赫赛汀mbc治疗

Targeted on HER2, Focused on living,延长各期HER2阳性乳腺癌患者的生存,HER2的认知 赫赛汀的独特作用机制 赫赛汀治疗HER2阳性MBC关键性临床研究 赫赛汀安全性分析 用法与剂量,1987著名杂志科学发表HER2对乳腺癌的意义,HER2 HER2是有别于肿瘤大小、淋巴结及激素受体外的乳腺癌重要的预后因子 HER2是肿瘤复发和生存期长短的独立预后因子,HER2阳性对生存期的影响,HER2阳性的乳腺癌患者的生存率降低！,中位生存期 HER2 阳性 3年 HER2 阴性 6-7年,Slamon DJ et al. Science 1987;235:17782,1 = ­ 基因拷贝数 2 = ­ mRNA 转录 3 = ­ 细胞表面受体蛋白表达 4 = ­ 细胞外受体功能域释放,A = HER2 DNA B = HER2 信使RNA C = HER2 受体蛋白,正常,过度表达/扩增,细胞核,细胞质,细胞膜,1,2,3,4,C,B,A,HER2阳性：过度表达/扩增,HER2 表达在原发肿瘤和转移灶呈高度一致,*Mainly distant metastases. *Liver and lung metastases. Lymph node metastases were analysed in all cases, except in the studies by Vincent-Salomon et al (2002) and Gancberg et al (2002), where distant metastases were analysed.,Study Masood & Bui (2000) Shimizu et al (2000) Simon et al (2001) Tanner et al (2001) Gancberg et al (2002) Vincent-Salomon et al (2002) Tsutsui et al (2002) Carlsson et al (2004),Primary tumours 32% 38% 25% 28% 29% 25% 25% 55%,Metastases 32% 38% 22% 28% 27%* 20%* 25% 55%,Percentage IHC overexpression,HER2的认知 赫赛汀的独特作用机制 赫赛汀治疗HER2阳性MBC关键性临床研究 赫赛汀安全性分析 用法与剂量,赫赛汀®：靶向HER2的人源化单抗,用于治疗HER2阳性乳腺癌 治疗结果 生存率提高达45% 疗效改善并持续 维持生活质量,95% 人源化, 5% 鼠抗，具有高度亲和性 (Kd=0.1nM) 和特异性，显著降低免疫原性(HAMA),HER2,赫赛汀,Tumour cell,+,ADCC是赫赛汀重要的作用机制之一,ADCC,FcgRIII,NK cell,HER2的认知 赫赛汀的独特作用机制 赫赛汀治疗HER2阳性MBC关键性临床研究 赫赛汀安全性分析 用法与剂量,Vogel C, et al. J Clin Oncol 2002;20:71926,临床获益(n=84),治疗有效率 (95% CI),所有患者 (n111),26% (18,34),IHC 3+ (n=84),35% (24,44),FISH+ (n=79),34% (26,56),CR, PR, SD 6m,48%,39例患者12个月后仍然没有出现疾病进展,TTP 3.8个月，中位生存期24.4个月,赫赛汀®一线单药临床显示IHC 3+与FISH+患者临床获益最大 (H0650g),H0648g,R,HER2, human epidermal growth factor receptor 2; MBC:metastatic breast cancer; IHC: immunohistochemistry AC : docorubicin 60mg/m2 or epirubicin 75mg/m2 + cyclophosphamide 600mg/m2 P : paclitacel 175mg/m2 H, trastuzumab 4 mg /kg loading does then 2mg/kg qw until progressive disease;,No prior anthrayclines,Prior adjuvant anthrayclines,HER2-positive MBC (IHC3+ and / or IHC 2+) No prior chemotherapy for MBC (n=469),AC q3w × 6cycle,赫赛汀一线联合化疗及紫杉醇生存优势显著(H0648g),1.0 0.8 0.6 0.4 0.2 0,0 5 10 15 20 25 30 35 40 45 50,18,25,时间 (月),赫赛汀® + 紫杉醇 紫杉醇组*,40%,赫赛汀® +化疗 化疗组*,p0.05,1.0 0.8 0.6 0.4 0.2 0,20,29,0 5 10 15 20 25 30 35 40 45 50,时间 (月),生存概率,45%,生存概率,*70% 单纯化疗组的病人疾病进展后交叉使用赫赛汀®,Slamon D et al. N Engl J Med 2001;344;78392,M77001,R,HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; FISH, fluorescence in situ hybridisation; IHC, immunohistochemistry; R, randomisation; PD, progressive disease; H, trastuzumab; T, docetaxel;,1st-line therapy for HER2-positive MBC,T: 100 mg/m2 q3w×6cycle,T: 100 mg/m2 q3w ×6cycle,H: 4 mg/kg loading dose 2 mg/kg qw,HER2-positive MBC (FISH+ and / or IHC 3+) No prior chemotherapy or taxanes for MBC Baseline LVEF50% (n=188),Extra et al. Eur J Cancer. 2004;2:125.,1.0,生存概率,36,P = 0.0325,8.5 个月,22.7月,31.2月,赫赛汀® + 多西紫杉醇 多西紫杉醇,0.8,0.6,0.4,0.2,0.0,33,30,27,24,21,18,15,12,9,6,3,0,赫赛汀一线联合多西紫杉醇延长患者总生存期(M77001),时间 (月),1 Slamon et al. N Engl J Med. 2001;344:783792. 2 Baselga J. Oncology. 2001;61(Suppl. 2):1421. 3 Extra et al. Eur J Cancer. 2004;2:125. Abstract 239.,H0648g*1,2,M770013,临床疗效,H + P,(n=68),P,(n=77),H + D,(n=92),D,(n=94),ORR (%),49.0,17.0,61.0,34.0,TTP (月),7.1,3.0,10.6,5.7,OS (月),24.8,17.9,31.2,22.7,赫赛汀联合紫杉一线治疗改善长期生存,*转移性乳腺癌患者IHC 3+,TAnDEM: 赫赛汀+阿那曲唑一线治疗 MBC III期临床试验,阿那曲唑单药治疗出现疾病进展者给予含赫赛汀方案治疗,HER2阳性, ER阳性 MBC (n=208*),R,阿那曲唑 1mg qd + 赫赛汀 4mg/kg 起始剂量 2mg/kg qw 直至疾病进展,*剔除一例未服用所给药物患者,Kaufman B, et al. Oral presentation at ESMO 2006 (Abstract LBA2),阿那曲唑 1mg qd 直至疾病进展,PD,1 Wardley A, et al. Poster presented at SABCS 2007 2 Kaufman B, et al. Oral presentation at ESMO 2006 (Abstract LBA2),TAnDEM 2,临床疗效,H + An,(n=103),An,(n=104),TTP (月),4.8,2.4,PFS (月),4.8,2.4,赫赛汀其他一线联合治疗改善长期生存,OS (月),28.5,17.2,P值,0.0007,0.0016,0.048,对HER2阳性和激素受体阳性的转移性乳腺癌患者通过赫赛汀联合芳香化酶抑制剂的联合治疗可以显著改善生存,赫赛汀®联合化疗临床数据汇总,ORR,赫赛汀治疗进展后继续赫赛汀治疗的临床研究,Hermine研究,221例患者接受了赫赛汀一线治疗并随访两年,两年期间185例患者出现了疾病进展或死亡a,其中107例患者出现进展后进行使用含赫赛汀的方案治疗b,70例患者疾病进展后停用了赫赛汀治疗c,A8例患者无数据; b继续赫赛汀治疗或进展后继续治疗 30 天; c进展后停止了赫赛汀治疗或出现进展 (± 30 days) 或 30 days前已停止了赫赛汀治疗,623例患者入组: 均为HER2阳性 MBC 接受赫赛汀治疗,Extra et al 2006,HER2阳性患者疾病进展时改用化疗方案继续赫赛汀治疗是最好的选择,概率,月,0,5,10,15,20,25,30,21.3,n=70,n=107,中位OS, 月,p 值,21.3 4.6,0.001,95% CI,17.9, 29.4 2.8, 10.5,4.6,Extra et al 2006,1.0,0.8,0.6,0.4,0.2,0.0,HER2-positive MBC Progression under Herceptin-based 1st-line therapy + taxane or under Herceptin monotherapy or non-taxane (n=156),GBG-26 研究,von Minckwitz et al 2008,HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; R, randomisation; bid, twice a day; q21d, every 21 days; q3w, every 3 weeks,R,Trial conducted by: GBG, AGO, CEGOG, BOOG, Slovenia, DBG, CR-UK, BIG,GBG-26: continuation of Herceptin prolongs TTP by nearly 3 months,von Minckwitz et al 2008,Median follow up: 15.6 months aMedian TTP in months,GBG-26: continuation of Herceptin suggests impr