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1、从近年来临床肿瘤学进展看内科治疗的发展前景,近年来临床肿瘤学的重要进展 WHO将肿瘤定位为慢性可控疾病 分子靶向治疗 肿瘤内科治疗的新时代 中医理论和靶向治疗融合 结语 孙燕 中国医学科学院北京协和医学院肿瘤医院 2008-7-25,ASCO 2006年临床肿瘤研究的主要进展,1、Dasatinib可有效治疗伊 马替尼耐药的CML 2、Lapatinib改善晚期 乳腺癌疗效 3、预测少突胶质细胞瘤患 者预后的分子标志物 4、奥沙利铂加吉西他滨对 胰腺癌治疗无优势 5、肾癌一线和二线治疗 均有新药问世 6、人乳头瘤病毒（HPV)疫苗 能预防子宫颈癌和外阴癌,7、腹腔化疗可延长卵巢癌 患者生存期
2、 8、大剂量化疗治疗睾丸癌 疗效不优于常规化疗 9、西妥昔单抗加放疗能延 长头颈部癌患者生存期 10、肺癌预后可预测 11、FDA批准了两种治疗儿 童血液系统癌症的药物 12、黑色素瘤患者应常规接 受前哨淋巴结活检,ASCO 2007年临床肿瘤研究进展,24大进展 涵盖肿瘤预防、筛查、治疗和患者生存状态 6大重要进展：4项涉及肿瘤预防和筛查；2项为分子靶向治疗 18大显著进展,MRI用于乳腺癌高危人群筛查 肾癌治疗又添新靶向药物 PCI有效降低肺癌脑转移危险 HPV感染与头颈部肿瘤相关 索拉非尼改善肝癌患者生存 乳腺癌发病率降低与HRT应用减少相关,2007年临床肿瘤研究6大重要进展,2006
3、年WHO将癌症定位为可控慢性病,1、发生发展慢性过程预防、干预、早期 发现、早期治疗； 2、改变以前“根治”治疗的概念，如果超越可 能根治范畴，可以和其他慢性病一样控 制、保持正常生活和工作，“和平共处”； 3、内科治疗的地位提高和任务加重。,近十年来分子靶向治疗进入临床,为实现个体化前进一步 同病异治、异病同治调控和病理生理治疗,肿瘤治疗的靶点,传统靶点 DNA DNA合成的前体 细胞分类 微管蛋白 内分泌腺 受体 ER/PR,新靶点 信号转导 TK酶抑制剂格列卫、吉非替尼、厄罗替尼、索拉芬尼、苏尼替尼 新生血管VEGF 小分子化合-恩度 单克隆抗体-贝伐单抗 调控基因-曲妥珠单抗 EGF受
4、体 小分子化合物 单克隆抗体西妥昔单 抗、尼莫珠单抗 表面受体美罗华 疫苗HBV、HPV疫苗 EGF/VEGF疫苗,Deregulation of EGF System in Cancer,erbB1 HER1 EGFR,erbB2 HER2 neu,erbB3 HER3,erbB4 HER4,No specific ligands - often acts as dimer partner,Heregulins,NRG2 NRG3 Heregulins -cellulin,EGF, TGFa , b Cellulin Amphiregulin, HB-EGF,Human Epidermal
5、Growth Factor Receptor Family,抗肿瘤抗体靶向治疗,EGFR expression in the various cancer types,Cancer 2002;94:1593-1611,已经进入我国的EGFR 抑制剂,酪氨酸激酶抑制剂 (TKIs) Gefitinib（Iressa,吉非替尼，易瑞沙） Erlotinib（Tarceva,厄罗替尼,特罗凯） Sorafinib（索拉非尼，多吉美） Sutentinib（Sutent，索坦） Zactima(Vandetanib,凡德他尼） 单克隆抗体 (MAbs) Cetuximab（C225，西妥昔单抗） Ni
6、motuzumab (h-R3，泰新生）,已经来到我国的VEGF抑制剂,TKIs Sorafinib（索拉非尼，多吉美） Sutentinib（Sutent，苏尼替尼） Zactima(Vandetanib,凡德他尼） 单克隆抗体 Bevacizumab(Avastin,贝发单抗) 血管内皮抑素 恩度（Endostar) 中药成分 参一胶囊（Rg3）,Activation of the EGFR: a pivotal driver of malignancy,EGFR-TK,EGFR,Ligand,Gene transcription Cell-cycle progression,DNA,My
7、c,Myc,Cyclin D1,JunFos,P P,Cyclin D1,PI3-K,RAS,RAF,SOS,GRB2,PTEN,Akt,STAT3,MEK,MAPK,pY,pY,pY,Pharmacokinetics of IRESSA,IRESSA is given as a once-daily tablet peak plasma concentration within 3-7 h mean terminal half-life of 41 h in cancer patients steady-state concentrations achieved within 7-10 da
8、ys of daily dosing in cancer patients The large volume of distribution in cancer patients indicates extensive distribution into tissue,Swaisland et al 2001; Swaisland et al 2005; Ranson et al 2002; Wolf et al 2004,Study design,amodified Hochberg procedure applied to control for multiple testing CT,
9、chemotherapy; PS, performance status; EGFR, epidermal growth factor receptor,Patients Age 18 years Life expectancy 8 weeks Progressive or recurrent disease following CT Considered candidates for further CT with docetaxel 1 or 2 CT regimens (1 platinum) PS 0-2,Primary Overall survival (co-primary ana
10、lysesa of non-inferiority in all patients and superiority in patients with high EGFR gene copy number) Secondary Progression-free survival Objective response rate Quality of life Disease related symptoms Safety and tolerability Exploratory Biomarkers,Endpoints,Docetaxel,Gefitinib,Post-discontinuatio
11、n treatments (ITT population),aPatients may have also received other chemotherapy and/or erlotinib during the study Radiotherapy, surgery, medical procedures and other treatment excluded ITT, intent-to-treat; EGFR TKI, EGFR tyrosine kinase inhibitor,Other chemotherapy without docetaxel 15%,Other che
12、motherapy without EGFR TKI 10%,Objective tumor response (RECIST) (EFR population),RECIST, response evaluation criteria in solid tumors; EFR, evaluable for response; OR, odds ratio; CI, confidence interval,Patients (%),(n=659),(n=657),OR 1 implies a greater chance of response on gefitinib OR and p-va
13、lue from logistic regression with covariates,Quality of life and symptom improvement rates (EFQ population),p 0.0001,p = 0.0026,p = 0.1329,EFQ, evaluable for quality of life, FACT-L, Functional Assessment of Cancer Therapy-Lung; TOI, Trial Outcome Index; LCS, Lung Cancer Subscale,% patients with sus
14、tained clinically relevant improvement,p-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 least 21 days,Overall survival in overall PP population,96% of historical do
15、cetaxel advantage over BSC from TAX-317 retained by gefitinib (96% CI: 52%, 129%) Indirect comparison of gefitinib to BSC: HR (96% CI) = 0.63 (0.42, 0.92), p=0.0137 PP, per-protocol; NI, non-inferiority; HR, hazard ratio; OS, overall survival; BSC, best supportive care,Pre-specified NI limit in HR t
16、erms (translates to 50% effect retention Rothmann 2003) = 1.154,723,336,225,131,83,50,31,14,0,0,710,339,228,139,89,46,24,7,0,0,518,503,0,4,8,12,16,20,24,28,32,36,40,0.0,0.2,0.4,0.6,0.8,1.0,Months,Probability of survival,At risk :,Gefitinib,Docetaxel,Overall survival in patients with high EGFR gene c
17、opy number (ITT population),Probability of survival,85,44,26,13,10,6,4,3,0,0,89,42,31,22,14,7,4,1,0,0,66,63,0,4,8,12,16,20,24,28,32,36,40,0.0,0.2,0.4,0.6,0.8,1.0,Months,At risk :,Gefitinib,Docetaxel,FISH, fluorescence in situ hybridization,Thatcher et al 2005; Chang et al 2006; Fukuoka et al 2003; N
18、ishiwaki et al 2004; Park et al 2004; Guan et al 2005; Wu et al 2004; Takano et al 2004,IRESSA: 1-year survival rates in Asian patients,1-year survival (%),ISEL (all),ISEL (Asian),IDEAL 1 (all),IDEAL 1 (Japanese),Park et al,Guan et al,Wu et al,Takano et al,27,41,35,57,44,44,45,37,IRESSA (250 mg/day)
19、 + BSC,Primary end point Survival overall population adenocarcinoma Secondary end points TTF ORR QoL, symptoms Safety Exploratory end point Tumour biomarker analysis (eg EGFR),ISEL trial design,1692 patients in 210 centres across 28 countries Stratified for histology, sex, intolerant / refractory, P
20、S and smoking history,Placebo + BSC,Randomisation (2:1 ratio),BSC, best supportive care; CT, chemotherapy; ISEL, IRESSA Survival Evaluation in Lung cancer; ORR, objective response rate; PS, performance status; QoL, quality of life; TTF, time to treatment failure,Patients Locally advanced or metastat
21、ic NSCLC 1 or 2 prior CT regimens Intolerant to most recent CT regimen or progression 90 days of last CT cycle,Thatcher et al 2005,ISEL: survival in the overall population,0,2,4,6,8,10,12,14,16,Time (months),At risk:,1692,1347,877,485,252,104,31,Median, months 1-year survival, % Log-rank HR 0.89; 95
22、% CI 0.77, 1.02; p=0.087 Cox analysis, p=0.030,IRESSA 5.6 27,Placebo 5.1 21,0.0,0.2,0.4,0.6,0.8,1.0,Proportion surviving,IRESSA,Placebo,Median follow-up: 7 months (range 3-15); 58% deaths,Thatcher et al 2005,HR, hazard ratio,Median, months 1-year survival, % Log-rank HR 0.84; 95% CI 0.68, 1.03; p=0.
23、089 Cox analysis, p=0.033,IRESSA 6.3 30,Placebo 5.4 18,ISEL: survival in the adenocarcinoma population,Time (months),At risk:,812,669,446,262,145,66,18,0,2,4,6,8,10,12,14,16,0.0,0.2,0.4,0.6,0.8,1.0,Proportion surviving,Thatcher et al 2005,ISEL: significant improvement in TTF and ORR,1692,1051,539,27
24、8,129,49,17,IRESSA,Placebo,IRESSA Placebo Cox analysis (95% CI) Log rank Odds ratio (95% CI),Median TTF, months 3.0 2.6 0.82 (0.73, 0.92) p=0.0006 p=0.002 -,ORR, % (n) 8.0 (77 / 959) 1.3 (6 / 480) - - 7.28 (3.1, 16.9) p0.0001,TTF (months),At risk:,0,2,4,6,8,10,12,14,16,0.0,0.2,0.4,0.6,0.8,1.0,Propor
25、tion without treatment failure,Thatcher et al 2005,Survival,HR and 95% CI,0.4,0.6,0.8,1.0,1.5,Adenocarcinoma,11.9,8.0,14.7,8.8,7.6,7.9,18.1,4.8,5.3,9.4,8.4,6.6,5.1,ORR, %,ISEL: survival and ORR in subsets (1),Favours IRESSA,Favours placebo,Thatcher et al 2005,ISEL: survival and ORR in subsets (2),11
26、.1,8.0,12.4,7.4,6.9,9.0,6.8,7.5,10.1,7.7,6.4,7.2,10.2,Prior docetaxel,All patients,Asian ethnicity,65 years,No prior docetaxel,65 years,Non-Asian ethnicity,Prior CT response: PD / NE,Prior CT response: CR / PR,Prior CT response: SD,Time since Dx: 6 months,Time since Dx: 6-12 months,Time since Dx: 12
27、 months,Favours IRESSA,Favours placebo,0.4,0.6,0.8,1.0,1.5,HR and 95% CI,CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, non-evaluable,Thatcher et al 2005,Survival,ORR, %,ISEL: survival and ORR in subsets (2),11.1,8.0,12.4,7.4,6.9,9.0,6.8,7.5,10.1,7.7,6.
28、4,7.2,10.2,Prior docetaxel,All patients,Asian ethnicity,65 years,No prior docetaxel,65 years,Non-Asian ethnicity,Prior CT response: PD / NE,Prior CT response: CR / PR,Prior CT response: SD,Time since Dx: 6 months,Time since Dx: 6-12 months,Time since Dx: 12 months,Favours IRESSA,Favours placebo,0.4,
29、0.6,0.8,1.0,1.5,HR and 95% CI,CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, non-evaluable,Thatcher et al 2005,Survival,ORR, %,ISEL: survival by smoking history and racial origin,IRESSA,Placebo,Proportion surviving,0,2,4,6,8,10,12,14,16,0.0,1.0,0.8,0.6,
30、0.4,0.2,0,2,4,6,8,10,12,14,16,Time (months),Never smoked (n=375),Ever smoked (n=1317),HR 0.92; 95% CI 0.79, 1.06; p=0.242,HR 0.67; 95% CI 0.49, 0.92; p=0.012,Proportion surviving,0.0,1.0,0.8,0.6,0.4,0.2,0,2,4,6,8,10,12,14,16,0,2,4,6,8,10,12,14,16,Asian origin (n=342),Non-Asian origin (n=1350),HR 0.9
31、2; 95% CI 0.80, 1.07; p=0.294,HR 0.66; 95% CI 0.48, 0.91; p=0.010,Cox regression analysis,Thatcher et al 2005,TALENT and TRIBUTE: study design,Patients with HER1/EGFR-positive or -negative, stage IIIB/IV NSCLC,Primary objective overall survival (80% power to detect a 25% survival benefit and a 33% 1
32、-year survival benefit, =0.05) Secondary objectives time to disease progression response rate/duration of response time to symptomatic progression safety,150mg/day Tarceva p.o. + six cycles of chemotherapy,Placebo + six cycles of chemotherapy,Daily oral Tarceva alone,Placebo alone,TALENT = gemcitabi
33、ne and cisplatin (n=1,172) TRIBUTE = carboplatin and paclitaxel (n=1,079),TALENT and TRIBUTE: results,Two very similar negative studies with gefitinib (INTACT 1 and INTACT 2),Docetaxel induces M-phase arrest and apoptosis that is enhanced by the anti-cell survival effect of Tarceva,Apoptosis,Tarceva
34、 induces G1 arrest, which can block the M-phase activity of docetaxel,Tarceva Docetaxel,Docetaxel Tarceva,G1,M,S,G2,Cell Cycle,Apoptosis,G1,M,S,G2,Cell Cycle,Apoptosis,Sequence effects of docetaxel plus Tarceva: a model of response,Gumerlock, UC Davis,TALENT: survival and rash (Tarceva),Proportion e
35、vent-free,1.0 0.8 0.6 0.4 0.2 0,0 100 200 300 400 500 600,Study day,Log-rank test p=0.0001,Median survival (months) Grade 1 10.7 Grade 2 10.4 Grade 3 12.9 No AE 7.6,Grade 1 Grade 2 Grade 3 No AE,Gatzemeier U, et al. J Clin Oncol 2004;23(Suppl. 14):617 (Abs. 7010),TRIBUTE: carboplatin + paclitaxel pl
36、us continuous Tarceva improved survival in never smokers,Miller V, et al. J Clin Oncol 2004;22(Suppl. 14S):628 (Abs. 7061),Avastin在非小细胞肺癌的III期临床 (E4599): 试验设计,主要终点: 总生存期 Avastin 15mg/kg i.v. 每三周 卡铂 iv. AUC 6mg/mL和 紫杉醇 200mg/m2 i.v. 每三周 Avastin联合CP组患者接受 Avastin单药直至疾病进展,未经治疗 IIIB期/IV期 非鳞癌非小细胞肺癌 (n=878
37、),CP 6 (n=444),Avastin (15mg/kg) 每三周 + CP 6 (n=434),PD*,PD,*No cross over permitted,Avastin 每三周直至进展,Sandler A, et al. N Engl J Med 2006;355:254250,E4599 试验: 一线治疗中加入Avastin 能改善生存期,在这个里程碑的试验中，Avastin为基础的治疗能延长中位生存期超过一年。,1.0 0.8 0.6 0.4 0.2 0,0 6 12 18 24 30 36 42,Months,Probability,HR=0.79 (0.670.92);
38、p=0.003,10.3,12.3,Sandler A, et al. N Engl J Med 2006;355:254250,E4599试验:一线治疗中加入Avastin 能改善PFS,1.0 0.8 0.6 0.4 0.2 0,0 6 12 18 24 30,时间(月),Probability,化疗 + Avastin 化疗,HR=0.66 (0.570.77); p0.001,4.5,6.2,Sandler A, et al. N Engl J Med 2006;355:254250,E4599 试验:客观缓解率 (可测量疾病),化疗,(n=,392,),化疗 + Avastin,(n
39、=,381,),p,value,总的反应期,(%),15,35,0.0,01,Sandler A, et al. N Engl J Med 2006;355:254250,化疗,(n=440),化疗 + Avastin,(n=427),Grade (%),Grade (%),3,4,5,3,4,5,p value,所有出血事件,0.7,4.4,0.001,中枢神经系统出血,0.7,鼻出血,0.2,0.7,呕血,0.5,咯血,0.2,0.5,0.2,1.2,黑便/消化道出血,0.2,0.2,0.7,0.2,其他出血,0.2,0.2,E4599试验: 出血事件,Sandler A, et al.
40、N Engl J Med 2006;355:254250,E4599 试验: 死亡原因,CP,(n=440),CP + Avastin,(n=427),p value,总死亡数,344,305,死因,肺癌,309,260,NR,毒性反应,2,14,*,p=0.001,合并情况,16,16,NR,未知原因,17,15,NR,*One patient in the CP + Avastin group who had a grade 5 AE was considered to be ineligible because of undocumented advanced disease; data
41、 on this patient are not included in the table (but were included in the analysis of AEs) NR = not reported,Sandler A, et al. N Engl J Med 2006;355:254250,E4599试验: 总结,PS评分好的非鳞癌的非小细胞肺癌，Avastin加上标准的以铂类为基础的化疗方案能显著改善生存期，无进展生存期和客观缓解率 。 加入Avastin后，可增加一些毒副反应。 研究中可发现有高血压，蛋白尿和头痛 (与 Avastin相关的不良反应)， 通常可处理，不需要
42、长期停用Avastin。 非小细胞肺癌标准治疗中加入Avastin取得生存获益时，必须考虑这些危险因素。,Avastin: 改变美国的治疗现状,根据 E4599试验的阳性结果， Avastin联合CP 成为ECOG 对于非鳞癌的非小细胞肺癌一线治疗标准1 Avastin 联合化疗也被NCCN推荐为非小细胞肺癌一线治疗的临床指南 (v.1.2007)1 E4599试验是Avastin进入美国的基础。 2006年10月，美国FDA批准 Avastin联合CP作为非鳞癌的非小细胞肺癌一线治疗,1NCCN clinical practice guidelines in oncology. Non-sm
43、all cell lung cancer, version 1 2007. Available at: http:/www.nccn.org/professionals/physician_gls/PDF/nscl.pdf,NSCLC First or 2nd lines 493pts PS 0-2 期,NVB 25mg/m2,NVB 25mg/m2,Rndoistar 7.5mg/m2+NS 250ml IV gtt,d1,d2,3,4,d5,d1-14,d21,R,NVB 25mg/m2,CDDP 30mg/m2,NVB 25mg/m2,d21,d1,d2,3,4,d5,Placebo N
44、S 3.5ml)+NS250ml IV gtt,24 Centers R、double blind 、placebo control、multicenter first：2nd line = 2：1 T：C= 2：1,CDDP 30mg/m2,d1-14,Phase III Clinical Trial,Clinical Response,Phase III Clinical Trial,复治病人的生存情况,恩度IV期阶段性总结 结果分析,2008年7月25日,总的疗效分析,分层分析-初/复治,分层分析-病理类型,不良反应比较,Gefitinib in China,吉非替尼治疗最佳疗效的单因素
45、分析,客观疗效：logistic多因素回归分析,因素：性别，年龄，病理类型，吸烟，紫杉类耐药，EGFR基因突变； Odds Ratio值1表明左侧一栏因素有效的机率大,疗效预测模型方程式,方程式 =2x病理类型 + 吸烟状况 + 年龄 + EGFR基因突变 病理类型： 腺癌=1分，非腺癌=0分 年龄： 65岁=1分，65岁=0分 吸烟状况： 不吸烟=1分，吸烟=0分 EGFR突变：有突变=1分，无突变=0分,界值上下两组人群的疗效,疗效预测模型评分对应的RR和DCR,Cut-off value（界值）=2，每增加1分，疗效增加1倍。,A组:,第一阶段,第二阶段,TXT,吉非替尼,B组:,吉非替
46、尼,TXT,PD,PD,吉非替尼:250mg/天,口服至疾病进展 单药多西紫杉醇60mg/m2-75mg/m2 ，d1, ；或多西紫杉醇35mg/m2,d1，d8，顺铂30mg/m2第2，3，4天，每21天重复X3-6个周期。,吉非替尼/多西紫杉醇二线治疗晚期NSCLC的用药顺序比较,吉 非 替 尼, ,吉非替尼/多西紫杉醇二线治疗晚期NSCLC的疗效, , ,吉 非 替 尼,吉 非 替 尼,第一、第二阶段及调整后两组的 PFS,生存率,B组: Iressa 5.0月,A组: TXT 3.0月,生存率,A组: Iressa 7.0月,B组: TXT 4.0月,生存率,Iressa : 6.0月,TXT : 4.0月,p =0.0383,p =0.017,p =0.046,TXT,Iressa,皮 疹,指甲改变,皮肤干燥,靶向治疗的不良反应需要处理,人参（ Ginsing Radix ）,人参甙的结构,Rg3,CAM实验0.9%N.S,CAM实验Rg3组,（ 500u