1、无限生长无限生长新生血管形成新生血管形成侵袭和转移侵袭和转移无限增殖无限增殖凋亡逃逸凋亡逃逸对生长抑制信号对生长抑制信号不敏感不敏感肿瘤细胞肿瘤细胞20世纪末21世纪 Cytotoxics继续发展 新的分子靶点药物(EGFR VEGF)Biotherapy研究 Gene Therapy?细胞毒化疗药物细胞毒化疗药物分子靶向药物分子靶向药物 细胞毒药物缺乏选择性细胞毒药物缺乏选择性 骨髓抑制：粒细胞缺乏，感染 血小板减少，出血 免疫抑制：感染 粘膜上皮损伤：口腔炎，胃肠炎，恶心/呕吐，腹泻，便血 脱发 器官毒性器官毒性 ADR：心脏毒性 BLM：肺纤维化 DDP：肾毒性 L-OHP、VCR、PT
2、X：神经毒性 BCNU：肝毒性细胞毒化疗药物细胞毒化疗药物分子靶向药物分子靶向药物 人类基因图谱有10多万基因,其中3万多与肿瘤有关:形成网络及调控尤其是细胞传导系统的调控,细胞传导系统和网络调控是肿瘤增殖.分化.转移.血管形成.调亡及和化/放疗疗效有关。人体有518个蛋白激酶,其中100个为酪氨酸激酶,50%酪氨酸激酶参与人肿瘤的发生发展.酪氨酸酶活化需磷酸化 针对酪氨酸酪酶的小分子化合物或针对单个基因的单抗靶向治疗不能解决全部肿瘤的治疗问题。胞外区：在氮端，为配体结合区胞外区：在氮端，为配体结合区 跨膜区：氨基酸残基构成的疏水区跨膜区：氨基酸残基构成的疏水区 胞内区：由近膜区、酪氨酸激酶胞
3、内区：由近膜区、酪氨酸激酶 （TKTK）区、碳）区、碳-末端三个亚区构成。末端三个亚区构成。C C端端配体结合区配体结合区酪氨酸激酶区酪氨酸激酶区胞外区胞外区跨膜区跨膜区胞内区胞内区N N端端TK抑制配体和受体结合 配体 配体结合位点 受体受体垮膜区 细胞膜酪氨酸激酶区细胞核ATP结合位点ATPDNA 增殖 迁移血管生成 生长因子肿瘤的发生、肿瘤的发生、发展取决于细发展取决于细胞内信号转导胞内信号转导途径中发生的途径中发生的遗传突变，阻遗传突变，阻断癌细胞中特断癌细胞中特异性增殖异性增殖 的依的依赖性信号可导赖性信号可导致肿瘤细胞增致肿瘤细胞增殖停止。靶向殖停止。靶向癌症治疗就是癌症治疗就是通
4、过作用于控通过作用于控制肿瘤细胞信制肿瘤细胞信号转导途径而号转导途径而抑制肿瘤生长。抑制肿瘤生长。J Clin Oncol,Vol 21,Issue 14(July),2003:2787-2799Adapted from Poon,et al.JCO 2001“En Espaa pendiente de autorizacin de precio y condiciones de reembolso”Stages at which angiogenesis plays a role in tumour progressionPremalignanttumourMalignanttumourTu
5、mourgrowthVascularinvasionMicro-metastasesMetastaticgrowthAngiogenicswitch“En Espaa pendiente de autorizacin de precio y condiciones de reembolso”VEGF=vascular endothelial growth factor;IGF=insulin-like growth factorPDGF=platelet-derived growth factor;EGF=epidermal growth factor1.肿瘤微血管退变肿瘤微血管退变 3.3.
6、抑制新生血管形成抑制新生血管形成2.2.肿瘤血管正常化肿瘤血管正常化早期作用早期作用 继续作用继续作用Baluk,et al.Curr Opin Genet Dev 2005;Inai,et al.Am J Pathol 2004;Erber,et al.FASEB J 2004 Tong,et al.Cancer Res 2004;Jain.Nat Med 2001;Jain.Science 2005;Lee,et al.Cancer Res 2000Willett,et al.Nat Med 2004;Gerber,et al.Cancer Res 2005;Warren,et al.J
7、Clin Invest 19952000200020012001200220022003200320042004200520052006200620072007美罗华美罗华 MabTheraMabThera 赫赛汀赫赛汀 HerceptinHerceptin 格列卫格列卫 GlivecGlivec 易瑞沙易瑞沙 IressaIressa 多吉美多吉美 SorafinibSorafinib 爱必妥爱必妥 ErbituxErbitux 特罗凯特罗凯 TarcevaTarceva n 罗氏罗氏n 诺华诺华n 阿斯利康阿斯利康n 默克默克n 拜尔拜尔 辉瑞辉瑞2008 索坦索坦 Sunitinib 泰
8、欣生泰欣生 Nimotuzumab 百泰百泰恩度恩度 Endostar先声先声 2009 2010 2009 2010 安维汀安维汀 AvastinAvastin 易瑞沙 皮疹、痤疮、皮 肤干燥、瘙痒、恶心、呕吐、腹泻、食欲减退、乏力和体重下降 间质性肺病特罗凯 皮疹、瘙痒、皮肤干燥、腹泻、食欲减退、乏力、恶心、呕吐、口腔炎、结膜炎、干性 角膜结膜炎、腹痛。角膜溃疡 多吉美皮疹、手足皮肤反应、粘膜炎/口腔炎、乏力、高血压、恶心、腹泻、血液学毒性高血压发烧、腹泻、感染、寒 战、过敏反应、LVEF下降、心室功能不全和充血性心力衰竭 爱必妥痤疮疹、乏力/不适、恶心、发热、便秘、腹痛、头痛、腹泻。严重
9、的输液反应（支 气管痉挛、喘鸣、嘶哑、荨麻疹、低血压)格列卫 水肿、恶心、腹泻、腹痛、肌肉痛性痉挛、疲劳和皮疹。肺水肿、胸膜腔积液、充血性 心力衰竭 美罗华发热、寒战、关节炎、过敏免疫抑制诱发病毒性肝炎赫赛汀安维汀高血压、蛋白尿、出血、皿栓 穿孔、伤口愈合不良动脉血栓、肿瘤出血 乳腺癌内科治疗进展乳腺癌内科治疗进展 晚期非小细胞肺癌内科治疗进展晚期非小细胞肺癌内科治疗进展 结肠癌内科治疗进展结肠癌内科治疗进展 CT-chemotherapyET-endocrine therapyRelative risk reduction of recurrence(%)01020304017%42%46%
10、31%CEF vs CMFLevine 2005AC T vs AC Henderson 2003CTHerceptin vs CTPiccart 2005Tamoxifen vs placeboFisher 2004DAC vs FACMartin 200528%HER2HER2+&HER2-HER2-CT+Herceptin vs CT Romond 20055052%HER2HER2+MBCMBC的治疗选择的治疗选择 细胞毒药物细胞毒药物蒽环类紫杉类卡培他滨长春瑞滨吉西他滨 新的激素药物新的激素药物三苯氧胺芳香化酶抑制剂FulvestrantLHRH类似物生物靶向治疗生物靶向治疗曲妥株单
11、抗曲妥株单抗 Lapatinib Bevacizumab T-DM1?Pertuzumab?Sutinib?Sorafenib?Iressa?Tarciva?双磷酸盐类双磷酸盐类支持与姑息治疗支持与姑息治疗Marty et al.2005紫杉醇+健择紫杉醇+赫赛汀多西紫杉醇+健择多西紫杉醇+赫赛汀单药多西紫杉醇多西紫杉醇希罗达Slamon et al.2001Melemed et al.2007E2100 2007紫杉醇+贝伐Jones et al.2005Melemed et al.2007E2100 2007Slamon et al.2001Jones et al.2005Marty et
12、 al.2005OShaughnessy et al.2002OShaughnessy et al.2002Chan et al.2005Chan et al.2005*仅包括有可测量病灶的患者Slamon DJ,et al.N Engl J Med 2001;344:78392;OShaughnessy J,et al.J Clin Oncol 2002;20:281223;Jones SE,et al.J Clin Oncol 2005;23:554251;Marty M,et al.J Clin Oncol 2005;23:426574;Chan S,et al.J Clin Oncol
13、 2005;23(June 1 suppl.):24s(Abstract 581);Melemed AS,et al.Presented at ASCO Breast Cancer 2007;Avastin Summary of Product Characteristics客观缓解率(%)单药紫杉醇010203040506070 DocetaxelChan 1999DoxorubicinChan 1999PaclitaxelSeidman 2004VinorelbineMuhoz 2006Doxorubicin+paclitaxelJassem 2001Capecitabine+doceta
14、xelOShaughnessy 2002Gemcitabine+paclitaxelAlbain 2004Fluorouracil+epirubicinZielinski 2005Gemcitabine+vinorelbineMuoz 2006Epirubicin+taxanePacilio 2006Avastin+paclitaxelE2100 2005PaclitaxelE2100 200502468101214MonthsMonotherapyCombinationchemotherapyAnti-angiogenic therapy+chemotherapyMedian PFS/TTP
15、9 monthsEMEA Avastin European Public Assessment Report,2007 ASCO 2006 June 2-6 病人数病人数160161进展或死亡进展或死亡60(38%)78(48%)中位中位PFS(月月)8.44.4 Hazard Ratio(95%CI)0.49(0.34-0.71)P值值(log-rank,1-side)0.001蒽环、紫彬、赫赛汀治疗失败患者蒽环、紫彬、赫赛汀治疗失败患者ORR(95%CI)28.8%(21.9-36.4)16.1%(10.8-22.8)p值值(Fisher,s exact,2-sided)0.017AVAD
16、O多西紫杉醇E2100紫杉醇RIBBON1,2卡培他滨，紫杉类或蒽环类随机入组仅化疗化疗+贝伐单抗直至进展选择性二线治疗：化疗+贝伐单抗（AVADO 和RIBBON-1）初治初治的转的转移性移性乳腺乳腺癌癌Joyce OShaughnessy et al,ASCO 2010,abs 1005 OShaughnessy J,et al.ASCO 2010.Abstract 1005.*Assessed in patients with measurable disease at baseline:n=1105 for chemotherapy plus bevacizumab;n=788 for
17、 chemotherapy alone.Joyce OShaughnessy et al,ASCO 2010,abs 1005 Joyce OShaughnessy et al,ASCO 2010,abs 1005 乳腺癌内科治疗进展乳腺癌内科治疗进展 晚期非小细胞肺癌内科治疗进展晚期非小细胞肺癌内科治疗进展 结肠癌内科治疗进展结肠癌内科治疗进展 Previously untreated stage IIIb/IV non-squamous NSCLC(n=878)CP 6(n=444)Bevacizumab(15mg/kg)every 3 weeks+CP 6(n=434)lPrimary
18、endpoint:overall survivallBevacizumab 15mg/kg i.v.administered every 3 weekslCarboplatin i.v.to AUC 6mg/mL and paclitaxel 200mg/m2 i.v.every 3 weeksPD*PD*No cross over permittedPD=progression of disease;i.v.=intravenous;AUC=area under the curveBevacizumab every 3 weeks until progressionSandler,et al
19、.NEJM 20061.00.80.60.40.200612182430Time(months)ProbabilityCP+AvastinCPHR=0.66(0.570.77)p 1 implies a greater chance of response on gefitinibOR and p-value from logistic regression with covariatesPatients(%)(n=659)(n=657)Doulliard et al;Data presented at WCLC 2007 in Seoul,KoreaP=0.1329Doulliard et
20、al;Data presented at WCLC 2007 in Seoul,KoreaP=0.0026P0.0001Doulliard et al;Data presented at WCLC 2007 in Seoul,Koreap-values from logistic regression with covariates.Clinically relevant improvement pre-defined as 6 point improvement for FACT-L and TOI;2 point improvement for LCS,maintained for at
21、least 21 daysEFQ,evaluable for quality of life*Interpret with caution due to open-label study designAE,adverse event;SAE,serious adverse event;CTC,common toxicity criterian(%)不良事件不良事件严重不良事件严重不良事件不良反应导致死亡不良反应导致死亡不良反应导致停药不良反应导致停药CTC3-4级不良反应级不良反应GefitinibN=729(%)687(94.2)161(22.1)31(4.3)59(8.1)272(37.3
22、)DocetaxelN=715(%)668(93.4)210(29.4)28(3.9)102(14.3)400(55.9)GefitinibN=729(%)527(72.3)28(3.8)6(0.8)30(4.1)62(8.5)DocetaxelN=715(%)588(82.2)130(18.2)15(2.1)78(10.9)291(40.7)所有不良事件所有不良事件治疗相关治疗相关*Doulliard et al;Data presented at WCLC 2007 in Seoul,Korea Calculations only include patients with a basel
23、ine and at least one post baseline value for that lab parameterDoulliard et al;Data presented at WCLC 2007 in Seoul,KoreaUhm JE,et al.Presented at 2009 WCLC.2009WCLC：前瞻、开放、随机、II期研究(二线治疗)厄洛替尼150mg/d，每4周至少满足以下2项l 腺癌l 女性l 不吸烟或l EGFR突变易瑞沙250mg/d，每4周随机分组于第4、8周评估疗效PD或出现不可耐受的毒性PD或出现不可耐受的毒性主要终点：客观缓解率Uhm JE,
24、et al.Presented at 2009 WCLC.Uhm JE,et al.Presented at 2009 WCLC.无进展生存概率(月)241.00612180.80.60.40.20.0P=0.083Gefitinib(250 mg/day)Carboplatin(AUC 5 or 6)/paclitaxel(200 mg/m2)3 weekly#1:1 randomisation *Never smokers,1 implies greater chance of response on gefitinib 71.2%47.3%1.1%23.5%Gefitinib,HR=0.
25、19,95%CI 0.13,0.26,p0.0001No.events M+=97(73.5%)No.events M-=88(96.7%)Carboplatin/paclitaxel,HR=0.78,95%CI 0.57,1.06,p=0.1103No.events M+=111(86.0%)No.events M-=70(82.4%)04812162024Time from randomisation(months)0.00.20.40.60.81.0Probabilityof PFSGefitinib EGFR M+(n=132)Gefitinib EGFR M-(n=91)Carbop
26、latin/paclitaxel EGFR M+(n=129)Carboplatin/paclitaxel EGFR M-(n=85)Mok T,et al.ESMO LBA 2,2008.111EGFR Mutation+EGFR Mutation-Median OSGefitinib:21.6 monthsC/P:21.9 monthsMedian OSGefitinib:11.2 monthsC/P:12.7 monthsIPASSIPASS：更新的：更新的中位生存期中位生存期吉非替尼吉非替尼(n=115)卡铂卡铂+紫杉醇紫杉醇(n=115)IIIB/IV期NSCLCEGFR基因敏感突变
27、既往未化疗ECOG PS 0-2=75岁(N=230)主要终点PFSR突变检测方法：PNA-LNA PCR Clamp法N Engl J Med 2010;362:2380-8.NEJGSG002主要终点：PFSN Engl J Med 2010;362:2380-8.吉非替尼 10.8M标准化疗 5.4MHR(95%CI)=0.30(0.22-0.41)P0.001 NEJGSG002研究：ORRN Engl J Med 2010;362:2380-8.客观缓解率(%)P0.001Maemondo M,et al.NEJM 2010;362:2380-2388.071421283542080
28、204060100生存概率(%)时间(月)P0.316.9个月23.630.5易瑞沙易瑞沙 (n=114)(n=114)卡铂卡铂/紫杉醇紫杉醇 (n=114)(n=114)即使一线化疗的患者二线得到高达即使一线化疗的患者二线得到高达95%95%的易瑞沙交叉治疗，的易瑞沙交叉治疗，一线使用易瑞沙组，患者总生存仍一线使用易瑞沙组，患者总生存仍延长了延长了6.96.9个月个月nEGFR IHC(positive vs negative vs indeterminate)nStage(IIIB vs IV)nECOG PS(0 vs 1)nCT regimen(cis/gem vs carbo/doc
29、 vs others)nSmoking history(current vs former vs never)nRegion1:1Chemonave advanced NSCLC(n=1,949)Non-PD(n=889)4 cycles of 1st-line platinum-based doublet*PlaceboPDTarceva150mg/dayPDMandatory tumour sampling*Cisplatin/paclitaxel;cisplatin/gemcitabine;cisplatin/docetaxel cisplatin/vinorelbine;carbopl
30、atin/gemcitabine;carboplatin/docetaxel carboplatin/paclitaxelCo-primary endpointsPFS in all patientsPFS in patients with EGFR IHC+tumoursSecondary endpointsOS in all patients and those with EGFR IHC+tumours,OS and PFS in EGFR IHC tumours;biomarker analyses;safety;time to symptom progression;QoLSubse
31、quent therapySubsequent therapyPFS probability1.00.80.60.40.20081624324048566472808896Time(weeks)HR=0.71(0.620.82)Log-rank p0.0001PFS is measured from time of randomisation into the maintenance phase;assessments were every 6 weeksTarcivaPlacebo0369121518212427303336Time(months)OS probability 1.00.80
32、.60.40.20OS is measured from time of randomisation into the maintenance phaseHR=0.81(0.700.95)Log-rank p=0.0088Tarceva(n=437)Placebo(n=451)OS at 12 mos(%)5045OS at 24 mos(%)2619Median(mos)1211IIIB/IV期NSCLCPS 014周期一线含铂方案诱导化疗后未进展随机分组培美曲塞BSC N=441治疗方安：培美曲塞 500 mg/m2 d1，q3wk 安慰剂 d1，q3wk 患者均接受：VitB12、叶酸、
33、地塞米松治疗主要终点：PFS2 1安慰剂BSC N=222PDT.E.Ciuleanu et al.J Clin Oncol 2008;26(20S):Abstr 8011HR=0.59995%CI:0.49-0.73P0.00001 ASCO 20080369121518212427303336394245480.00.10.20.30.40.50.60.70.80.91.0培美曲塞 13.4 个月安慰剂 10.6个月生存率生存率时间时间 (月月)HR=0.79(95%CI:0.650.95)P=0.012培美曲塞组52%接受后续治疗安慰剂组67%接受后续治疗,但仅19%接受了二线培美曲塞治
34、疗 ASCO 2009036912 15 18 21 24 27 30 33 36 39 42 45 480.00.10.20.30.40.50.60.70.80.91.0036912 15 18 21 24 27 30 33 36 39 42 45 480.00.10.20.30.40.50.60.70.80.91.0培美曲塞 15.5个月培美曲塞 9.9个月安慰剂 10.3个月安慰剂10.8个月HR=0.70 (95%CI:0.56-0.88)P=0.002HR=1.07(95%CI:0.491.73)P=0.678生存率生存率时间时间(月月)时间时间(月月)ASCO 2009 乳腺癌内科
35、治疗进展乳腺癌内科治疗进展 晚期非小细胞肺癌内科治疗进展晚期非小细胞肺癌内科治疗进展 结肠癌内科治疗进展结肠癌内科治疗进展1990 5-FU+levamisole1994 5-FU/LV1998 6 months2001 elderly patients2003 CI 5-FU(LV5FU2,PVI 5-FU)2008 FOLFOX(MOSAIC),CapeOx FOLFOX+bevacizumab CapeOx+panitumumab CapeOx+bevacizumabCustomisedtreatmentPharmacogenomic and pharmacogenetic studie
36、sPastPresentFuture0510152025Months5-FU/LVIFLFOLFOXFOLFIRIFOLFOX/FOLFIRI+Avastin+Avastin+Avastin+Avastin+AvastinProgression free survival(CT)Overall survival(CT)Hurwitz,et al.NEJM 2004;Kabbinavar,et al.JCO 2005;Goldberg,et al.JCO 2004;Douillard,et al.Lancet 2000;Kozloff,et al.ASCO GI 2007;Tournigand,
37、et al.HCO 2004 Progression free survival Avastin+CTOverall survival Avastin+CT1stline2ndlineIntensive therapyFOLFIRI/(XELIRI)+Avastin/cetuximab(Kras W+)FOLFOX XELOXIrinotecanmonoFOLFOX/XELOX+Avastin/cetuximab(Kras W+)Irinotecan+cetuximab(Kras W+)FOLFIRI(XELIRI)3rd lineIrinotecan cetuximab(Kras W+)Ir
38、inotecan+cetuximab(Kras W+)FOLFOX/XELOXAdapted from NCCN Colon Cancer v2,20071stline2ndlinePatients not suitable for 1st line oxaliplatin or irinotecan5-FU/LV/Xeloda+AvastinFOLFOX/XELOXFOLFIRI/(XELIRI)Single-agent irinotecan3rd lineIrinotecan cetuximab(Kras W+)Irinotecan+cetuximab(Kras W+)Adapted from NCCN Colon Cancer v2,2007
