医学胃癌靶向治疗

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 n 理解分子靶点 n 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 n 分子靶向治疗药物的应用实践 n 做到真正的translational research n指导临床研究设计 n指导临床指南 近十年的晚期胃癌临床研究 n MAGIC in NEJM (Cunningham,2006) n TAX 325 in JCO （Eric Van Cutsem,2006） n REAL-2 in NEJM (Cunningham,2008) n ML-17032 in Ann Oncology（Kang,2009） n FLAGS in ASCO GI（Ajani,2009） n ToGA in ASCO (Eric Van Cutsem 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 GSK089Ras Raf MEK ERK P13K Akt mTOR Smo Gli-1 Ptch-1 PTEN Hh IGF-1RPDGFRVEGFRHER-2HER-1 VEGF Met 合理治疗靶点的标准 n 与肿瘤的恶性表型相关 n 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 n 能在临床较易获得的样本中重复检测 n 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 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 n KRAS MT40%) n HER-2 过表达10-25% 单药应用疗效有限（ Phase 2） Phase II Study RegimenN Response (%) TTP/OS Bang 2007Sunitinib383%NS Muro 2008RAD001240%NS Gold 2008Cetuximab552% 1.8 mos/ 4 mos Hecht 2008Lapatinib210%- Lqbal 2007477%2 mos/ 5mos 靶向化疗：成绩较好（Phase 2） Phase II Study RegimenNRR(%)TTP/OS Lordick et al.20064 Cetuximab +FUFOX 2856% 8.1/28.2 mos Di Fabio et al.20062 Cetuximab +FOLFIRI 2752% Pinto et al. 20063 Cetuximab +FOLFIRI 2556%8/16 mos Jhawer 2009Bev+Modified DCF3664% 12 mos / 16mos Shah et al. 20061 Bev+Cisplatin+ Irinotecan3465% 8.3/12.3 Mos Enzinger et al. 2008 Bev+Irino/Docet /Cisplatin 2268%NS 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 目标标：延长长生存 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 Survival (anti- apoptosis) Gene transcription Cell-cycle progression MYC MYC Cyclin D1 FOSJUN P P Cyclin D1 Angiogenesis Invasion and metastasis Chemotherapy/ radiotherapy resistance Proliferation/ maturation MAPK MEK RAS RAF SOS GRB2 PTEN AKT STAT P13K pY pY Ligand: AREG/EREG Target for EGFR-ERBITUX EGFR-TK Target for EGFT-TK inhibitor pY 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) GastricCase Number Response(%) Dragovich (erlotinib) 250 Doi (Gefitinib)751 GE Junction Ferry (Gefitinib)2711 Janmaat(Gefitinib)260 Tew (Erlotinib)170 Dragovich(Erlotinib ) 439 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 方案病例数RR (%)PFS (mo)OS (mo)作者 FOLFIRI + Erbitux38448.016.0Pinto, Ann Onc. 2007 FUFOX + Erbitux46657.69.5Lordick, ASCO 2007 Iri/5-FU/FA + Erbitux 49428.516.6Kanzler, ASCO 2009 Irino/Oxa + Erbitux 31426.29.5Woell, ASCO 2009 Docetaxel + Erbitux 3441Pinto, ASCO GI 2008 Cispl. + Cape + Erbi 47485.2Zhang, ASCO GI 2009 Cis + 5-FU + Erbitux 35691114.5Yeh, ASCO 2009 XELOX + Erbitux44526.611.7Kim, ASCO GI 2009 FOLFOX-6 + Erbitux 38505.59.9Han, 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/L ECOG 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 Zhao et al., Int J Cancer 2004; 108:167108:167 94948 (8.5%)8 (8.5%) Lee et al., Oncogene 2003; 22: 6942Lee et al., Oncogene 2003; 22: 6942 60 early GC 60 early GC 259 advanced 259 advanced GCGC 1 in EGC (1.7%), 1 in EGC (1.7%), 8 in AGC (3.1%)8 in AGC (3.1%) Kim et al., Hum Genet 2003; 114:118Kim et al., Hum Genet 2003; 114:11866664 (6.1%)4 (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 Cisplatin 80mg/m2 d1 Capecitabine 1000mg/m2 twice daily; d1-14 q3w R A N D O M Until radiographically documented PD or unacceptable toxicity Primary endpoint: PFS time (as assessed by Independent Review Committee) Cisplatin 80mg/m2 d1 Capecitabine 1000mg/m2 twice daily; d1-14 q3w Cetuximab 400mg/m2 loading dose, then 250mg/m2 per week EXPAND EXPAND Phase IIIPhase III EGFREGFR单克隆抗体的分类单克隆抗体的分类 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？如何改进？ 进行亲和力设计，实现最适亲和力 TITLETITLE TITLETITLE TITLETITLE TITLETITLE 皮疹与疗效相关？ ToGA研究中HER-2检测情况 n HER2 with IHC Abstract 4556, ASCO 2009 3807 位患者接受筛选筛选 1 810 HER2-阳性 (22.1%) 患者的人口统计学以及基线特征 特征F+C n=290 F+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 (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 74.2a 8.7a 17.1a 76.8b 8.9b 14.3b 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=293 Primary end point: OS Time (months) 294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 0 1 0 0 0 No. at risk 11.113.8 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 02468 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Event FC + T FC Events 167 182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 Median OS 13.8 11.1 T, trastuzumab Secondary end point: PFS 0246810 12 14 16 18 20 22 24 26 28 30 32 34 Event 294 290 258 238 201 182 141 99 95 62 60 33 41 17 28 7 21 5 13 3 9 3 8 2 6 2 6 1 6 1 4 0 2 0 0 0 5.56.7 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 Events 226 235 HR 0.71 95% CI 0.59, 0.85 p value 0.0002 Median PFS 6.7 5.5 Secondary end point: tumor response rate 2.4% 5.4% 32.1% 41.8% 34.5% 47.3% Intent to treat ORR= CR + PR CR, complete response; PR, partial response p=0.0599 p=0.0145 F+C + trastuzumab F+C p=0.0017 Patients (%) CRPRORR Cross-trial Comparation of 1st Tx of GC 张张俊,中国医学论坛报论坛报 ,20090723 nThe 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 treatment nThe underlying mechanism is still unclear Comments (Response rate) TITLE n 标本储藏条件对IHC 和 FISH结果的影响 n 胃癌的异质性 n 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) n 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？ n 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？ n EGFR 单抗治疗中KRAS 的故事 11 3 OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) 1.0 0.8 0.6 0.4 0.2 0.0 363432302826242220181614121086420 Time (months) 11.816.0 FC + T FC Events 120 136 HR 0.65 95% CI 0.51, 0.83 Median OS 16.0 11.8 Event 0.1 0.3 0.5 0.7 0.9 218 198 4 0 5 3 12 4 20 11 228 218 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 1 0 0 0 No. at risk 39 20 28 13 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 l mTOR是细胞代谢、生长、增殖 和血管生成的核心调控者1,2 l mTOR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 l 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 Probability of overall survival (%) 100 80 60 40 20 0 024681012 Time (months) 14 Censoring Times Everolimus + BSC (n/N = 352/439) Placebo + BSC (n/N = 180/217) Kaplan-Meier medians Everolimus + BSC: 5.39 months Placebo + BSC: 4.34 months Hazard ratio: 0.90 (95% CI, 0.75-1.08) Log-rank P value = 0.1244 No. of patients still at risk Time (months) Everolimus Placebo 1618202224 024681012141618202224 2171721178260352816128410 439355253195139875230136310 Everolimus用于胃癌的思考 l 单药用于二线/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 0.001 l 疾病控制率 22%43% l 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 contraindicated Cape 1000 mg/m2 oral bid, d114, 1-week rest Cisplatin 80 mg/m2 d1 Bevacizumab 7.5 mg/kg d1 Maximum of 6 cycles of cisplatin Cape and bevacizumab/placebo until PD Stratification factors: 1. Geographic region 2. Fluoropirimidine backbone 3. Disease status 病例特征 (I) Number of patients N=774 (%) XP + Placebo N=387 XP + Bev N=387 GenderMale258 (67)257 (66) Age, yearsMedian (range)59 (2282)58 (2281) ECOG PS01 2 367 (95) 20 (5) 365 (94) 22* (6) RegionAsia Europe Pan-America 188 (49) 124 (32) 75 (19) 188 (49) 125 (32) 74 (19) FluoropyrimidineCapecitabine 5-FU 365 (94) 22 (6) 364 (94) 23 (6) Disease statusLocally advanced Metastatic 9 (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 + Placebo N=387 XP + Bev N=387 Primary site Stomach GEJ 338 (87) 49 (13) 333 (86) 54 (14) Histologic type Intestinal Diffuse Mixed 135 (35) 206 (53) 26 (7) 155 (40) 176 (46) 35 (9) Disease measurability Measurable Evaluable 297 (77) 90 (23) 311 (80) 76 (20) Metastatic sites, n 0 1 2 8 (2) 131 (34) 247 (64) 8 (2) 131 (34) 247 (64) Prior gastrectomyYes107 (28)110 (28) Liver metastasisYes126 (33)130 (34) 总生存 387 387 343 355 271 291 204 232 146 178 98 104 15 19 XP + Placebo XP + Bev Number at risk 54 50 0 0 XP + Placebo XP + Bev HR = 0.87 95% CI 0.731.03 p = 0.1002 Survival rate 39151821240 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 612 Study month 10.1 12.1 无进展生存 387 387 279 306 145 201 86 123 55 71 32 38 3 3 15 11 0 0 XP + Placebo XP + Bev Number at risk XP + Placebo XP + Bev HR = 0.80 95% CI 0.680.93 p = 0.0037 Progression-free survival rate 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 39151821240612 5.3 6.7 Study month 最佳总体反应率 XP + Placebo N=387 XP + Bev N=387 Patients with measurable disease297311 Overall response111 (37%)143 (46%) 95% CI31.943.140.351.7 Difference9% 95% CI0.616.6 P value (2)0.0315 Complete response3 (1%)5 (2%) Partial 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-America 2 No Disease status ECOG performance Prior gastrectomy Region Site of primary disease No. of metastatic sites at baseline Disease measurability Histologic type All Locally advanced* Metastati c 0 Yes Europe All 1 Asia Stomach GE junction 1 Measurable Non-measurable Intestina l Diffuse Mixe d Subgrou p Category 2 Hazard Ratio 01 * 29 patients with locally advanced disease only HR 0.97 0.85 0.63 不同地理区域的患者特征 % of patientsAsiaEuropePan-America Age65726877 65283223 ECOG PS01979196 23*94 Primary siteStomach947884 GEJ62216 Extent of diseaseMetastatic999592 Locally advanced158 Prior gastrectomyyes322327 no687773 Measurable lesionyes738877 no271223 Liver metastasisyes273742 no736358 *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 Region Patients entered Patients receiving second-line treatment % Asia37624866 Europe2497831 Pan- America 1493221 AVAGAST 分析 n 东西方的胃癌因发病机制、遗传背景、高发部位 、人种差异 n ToGA研究的干扰 n 分子标志物的探索 Resectable adenocarcinoma of the stomach or Type III OGJ