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1、复旦大学附属肿瘤医院李 进,消化道肿瘤的分子靶向治疗,Alkylate,Anthracycline,Platinum,Target Molecular,Taxol,1960s,1970s,1980s,1990s,2000s,肿瘤的药物治疗变迁,肿瘤发生的分子机制,？,血管内皮细胞,Proliferation,Migration,Angiogenesis:,Tubule formation,PDGF-b,VEGF,VEGFR-2,PDGFR-b,Paracrine stimulation,Differentiation,Mitochondria,Apoptosis,肿瘤细胞,PDGF,VEGF,
2、EGF,Proliferation,Survival,Mitochondria,EGF,HIF-2,细胞核,VHL,Autocrine loop,Apoptosis,RAF,细胞核,Wilhelm S et al.Clin Cancer Res.2004;64:7099-7109.,分子靶向治疗主要途径,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ZD2171ZD6474,EGFR 信号传导通路,西妥昔一线联合化疗,CRYSTAL 研究:研究设计,分层因素:种族ECOG PS患者群：随即分组的患者 n=1217安全性评价人群 n=1202ITT 人
3、群:n=1198,m FOLFIRI,西妥昔单抗+m FOLFIRI,随机,EGFR 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(months),PFS estimate,1.0,HR=0.851;95%CI=0.726-0.998,Stratified log-rank p-value=0.0479,8.9 mo,8.0 mo,1-year PFS rate23%vs 34%,2007.ASCO annual meeting.Abstra
4、ct No.4000,西妥昔二线联合化疗,EPIC 的试验设计,Cetuximab/Irinotecan,Irinotecan,以奥沙利铂为基础的一线治疗失败,Survival,分层因素:研究中心 ECOG PS(0-1,2),主要终点:总生存(OS)次要终点:PFS,RR,DCR,Safety,QoL 样本量:221个中心，1298 例患者,N=648,N=650,Abstract#4003 2007 ASCO annual meeting,有效率和疾病控制率,p-value=0.0001,p-value=0.0001,Abstract#4003 2007 ASCO annual meeti
5、ng,PROPORTION PROGRESSION FREE,0.0,0.2,0.4,0.6,0.8,1.0,0,3,6,9,12,15,18,4.0 mo,2.6 mo,MONTHS,HR=0.692 95%CI=0.617 0.776,西妥昔单抗+伊立替康;N=648,伊立替康单用;N=650,P-value=0.0001,EPIC 研究 PFS,Abstract#4003 2007 ASCO annual meeting,奥沙利铂治疗失败后mCRC二线治疗,Abstract#4003 2007 ASCO annual meeting,西妥昔三线联合化疗,BOND 试验,随机入组,西妥昔
6、起始剂量 400 mg/m2 2-h 滴注 250 mg/m2 1-h 滴注1/周+伊立替康*n=218,西妥昔 起始剂量 400 mg/m2 2-h 滴注 250 mg/m2 1-h 滴注1/周 n=111,329例 EGFR表达阳性的病人,伊立替康用药后三个月内复发,病情进展,西妥昔+I伊立替康*n=56,Cunningham et al.N Engl J Med 2004;351:337-345,*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.,西妥昔+伊立替康(n=218)西妥昔(n=111),23*,11
7、*,32*,56*,*p=0.0074;*p0.001;intent to treat,化疗后的西妥昔的效能,Cunningham et al.N Engl J Med 2004;351:337-345,VEGF/VEGFR 系统,TKI=tyrosine kinase inhibitors,Steward.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 de
8、monstrated the safety of therapy with 5-FU/LV/CPT-11+bevacizumab.Patients receiving 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
9、(n=923),PD,IFL+安慰剂(n=411),PD,FL+贝伐*(5 mg/kg,q2w)(n=110),PD,IFL+贝伐(5 mg/kg,q2w)(n=402),主要终点:生存,随机入组,有效率,Hurwitz et al.Proc Am Soc Clin Oncol.2003;22.Abstract 3646 and oral presentation.Avastin PI.,无进展生存,0.2,0,10,20,30,0,0.8,1.0,0.4,0.6,Progression-free survival(mo),Proportion progression-free,Treatme
10、nt Group,IFL+placeboIFL+bevacizumab,Hurwitz 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:15.6 vs 20.3 mo,Duration of survival(mo),Proportion surviving,0.2,20,0,10,30,40,0,0.8,1.0,0.4,0.6,治疗组,IFL+安慰剂IFL+
11、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:E3200,二线治疗晚期大肠癌(n=880),FOLFOX-4,贝伐单药*(10 mg/kg,q2w),FOLFOX-4+贝伐(10 mg/kg,q2w),PD,PD,PD,主要终点:生存时间次要终点:ORR,*Arm stopped to enrolment.PI=B.Giantonio.,RANDOMIZATION,RR,9.2%,21.8%,无进展生存,Probab
12、ility of being progression-free,1.00.80.60.40.20,Progression-free survival(months),02468101214161820,Cens,Fail,Median,Total,273,228,45,7.2,273,241,32,4.8,229,215,14,2.7,A:FOLFOX4+Avastin,B:FOLFOX4,C:Avastin,HR=0.64A vs B:p0.0001B vs C:p0.0001,2.7,4.8,Giantonio BJ,et al.J Clin Oncol 2005;23(June 1 Su
13、ppl.):1s(Abstract 2),7.2,总生存,Probability of survival,1.00.80.60.40.20,Time(months),Alive,Dead,Median,Total,A:FOLFOX4+Avastin,289,246,43,12.9,B:FOLFOX4,290,257,33,10.8,C:Avastin,243,216,27,10.2,HR=0.76A vs B:p=0.0018B vs C:p=0.95,Giantonio BJ,et al.J Clin Oncol 2005;23(June 1 Suppl.):1s(Abstract 2),1
14、0.2,10.8,0369121518212427303336,12.9,贝伐三线联合化疗,抢救治疗,H.X.Chen et al.,ASCO 2004,对奥沙利铂和依立替康耐药的大肠癌,贝伐相关毒性,Kozloff M,et al.Presented at:2006 Gastrointestinal Cancers Symposium;2628 January 2006;San Francisco,Ca.Abstract 247.Available at http:/www.asco.org.Accessed 24 February 2006,ras 癌基因家族(homologous to
15、the rat sarcoma virus)有三个主要成员(H-ras,K-ras,and N-ras).K-RAS最重要。ras 基因表达的产物是细胞内(p21)，它是一种GTP酶，是细胞内信号传导的关键。ras 癌基因的点突变改变了p21的氨基酸序列，激活了K-RAS，并导致EGFR下游通道的激活。,RAS 家族,EGFR的传导通路,KRAS 状态与PFS的关系,Cetuximab+FOLFIRI HR=0.63;p=0.007 mPFS wild-type(n=172):9.9 monthsmPFS mutant(n=105):7.6 months,FOLFIRI HR=0.97;p=0
16、.87 mPFS wild-type(n=176):8.7 monthsmPFS mutant(n=87):8.1 months,KRAS not clearly prognostic,but is predictive(for resistance),FOLFOX-4 联合吉菲替尼,G.A.Fisher,et al.ASCO 2004,First Line28 cases,First cycle:FOLFOX4，then FOLFOX4+Gefitinib,?,PR,Second Line22 cases,78%,32%,1168 PatientsStratification Factors
17、:PS:0,1-2LDH:,1.5 x ULN,FOLFOX 4+PTK/ZK 1250 mg po qd,FOLFOX 4+Placebo,Multinational randomized Phase III trial in previously untreated mCRC,RANDOMIZE,Hecht et al.ASCO 2005,CONFIRM-1 试验设计,无进展生存时间,HR=0.88(95%CI)=0.74,1.03P Value=0.118,Hecht et al.ASCO 2005,Cediranib,AZD2171Pan VEGFR,PDGFRa,PDGFRb TKI
18、OralMedian half-life:12-35 hoursDose:45 mg QD,Wikipedia,HORIZON II 试验,*2:1 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,免费赠药，二线治疗KPS 大于70分年龄：18-70岁目标：TTP 4个月最终目标：疾病的总生存大于15个月。入组病例：45人,病例1,病例 2,锁骨上淋巴结,目前进行情况,*因未使用G-CSF，骨髓恢复较慢，化疗延迟，未完成第一周期治疗即进展,*第一
19、周期治疗中出现肠梗阻,Kaplan-Meier法估计前15例患者中位TTP：7个月,西妥昔单抗可与化疗联合治疗晚期大肠癌检测K-RAS可判断西妥昔疗效贝伐单抗可联合化疗用于一、二线患者不推荐贝伐应用于多个化疗失败的病人西妥昔联合化疗治疗胃癌值得进一步探索,结 论,Anti-CRC TKIs,VEGF:SunitinibSorafenibAxitinibEGFR:GefitinibErlotinibmTOR:EverolimusTemsirolimus,Molecular Targeted Treatments for Colorectal Cancer,ApprovedAnti-VEGF:Be
20、vacizumab(MoAb)Anti-EGFR:Cetuximab(MoAb);Panitumumab(MoAb)ExperimentalAnti-VEGF:VEGF-Trap;Sunitinib(TKI),Cediranib(TKI),Apatinib(TKI)Anti-EGFR:Matuzumab(MoAb);Erlotinib(TKI),目前进行情况,*因未使用G-CSF，骨髓恢复较慢，化疗延迟，未完成第一周期治疗即进展,VEGFR-1VEGFR-2FLT4Fms,Split Kinase Domain RTKs,舒尼替尼(索坦):多靶点酪氨酸激酶抑制剂,IC50(mM)1VEGFR2
21、:4PDGFR:39KIT:1FLT3(WT):8EGFR:10,000,Chow LQ,et al.J Clin Oncol.2007;25:884-896.,PDGFR-aPDGFR-bCSF1RKITFLT3,有效抑制 VEGFR,PDGFR,KIT 和 FLT3这些靶点肿瘤增殖和血管生成GIST,肾细胞癌等,In a recent study with sunitinib,mTTP was only 2.2 and 2.5months respectively in the prior bevacizumab and bevacizumab-nave cohorts and OS ti
22、me was 7.1 months and 10.2 months respectivelyAb1.In BOND trial,cetuximab monotherapy provided the heavily treated patients with a mTTP of 1.5months,阿帕替尼,全新的分子靶向药物恒瑞公司研制开发针对VEGFR-2比PTK-787的结合能力强14倍对C-kit也有抑制作用,VEGF 家族及其受体,Ellis.Horizons in Cancer Therapeutics.2004;5(2):4-10,Two months later,治疗前,二个周期后,Monotherapy with apatinib in CRC,32 cases of heavy treated CRC,4.7,晚期胃癌的OS,10例胃癌从首次复发转移至死亡,中位生存比国际标准延长了一倍！,10例胃癌从首次复发转移至死亡,化疗现状,5FU/顺铂或ECF方案为常规参考方案泰索帝,奥沙利铂,依立替康,作为备选化疗使晚期胃癌患者生存延长 4 6月 阿帕替尼有较好的研究前景FOLFIRI联合爱必妥有可能成为很好的二线化疗方案通过多学科联合治疗，辅以分子靶向治疗，有可能在不久的将来获得重大突破。,Thank you!,
