胃癌靶向治療課件

1、近十年的晚期胃癌臨床研究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療靶點(diǎn)與靶向藥物Wong H, Yau T. The Oncologist 2012; 17:346-358.西妥昔單抗帕尼單抗曲妥珠單抗貝伐珠單抗FigitumumabGDC-0449拉帕替尼厄洛替尼吉非替尼索拉非尼舒尼替尼依維莫司細(xì)胞生存/增殖GSK089RasRafMEKERKP13KAktmTORSmoGli-1Ptch-1PTENHhIGF-1RPDGFRVEGFRHER-2HER-1VEGFMet 合理治療靶點(diǎn)的標(biāo)準(zhǔn)與腫瘤的惡性表型相關(guān)重要臟器與組織中很少表達(dá)分子特性與生物學(xué)行為相關(guān)能在臨床較易獲得的樣本中重復(fù)檢測(cè)與臨床預(yù)后相關(guān)當(dāng)該靶點(diǎn)被阻斷、干擾或抑制

3、時(shí)，對(duì)高度表達(dá)該靶點(diǎn)的患者應(yīng)有一定的臨床反應(yīng)，對(duì)不表達(dá)該靶點(diǎn)者，應(yīng)無或產(chǎn)生較少臨床反應(yīng)胃癌的分子靶點(diǎn)尋找KRAS MT10%BRAF MT5%EGFR MT 5%C-met 擴(kuò)增40%)HER-2 過表達(dá)10-25%單藥應(yīng)用療效有限（ Phase 2）Phase IIStudyRegimenNResponse(%)TTP/OSBang 2007Sunitinib383%NSMuro 2008RAD001240%NSGold 2008Cetuximab552%1.8 mos/4 mosHecht 2008Lapatinib210%-Lqbal 2007477%2 mos/5mos靶向化療：成績(jī)較

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鉑類藥物替換氟尿嘧啶類藥物替換分子靶向藥物添加藥物替換藥物基于優(yōu)效性檢驗(yàn)的胃癌一線化療方案晚期胃癌藥物治療的優(yōu)化策略序貫治療誘導(dǎo)化療/維持化療其他策略目標(biāo)：延長(zhǎng)生存ToGA（XP/FPH）AVAGAST（XPBV）07/23/

6、2007胃癌 EGFR 表達(dá)包括EGF家族在內(nèi)的各類生長(zhǎng)因子及其受體在胃癌中呈過度表達(dá) (Gastric Cancer 2004; 7:61-77)免疫組化染色提示胃癌組織中EGFR表達(dá)率為59,5 86% (JCO2006; 24:4922-4927; ASCO2007 #4526)RT-PCR檢測(cè)提示胃癌組織中EGFR基因擴(kuò)增率約 62% (World J Gastroenterol 2007; 13:3605-3609) EGFR表達(dá)升高與以下臨床病理因素相關(guān): 進(jìn)展期胃癌淋巴結(jié)轉(zhuǎn)移 生存期縮短 (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西妥昔單抗一線治療胃癌的嘗試方案病例數(shù)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年齡18歲，KPS評(píng)分60分病理學(xué)和/或細(xì)胞學(xué)證實(shí)為胃腺癌，預(yù)計(jì)生存期3月局部晚期或轉(zhuǎn)移性癌，無法手術(shù)切除一線治療患者，接受輔助治療至少間隔6月以上血常規(guī)檢查正常：WBC3.0109/L，中性粒細(xì)胞 1.5109/L，PLT80109/LECOG 評(píng)分為 2無嚴(yán)重心、肺、肝、腎功能障礙，未伴發(fā)急性感染西妥昔單抗+FOLFOX4一線治療晚期胃癌臨床觀察Shi M, Zhang J, et al, Hepatoga

12、stroenterology, 2011臨床療效評(píng)價(jià) 例數(shù) 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治療前后CT病例1：胃癌肝轉(zhuǎn)移Shi M, Zhang J, et al, Hepatogastroenterology, 2011治療前后CT病例2：胃癌肝多發(fā)轉(zhuǎn)移Shi M, Zhang J, et al, Hepatogastroenterology, 2011治療前后CT病例3：

13、胃癌肝多發(fā)轉(zhuǎn)移Shi M, Zhang J, et al, Hepatogastroenterology, 2011PFS & OSmPFS=6.5個(gè)月mOS=10.6個(gè)月Shi M, Zhang J, et al, Hepatogastroenterology, 2011胃癌 KRAS 突變率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尚不能作為胃癌EGFR靶向抑制治療的療效預(yù)測(cè)標(biāo)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單克隆抗體的分類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反應(yīng)發(fā)生率降低如何改進(jìn)？進(jìn)行親和力設(shè)計(jì)，實(shí)現(xiàn)最適親和力 TITLETITLETITLETITLE皮疹與療效相關(guān)？ToGA研究中HER-2檢測(cè)情況HER2 with IHC & FISHResults2484 個(gè)進(jìn)展期胃癌蠟塊544 HER2+(21,9%)IHC-FISH一致率 87

17、,3與胃癌臨床病理因素的關(guān)系LocationCardia 32,2%Non cardia 19,9%P=0.02typeIntestinal:32,5%Diffuse: 6%P=0.001HER-2 在胃癌表達(dá)Ann Oncol, 2008,19:1523外科雜志1996,1:25宮立群133中國(guó)18,1IHCToGA 研究設(shè)計(jì)HER2-陽性晚期胃癌患者 (n=584)5-FU 或 卡培他濱a + 順鉑(n=290)Ra由研究者的判別來選擇GEJ, 胃食管連接部5-FU 或 卡培他濱a + 順鉑+ 赫賽汀(n=294)分層因素局部晚期或轉(zhuǎn)移性 胃體部 vs 胃食管連接部可測(cè)量 vs 不可測(cè)量E

18、COG 評(píng)分 0-1 vs 2卡培他濱 vs 5-FU全球、多中心、隨機(jī)、開放III期臨床研究1Bang et al; Abstract 4556, ASCO 2009 3807 位患者接受篩選1 810 HER2-陽性 (22.1%)患者的人口統(tǒng)計(jì)學(xué)以及基線特征特征F+Cn=290F+C + 赫賽汀n=294性別, %男性 / 女性75 / 2577 / 23中位年齡 (年齡范圍) 歲59.0 (21-82)61.0 (23-83)中位體重 (體重范圍) 公斤60.3 (28-105)61.5 (35-110)地區(qū), n (%)亞洲美洲歐洲其他166 (56)26 (9)95 (32)9 (

19、3)158 (53)27 (9)99 (33)14 (5)胃癌的類型 (中心實(shí)驗(yàn)室評(píng)估結(jié)果)腸型彌漫型混合型74.2a8.7a17.1a76.8b8.9b14.3b曾行胃部切除術(shù)21.424.1入組最多的為韓國(guó)，日本，中國(guó)和俄羅斯F, 氟尿嘧啶; C, 順鉑 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張俊,中國(guó)醫(yī)學(xué)論壇報(bào),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 標(biāo)本儲(chǔ)藏條件對(duì)IHC 和 FISH結(jié)果的影響胃癌的異質(zhì)性胃癌細(xì)

23、胞HER-2染色特征與乳腺癌的差異Comments (Standard techniques for HER-2 detection)Comments (Predictive marker)HER-2 與胃癌預(yù)后不良相關(guān)，HER-2作為Herceptin治療胃癌的療效預(yù)測(cè)標(biāo)志物的價(jià)值？HER-2/neu 信號(hào)通路內(nèi)的其他接頭蛋白或轉(zhuǎn)錄因子作為潛在療效預(yù)測(cè)標(biāo)志物的價(jià)值？EGFR 單抗治療中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研究設(shè)計(jì): 開放、單組、II期研究主要終點(diǎn): ORR次要終點(diǎn): PFS, 中國(guó)晚期胃癌患者HER2陽性率, OS, 安全性 HER2+晚期胃癌之前未接受治療 曲妥珠單抗8mg/kg 首劑, 然后 6mg/kg

25、 每3周卡培他濱1000 mg/m2 BID D1-14 每3周奧沙利鉑130 mg/m2, D1 每3周曲妥珠單抗6mg/kg 每3周卡培他濱1000 mg/m2 BID D1-14 每3周直到進(jìn)展6 cycles第一階段CGOG1001（ML25578）: 曲妥珠單抗聯(lián)合XELOX方案用于HER2陽性晚期胃癌的一線治療HER2+晚期胃癌之前未接受治療曲妥珠單抗8mg/kg 首劑, 然后 6mg/kg 每3周卡培他濱1000 mg/m2 BID D1-14 每3周奧沙利鉑130 mg/m2, D1 每3周曲妥珠單抗6mg/kg 每3周卡培他濱1000 mg/m2 BID D1-14 每3周直

26、到進(jìn)展6 cycles第二階段如果16例患者中有7例以上患者緩解，研究進(jìn)入第二階段全部 N=5142mTORmTOR是細(xì)胞代謝、生長(zhǎng)、增殖和血管生成的核心調(diào)控者1,2mTOR是腫瘤生長(zhǎng)開關(guān)1,2胰島素樣生長(zhǎng)因子-1（IGF-1）等激活mTOR通路 mTOR激活以下基因突變: PTEN, TSC2, NF1和VHL丟失抑制mTOR能抑制腫瘤的生長(zhǎng)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: 哺乳動(dòng)物雷帕霉素靶蛋白GRANITE-1研究N=656靶向組(439):BSC+ Everolimus對(duì)照組(217):BSC+安慰劑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用于胃癌的思考單藥用于二線/三線并未顯著延長(zhǎng)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期研究未能重復(fù)II期數(shù)據(jù) (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)總生存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無進(jìn)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最佳總體反應(yīng)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%)總生存: 亞組分析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不同地理區(qū)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不同地理區(qū)域患者接受二線治療情況RegionPatients enteredPatients receiving second-line treatment%Asia37624866Europe2497831Pan-America1493221AVAGAST 分析東西方的胃癌因發(fā)病機(jī)制、遺