特罗凯在晚期NSCLC治疗中的应用

特罗凯在晚期NSCLC治疗中的应用,同济大学附属肺科医院肿瘤科周彩存,晚期NSCLC: 治疗目的?,Longer life延长总体生存 Better life改善症状延长TTP改善疾病控制率较低毒性*改善QoL* 在二线治疗时尤其重要,Treatment algorithm,Significant toxicity myelosuppression neuropathy Limited improvement in QoL i.v. administration Need for premedication,Benefits,Disadvantages,Tumour control Improved survival,Chemotherapy,Chemotherapy: a balance between disease benefits and disadvantages for tolerability/QoL?,Longer survival, few side effects and improvement in QoL are main improvements to current therapy requested by patients,Patients,Mentioned spontaneously,Probed,Randomised trials comparing new drug regimens,不良事件 3/4 度中性粒细胞减少,病例 (%),Vin + Cis,Tax + Cis,Vin + Cis,Vin + Cis,Tax + Carbo,Pac + Carbo,Pac + Carbo,Gem + Cis,*,* p=0.01,79,75,74,65,50,38,76,57,不良事件中性粒细胞减少性发热,病例 (%),5,5,4,3,1,0.5,1,1.5,V+C,T+C,V+C,V+C,T+Cb,P+Cb,P+Cb,G+C,二线化疗也达到了平台,11,500mg/m2 i.v. every 3 weeks with folic acid/vitamin B12 and dexamethasone supplementation275mg/m2 i.v. every 3 weeks with dexamethasone support,Hanna N, et al. J Clin Oncol 2004;22:158997,结 论,对于PS 0-2分，一线和二线化疗疗效达到平台由于一线治疗有效，二线的需求在不断增加许多病人 (老年人,PS差)不适用化疗： 毒副反应轻-药物泰索帝和力比泰二线单药治疗有效，但毒性反应需引起注意,Novel agents: an important paradigm shift in our approach to the treatment of cancer,4. 蛋白体酶,1,2,3,4,5,6,1.生长因子和生长因子受体HER family, VEGF/R, c-kit/SCFR,2.信号传导通路Ras, raf, MAPK, MEK, ERK,protein kinase C, PI3K,3.肿瘤相关抗原 Gangliosides, CEA, MAGE, CD20, CD22,6.细胞外基质,5.细胞生长通路 Cyclin-dependent kinases,mTOR, cGMP, COX-2, p53, Bcl-2,Bronchud MH, et al eds. Principles of Molecular Oncology 2nd ed. Humana Press, Totowa NJ, 2003,Tumourcell,7,7.多靶点e.g. agents perturbing angiogensis and surface receptors,表皮生长因子受体信号通路,Grb2,Sos,Shc,Grb2,Sos,PI3K,Akt,Ras,Raf,MEK1/2,MAPK,BAD,生存,增殖,PTEN,mTOR,细胞周期进展,FKHR,GSK3,p27,Cyclin D1, E,表皮生长因子受体抑制剂,Matuzumab,Panitumumab,特罗凯,Cetuximab,吉非替尼,单克隆抗体,小分子,EGFR选择性酪氨酸激酶抑制剂 特罗凯(厄洛替尼),EGFR酪氨酸激酶抑制剂 易瑞沙(吉非替尼),相同的喹唑啉环结构,结构差异,类型结构时生物学效应也相同？,Tarceva, 增殖,侵润, 转移, 血管生成, 凋亡, 粘附, 化疗敏感性增加,特罗凯: 作用机制,Etessami A, et al. Drugs Fut 2000;25:8959Moyer J, et al. Cancer Res 1997;57:483848Harari PM, et al. Semin Radiat Oncol 2002;12(Suppl. 2):216,特罗凯对纯化EGFR TK的抑制作用,特罗凯浓度(nM),Adapted from Moyer J, et al. Cancer Res 1997;57:483848,EGFR磷酸化,100806040200,0.010.11101001,000,Tarceva: TK 选择性,Moyer J, et al. Cancer Res 1997;57:483848Data on file, OSI Pharmaceuticals Inc.,靶点,IC,50,(nM),表皮生长因子受体,2,HER2,350,血管内皮细胞生长因子受体,600,胰岛素受体,10,000,胰岛素样生长因子受体,-,10,000,CSF,-,1R,10,000,met,10,000,Src,1,300,Abl,1,500,lck,10,000,特罗凯对EGFR阳性荷瘤的作用 (A431),Desai B, et al. Eur J Cancer 2002;38:63 (Abs. 203),1,0008006004002000,1015202530,肿瘤细胞接种天数,平均肿瘤体积,媒介特罗凯 6.3mg/kg特罗凯 12.5mg/kg 特罗凯 25mg/kg特罗凯 100mg/kg,Tarceva 临床前资料:总结,口服有效，竞争性、选择性与可逆性地抑制TK ATP抑制纯化HER1/EGFR TK，IC50 为2nMHER1/EGFR的高度选择性诱导肿瘤细胞凋亡，抑制EGF介导的有丝分裂抑制移植瘤的生长 (ED50=9.2mg/kg p.o.)与化疗和生物制剂具有协同作用增强放疗的反应Active against EGFRvIII-transformed tumour cells需要高剂量来控制下游信号通路,特罗凯单药治疗晚期非小细胞肺癌的临床试验发展历程,剂量限制性毒性: 腹泻200mg/日推荐II期试验剂量= 150mg/日血浆浓度大于500ng/mL (体内具有抗肿瘤活性所需要的浓度)观察到抗肿瘤活性，尤其在非小细胞肺癌患者,特罗凯I期每日给药单药研究:总结,Hidalgo M, et al. J Clin Oncol 2001;19:326779,p.o. = orally,药代动力学研究,剂量依赖性的 Cmax 和 AUC 每日用药不会引起药物积聚每日口服特罗凯150mg/天，血浆特罗凯暴露浓度高,1Hidalgo M, et al. J Clin Oncol 2001;19:3267792Ranson M, et al. J Clin Oncol 2002;20:224050,II期临床试验: 特罗凯治疗晚期NSCLC,57例IIIb/IV NSCLCHER1 阳性18岁，PS0-2含铂方案PD或复发可测量病灶足够骨髓肝肾功能,特罗凯150mg/d,至少应用8周直到PD、不可耐受毒性或52周主要目的：RR次要目的： OS， TTP等,特罗凯150mg/日 治疗NSCLC的II期试验(n=57),Prez-Soler R, et al. J Clin Oncol 2004;22:323847Prez-Soler R, et al. Lung Cancer 2003;41(Suppl. 2):S246 (Abs. P-611),特罗凯II期试验: 毒性反应,治疗耐受性好最常见不良反应为皮疹与腹泻3例由于毒性而停药，另2例减量,Prez-Soler R, et al. J Clin Oncol 2004;22:323847,特罗凯II期临床试验:皮疹与生存之间关系,Survival distribution function,时间(月),Grade 2/3 (n=17),Grade 1 (n=26),No rash (n=14),051015202530,1.000.750.500.250,*vs no rash,Prez-Soler R, et al. J Clin Oncol 2004;22:323847,OS=8.4月,BR.21, a randomised phase III trial of Tarceva (erlotinib, OSI-774) as treatment following chemotherapy in patients with advanced NSCLC: an NCIC-CTG trial,BR.21: 研究设计,分层因素: 研究中心 PS (0/1 vs 2/3) 对以前治疗的反应 (CR/PR:SD:PD) 以前方案数 (1 vs 2) 含铂方案 (是与否),特罗凯150mg日,安慰剂,随机,BR.21: 病人特征,Shepherd F, et al. N Engl J Med 2005;353:12332,BR.21: 最佳反应 可测量病灶 (n=638)*,*Measurable disease was not an entry criterion,BR.21: 无进展生存,HR=0.61, p0.001*,25%,10%,Survival distribution function,生存时间 (月),1.000.750.500.250,051015202530,Shepherd F, et al. N Engl J Med 2005;353:12332,*HR and p (log-rank test) adjusted for stratificationfactors at randomisation and HER1/EGFR status,特罗凯显著延长总生存期,Shepherd FA, et al. N Engl J Med 2005; 353(2): 123-132,问题: 特罗凯治疗男性、非腺癌和吸烟患者能否提供临床获益？,BR.21: 有效率的亚组分析,BR.21: 总体生存亚组分析,01234,HR,Tarceva Prescribing Information 2005,OSI Pharmaceuticals, Inc., and Genentech, Inc.,HR 1 =特罗凯改善生存,BR.21: 总体生存亚组分析(续),01234,Tarceva Prescribing Information 2005,OSI Pharmaceuticals, Inc., and Genentech, Inc.,HR 1 = improved survival with Tarceva,BR.21: 是不是只有获得客观缓解的病人生存受益?,特罗凯的生存受益在未获得客观缓解的患者中也是明显的防止肿瘤进展可能产生重要的临床受益,BR.21: 副反应 (%),BR.21:到症状恶化时间(月),*Log-rank test, unadjusted for multiple symptoms,Bezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018),BR.21: 症状变化,*较基础水平变化10%Chi-squared test,Bezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018),改善 (%)*,稳定 (%),加重 (%)*,症状,特罗凯,安慰剂,特罗凯,安慰剂,特罗凯,安慰剂,p,值,疼痛,42,28,15,20,43,51,0.01,呼吸困难,34,23,27,33,40,44,0.03,咳嗽,44,27,24,31,32,41,0.0,1,疲乏,45,36,4,8,51,55,0.06,BR.21: QoL变化 (EORTC QLQ-C30),较基础水平改变*10%（临床明显的变化)p0.01,Bezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018),特罗凯和吉非替尼的III期临床研究: 研究设计,1Shepherd FA, et al. N Engl J Med 2005;353:12332 2Thatcher N, et al. Lancet 2005;366:152737,ISEL和BR.21试验病人特征比较,1Shepherd FA, et al. N Engl J Med 2005;353:12332 2Thatcher N, et al. Lancet 2005;366:152737,改善 42.5%,ISEL,BR.21,无显著性改善,BR.21 证实：特罗凯使患者生存期延长42.5%,总体生存,特罗凯 6.7月安慰剂 4.7月HR=0.73， p0.001,易瑞沙 5.6月安慰剂 5.1月HR=0.89， p=0.087,BR.21 证实：特罗凯对各种类型NSCLC患者均有效,吉非替尼的剂量可能不足以抑制野生型EGFR,体外100%抑制所需浓度1野生型 2.0M突变型L747-P753insS 0.2ML858R missense 0.2M,吉非替尼250mg/日的药物暴露浓度2,1Lynch TJ, et al. N Engl J Med 2004;350:2129392Albanell J, et al. J Clin Oncol 2002;20:11024,0.4M,标准剂量的吉非替尼可能不足以在无EGFR突变的病人中发挥作用,体外活性,特罗凯(厄洛替尼),易瑞沙(吉非替尼),1Moyer JD, et al. Cancer Res 1997;57:4838482Woodburn J, et al. Proc AACR 2000;41 (Abs. 2552),纯化HER1/EGFR 酪氨酸激酶,整个细胞HER1/EGFR TK,活性更高IC50 16-20nM,活性较低IC50 80nM,活性高,IC50 2nM,活性低,IC50 23-79nM,BR.21: 总结,BR.21试验达到它设计的研究终点：延长总体生存Tarceva是唯一HER1/EGFR TKI，显示统计学显著性生存受益亚组分析示广谱病人可从 Tarceva治疗中获得生存受益,不论性别、种族、吸烟史和组织学类型Tarceva 可引起明显的QOL的改善Tarceva耐受性好, 非血液学毒性轻到中度 (皮疹和腹泻),How do the different second-line treatment strategies compare?,二线治疗III期临床研究的比较：病人特征,1Tarceva product information; 2OSI and Roche data on file3Pemetrexed product information; 4Hanna N, et al. J Clin Oncol 2004;22:1589975Docetaxel product information,在BR.21研究中有更多的PS 2和 3患者，50% 二线治疗和50%的三线治疗,二线治疗临床III期研究的比较：疗效*,1Shepherd F, et al. N Engl J Med 2005;353:12332; 2OSI and Roche data on file; 3Shepherd F, et al. J Clin Oncol 2000;18:2095103; 4Fossella F, et al. J Clin Oncol 2000;18:235462; 5Hanna N, et al. J Clin Oncol 2004;22:158997,*Results cannot be compared directly because of different patient populations,特罗凯和化疗在二线治疗时具有相似的疗效,二线治疗III期临床研究的比较:耐受性,Shepherd F, et al. N Engl J Med 2005;353:12332Hanna N, et al. J Clin Oncol 2004;22:158997,Serious haematological toxicities may require hospitalisation and blood transfusions,特罗凯无血液学毒性主要毒性为皮疹和腹泻,二线治疗QOL结果,1Shepherd F, et al. N Engl J Med 2005;353:12332; 2Bezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018); 3Shepherd F, et al. J Clin Oncol 2000;18:2095103; 4Hanna N, et al. J Clin Oncol 2004;22:158997,总结: 二线治疗,*BSC和docetaxel 75mg/m2相比，无明显差异#力比泰和泰素帝在症状控制方面相似&咳嗽, 疼痛,呼吸困难，global QOL, 驱体功能,情感功能明显相似,特罗凯一线III期试验亚组分析,1Gatzemeier U, et al. J Clin Oncol 2005;23:(Suppl. 16 Pt I):627s (Abs. 7028)2Herbst RS, et al. J Clin Oncol 2005;23:58929,1 = Gemcitabine + cisplatin; 2 = Carboplatin + paclitaxel,目的评价特罗凯两种给药法联合泰索帝治疗晚期实体瘤的安全性与可行性,Davies AM, et al. Lung Cancer 2005;49(Suppl. 2):S61 (Abs. O-185),特罗凯联合泰索帝间歇应用: I期顺序应用,A组 = 600800mg/周; B组 = 150300mg/日,0123,3周方案,PLUS,OR,给药方案,初步结果 (n=22例 NSCLC )5 SD, 4 MR, 4 PR 选择B组进行II期研究,一线特罗凯单药II期研究 (MO17426) (non-targeted),n=53; 中期分析=16例3个中心:法国,英国,荷兰主要终点: 6周时的无疾病进展率次要终点:反应率,疾病控制率,反应维持时间,TTP,生存和安全性,未治疗的IIIB/IV期 NSCLC,至PD或不可接受毒性,特罗凯150mg/日,Giaccone G, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):638s (Abs. 7073),特罗凯单药II期临床试验 (non-targeted),6周时，无疾病进展率（疾病控制率）为55% (29/53) 最佳反应率23% (95% CI: 12.336.2) 中位生存期391天(56周) 中位TTP 94天 (95% CI: 49144),Giaccone G, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):638s (Abs. 7073)Giaccone G, et al. Oral presentation WCLC, Barcelona, July 2005,特罗凯一线治疗老年晚期NSCLC有效，耐受性好,疾病控制率 (CR+PR+SD)为60.3%中位生存期41周 (95% CI: 3260)2例反应者缺乏HER1/EGFR TK突变,Jackman D, et al. Lung Cancer 2005;49(Suppl. 2):39 (Abs. O188),Anti-tumour activity,病人数,(%,),Duration of,response,week,s,(range),Evaluable patients,6,8,CR,0,PR,8 (12,),Not yet reached,SD,3,3,(48,),17,(,5,118,+),PD,2,7,(,40,),7 (1,9),特罗凯一线治疗的总结,尽管这些结果 (反应率23%, 中位生存期)令人鼓舞。特罗凯在选择性病人中应用临床上:不吸烟者 (女性 腺癌)EGFR表达EGFR 突变EGFR 拷贝数EGFR 上