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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 ZD2171 ZD6474,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
3、性评价人群 n=1202 ITT 人群: 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 rate 23% vs 34
4、%,2007.ASCO annual meeting .Abstract 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.
5、0001,p-value = 0.0001,Abstract# 4003 2007 ASCO annual meeting,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m
6、CRC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 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
7、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*,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
8、(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 bevacizumab could continue therapy past disease progression in combination with second-line therapy. IFL =
9、 bolus 5-FU/LV/irinotecan Hurwitz et al. Proc Am Soc Clin Oncol. 2003;22. Abstract 3646. Avastin (bevacizumab) PI.,初治大肠癌 (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 a
10、nd 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,Treatment Group,IFL + placebo IFL + bevacizumab,Hurwitz et al. Proc Am Soc Clin Oncol. 2003;22. Abstract 3646 and oral presentation. Avastin PI.,HR=0.54, P0.00001 mPFS:
11、 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 + 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=8
12、80),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,Probability of being progression-free,1.0 0.8 0.6 0.4 0.2 0,Progression-free survival (months),02468101214161820,Cens,Fail,Me
13、dian,Total,273,228,45,7.2,273,241,32,4.8,229,215,14,2.7,A: FOLFOX4 + Avastin,B: FOLFOX4,C: Avastin,HR=0.64 A vs B: p0.0001 B vs C: p0.0001,2.7,4.8,Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2),7.2,总生存,Probability of survival,1.0 0.8 0.6 0.4 0.2 0,Time (months),Alive,Dead,M
14、edian,Total,A: FOLFOX4 + Avastin,289,246,43,12.9,B: FOLFOX4,290,257,33,10.8,C: Avastin,243,216,27,10.2,HR=0.76 A vs B: p=0.0018 B vs C: p=0.95,Giantonio BJ, et al. J Clin Oncol 2005;23(June 1 Suppl.):1s (Abstract 2),10.2,10.8,0369121518212427303336,12.9,贝伐三线联合化疗,抢救治疗,H.X.Chen et al., ASCO 2004,对奥沙利铂
15、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 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
16、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=0.87 mPFS wild-type (n=176): 8.7 monthsmPFS mutant (n=87):
17、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 Line 28 cases,First cycle:FOLFOX4，then FOLFOX4 + Gefitinib,?,PR,Second Line 22 cases,78%,32%,1168 Patients Stratification Factors: PS: 0, 1-2 LDH: , 1.5 x ULN,FOLFOX 4 + PT
18、K/ZK 1250 mg po qd,FOLFOX 4 + Placebo,Multinational randomized Phase III trial in previously untreated mCRC,R A N D O M I Z E,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, 1.03 P Value = 0.118,Hecht et al. ASCO 2005,Cediranib,AZD2171 Pan VEGFR, PDGFRa, PDGFRb TKI Oral Medi
19、an half-life: 12-35 hours Dose: 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
20、进展,*第一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: Sunitinib Sorafenib Axitinib EGFR: Gefitinib Erlotinib mTOR: Everolimus Temsirolimus,Molecular Targeted Treatments for Colorectal Cancer,A
21、pproved Anti-VEGF: Bevacizumab (MoAb) Anti-EGFR: Cetuximab (MoAb); Panitumumab (MoAb) Experimental Anti-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
22、RTKs,舒尼替尼 (索坦): 多靶点酪氨酸激酶抑制剂,IC50 (mM)1 VEGFR2:4 PDGFR: 39 KIT: 1 FLT3 (WT): 8 EGFR: 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
23、in the prior bevacizumab and bevacizumab-nave cohorts and OS time 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. Ho
24、rizons 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!,