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1、消化道肿瘤的分子靶向治疗消化道肿瘤的分子靶向治疗AlkylateAnthracyclinePlatinumTarget MolecularTaxol1960s1970s1980s1990s2000s肿瘤的药物治疗变迁肿瘤的药物治疗变迁RAS血管内皮细胞血管内皮细胞ProliferationMigrationAngiogenesis:Tubule formationPDGF-b bVEGFVEGFR-2PDGFR-bParacrine stimulationDifferentiationMitochondriaApoptosis肿瘤细胞肿瘤细胞PDGFVEGFEGFProliferationSu
2、rvivalMitochondriaEGFHIF-2细胞核VHLAutocrine loopApoptosisERKRASMEKRAF细胞核ERKMEKWilhelm S et al.Clin Cancer Res.2004;64:7099-7109.分子靶向治疗主要途径RAF单克隆抗体 西妥昔 贝伐 帕尼 尼妥珠 曲妥珠小分子靶向药物 吉菲替尼 埃罗替尼 舒尼替尼 索拉菲尼 ZD2171 ZD6474MAb NameTrade NameUsed to Treat:Approved in:RituximabRituxanNon-Hodgkin lymphoma1997TrastuzumabHe
3、rceptinBreast cancer1998Gemtuzumab ozogamicin*MylotargAcute myelogenous leukemia(AML)2000AlemtuzumabCampathChronic lymphocytic leukemia(CLL)2001Ibritumomab tiuxetan*ZevalinNon-Hodgkin lymphoma2002Tositumomab*BexxarNon-Hodgkin lymphoma2003CetuximabErbituxColorectal cancer2004BevacizumabAvastinColorec
4、tal cancer2004*conjugated monoclonal antibodies 西妥昔一线联合化疗CRYSTAL 研究:研究设计分层因素:种族种族 ECOG PS患者群：随即分组的患者随即分组的患者 n=1217 安全性评价人群安全性评价人群 n=1202 ITT 人群人群:n=1198 m FOLFIRI 西妥昔单抗西妥昔单抗+m FOLFIRI随随机机EGFR 表达的表达的 mCRC 2007.ASCO annual meeting.Abstract No.4000 PFS:针对ITT 人群的独立评估 Progression-free survival time(month
5、s)PFS estimate1.00.80.90.00.10.20.30.40.50.60.702468101214161820HR=0.851;95%CI=0.726-0.998Stratified log-rank p-value=0.04798.9 mo8.0 moFOLFIRI,n=599Cetuximab+FOLFIRI,n=5991-year PFS rate23%vs 34%Subjects at riskFOLFIRI alone 599492402293178833516741Cetuximab+FOLFIRI59949939229819610358291251 2007.A
6、SCO annual meeting.Abstract No.4000西妥昔二线联合化疗Cetuximab/Irinotecan Irinotecan以奥沙利铂为基础以奥沙利铂为基础的一线治疗失败的一线治疗失败Survival Abstract#4003 2007 ASCO annual meeting 61.416.445.84.20 01010202030304040505060607070Response rateDisease ControlPercentage(%)Cetuximab+Irinotecan(N=648)Irinotecan(N=650)Cetuximab+Irinot
7、ecan N(%)IrinotecanN(%)CR9(1.4)1(0.2)PR97(15)26(4.0)RR106(16.4)27(4.2)Disease Control398(61.4)298(45.8)p-value=0.0001p-value=0.0001 Abstract#4003 2007 ASCO annual meeting PROPORTION PROGRESSION FREE0.00.20.40.60.81.00369121518 Abstract#4003 2007 ASCO annual meeting StudyNTreatmentEfficacyORRPFS(月)OS
8、(月)Oxaliplatin failureTournigand 200469FOLFIRI4%2.5NR Alberto F 2006650648伊立替康爱必妥伊立替康4.2%16.4%2.64.0 9.9910.71 Abstract#4003 2007 ASCO annual meeting 西妥昔三线联合化疗BOND 试验随机入组随机入组西妥昔西妥昔 起始剂量起始剂量 400 mg/m2 2-h 滴注滴注 250 mg/m2 1-h 滴注滴注1/周周+伊立替康伊立替康*n=218西妥昔西妥昔 起始剂量起始剂量 400 mg/m2 2-h 滴注滴注 250 mg/m2 1-h 滴注滴注1
9、/周周 n=111329例例 EGFR表达阳性的病人表达阳性的病人,伊立替康用药后三个月内复发伊立替康用药后三个月内复发病情进展病情进展西妥昔西妥昔+I伊立替康伊立替康*n=56Cunningham et al.N Engl J Med 2004;351:337-345*伊立替康剂量同以往相同伊立替康剂量同以往相同有效率 Cunningham et al.N Engl J Med 2004;351:337-345.n西妥昔西妥昔+伊立替康伊立替康(n=218)n西妥昔西妥昔(n=111)23*11*32*56*p=0.0074;*p3524以往奥沙利铂用药有922无1524Cunningham
10、 et al.N Engl J Med 2004;351:337-345TKI=tyrosine kinase inhibitorsSteward.Horizons in Cancer Therapeutics.2004;5(2):11-21贝伐一线联合化疗贝伐的 III 期临床*Third arm was discontinued after a predetermined interim safety analysis demonstrated the safety of therapy with 5-FU/LV/CPT-11+bevacizumab.Patients receiving
11、bevacizumab could continue therapy past disease progression in combination with second-line therapy.IFL=bolus 5-FU/LV/irinotecanHurwitz et al.Proc Am Soc Clin Oncol.2003;22.Abstract 3646.Avastin(bevacizumab)PI.初治大肠癌初治大肠癌(n=923)PDIFL+安慰剂安慰剂(n=411)PDFL+贝伐贝伐*(5 mg/kg,q2w)(n=110)PDIFL+贝伐贝伐(5 mg/kg,q2w)(
12、n=402)主要终点主要终点:生存生存随机入组有效率IFL+安慰剂安慰剂(n=411)IFL+贝伐贝伐(n=402)P 值值中位生存中位生存(月月)15.620.30.00004PFS(mo)6.2410.60.00001ORR(%)CR PR352.2 32.5453.741.20.0036有效持续时间有效持续时间(月月)7.110.40.0014Hurwitz et al.Proc Am Soc Clin Oncol.2003;22.Abstract 3646 and oral presentation.Avastin PI.无进展生存0.2010203000.81.00.40.6Prog
13、ression-free survival(mo)Proportion progression-freeTreatment GroupIFL+placeboIFL+bevacizumabHurwitz et al.Proc Am Soc Clin Oncol.2003;22.Abstract 3646 and oral presentation.Avastin PI.HR=0.54,P0.00001mPFS:6.2 10.6 mo生存HR=0.66,P=0.00004中位生存中位生存:15.6 vs 20.3 moDuration of survival(mo)Proportion survi
14、ving0.220010304000.81.00.40.6治疗组治疗组IFL+安慰剂安慰剂IFL+贝伐贝伐Hurwitz et al.Proc Am Soc Clin Oncol.2003;22.Abstract 3646 and oral presentation.Avastin PI.贝伐二线联合化疗III 期临床:E3200二线治疗二线治疗晚期大肠癌晚期大肠癌(n=880)FOLFOX-4贝伐单药贝伐单药*(10 mg/kg,q2w)FOLFOX-4+贝伐贝伐(10 mg/kg,q2w)PDPDPD 主要终点:生存时间 次要终点:ORR*Arm stopped to enrolment.
15、PI=B.Giantonio.RANDOMIZATIONRR9.2%21.8%无进展生存Probability of being progression-free1.00.80.60.40.20Progression-free survival(months)02468101214161820CensFailMedianTotal273228457.2273241324.8229215142.7A:FOLFOX4+AvastinB:FOLFOX4C:AvastinHR=0.64A vs B:p0.0001B vs C:p1.5 x ULNFOLFOX 4+PTK/ZK 1250 mg po q
16、dFOLFOX 4+Placebo Multinational randomized Phase III trial in previously untreated mCRC RANDOMIZEHecht et al.ASCO 2005HR=0.88(95%CI)=0.74,1.03P Value=0.118PTK/ZK+FOLFOX4Placebo+FOLFOX4Hecht et al.ASCO 2005 AZD2171 Pan VEGFR,PDGFRa,PDGFRb TKI Oral Median half-life:12-35 hours Dose:45 mg QDWikipedia一线治疗转移性结直一线治疗转移性结直肠癌肠癌(n=1050)FOLFOX/XELOX 安慰剂安慰剂FOLFOX/XELOX Cediranib 20 mg/dayRANDOMIZATION*2:1 随机随机Hoff 2008胃 癌 全球42%发生在中国 中位生存不超过一年 二线化疗基本无效，TTP 小于二个月 K-RAS 突变 10%大肠癌：西妥昔有逆转伊立替康耐药性能FOLFIRI 联合爱必妥 免费
