doses: 15 minutes,Capecitabine*/Cisplatin (XP) + Placebo q3w,Capecitabine*/Cisplatin (XP)+ Bevacizumab q3w,Locally advanced or metastatic gastric cancer,R,*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 PD,Stratification factors:1. Geographic region2. Fluoropirimidine backbone3. Disease status,病例特征 (I),*1 additional patient had an ECOG PS of 4,病例特征 (II),总生存,387387,343355,271291,204232,146178,98104,1519,XP + PlaceboXP + Bev,Number at risk,5450,00,无进展生存,387387,279306,145201,86123,5571,3238,33,1511,00,XP + PlaceboXP + Bev,Number at risk,最佳总体反应率,总生存: 亚组分析,Pan-America,* 29 patients with locally advanced disease only,不同地理区域的患者特征,*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,AVAGAST 分析,东西方的胃癌因发病机制、遗传背景、高发部位、人种差异 ToGA研究的干扰分子标志物的探索,Resectable adenocar