力比泰的临床应用

1、N-4-2-(2-氨基-3,4二羟基-4-氧基-7H-吡咯2,3-d 吡啶-5-yl)乙基苯氧基-L-谷氨酸 (培美曲塞)1. Shih C, et al. Adv Enzyme Regul 1998;38:135-152. 2. Zhao R, et al. Clin Cancer Res 2000;6:3687-3695. 3. Chattopadhyay S, et al. Mol Cancer Ther. 2007;6:404-417. Adjei AA. Expert Rev Anticancer Ther. 2003;3:145-156. Scagliotti GV, Novell

2、o S. Expert Opin Investig Drugs. 2003;12:853-863. Molina JR, Adjei AA. Clin Lung Cancer. 2003;5:21-27. Fossella FV. Semin Oncol. 2004;31(suppl 1):100-105. Vogelzang NJ, et al. J Clin Oncol 2003; 21(14):2636-2644Vogelzang NJ, et al. J Clin Oncol 2003; 21(14):2636-2644Manegold C et al. Sin Oncol. 2003

3、; l30(4 Suppl 10): 32-36.Vogelzang NJ, et al. J Clin Oncol 2003; 21(14):2636-2644Kelly K, et al. J Clin Oncol. 2001;19:3210-3218. 2. Schiller JH, et al. N Engl J Med. 2002;346:92-98. 3. Scagliotti GV, et al. J Clin Oncol. 2002;20:4285-4291. 4. Fossella F, et al. J Clin Oncol. 2003;21:3016-3024.41011

4、636071214BEV+PAC/CARB(N=427)PAC/CARB(N=440)p值MST (主要研究终点主要研究终点)12.3 月月10.3月月0.003 (HR 0.79; 95% CI, 0.67-0.92)PFS (次要研究终点)6.2 月4.5 月0.001(HR 0.66; 95% CI, 0.57-0.77)值得注意的毒副作用 G4中性粒细胞减少症 G3/4 高血压临床显著出血事件 G3/4鼻衄 G3/4 中枢神经系统出血 G3/4/5 呕血 G3/4/5 咯血 G3/4 黑便或消化道出血治疗相关性死亡26%7%4.4%0.7%0.7%0.5%1.9%0.9%1517%1%

5、0.7%0.2%000.2%0.4%20.0020.0010.0010.001867排除鳞癌患者以及有中枢神经系统转移、咯血、有出血体质或凝血病或治疗性抗凝病史、 规则应用阿司匹林/非甾体抗炎药/抗血小板制剂、心血管疾病、未控制的高血压病的患者Sandler A, et al. N Engl J Med. 2006;355:2542-2550.1. Zinner RG, et al. Cancer. 2005;104:2449-2456. 2. Scagliotti GV, et al. Clin Cancer Res. 2005;11:690-696. 3. Manegold C, et a

6、l. Ann Oncol. 2000;11:435-440. 4. Shepherd FA, et al. Cancer. 2001;92:595-600. Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51 Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51

7、1. Sigmond et al. Biochem Pharmacol 2003;66(3):431-438. 2. Giovannetti et al. Mol Pharmacol 2005;68(1):110-18. 3. Ceppi et al. Cancer 2006;107(7):1589-1596. 4. Peterson P et al. 12th World Conference on Lung Cancer, Seoul, Korea. 2007. Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51N=1725 Sc

8、agliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51N=1725 非劣效性P值0.001; Clinical Trials Registry available at (accessed April 27, 2008).Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51 非劣效性P值=0.008; Clinical Trials Registry available at www.clinicalstudyresults.o

9、rg (accessed April 27, 2008).Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51 ORR(95% 置信区间置信区间)30.6%(27.3%, 33.9%)28.2%(25.0%, 31.4%)0.312Scagliotti GV, et al. Presented at 12th World Conference on Lung Cancer; September 2- 6, 2007; Seoul, Korea.a 优效性P值Scagliotti GV, et al. J Clin Oncol. 2008

10、;26(21):3543-51力比泰力比泰/顺铂更好顺铂更好 健择健择 /顺铂更好顺铂更好a 优效性p值b 无法分辨腺癌、大细胞癌或鳞癌的患者Manegold C et al, Presented at 14th European Congress of Clinical Oncology (ECCO 14); September 23-27, 2007; Barcelona, Spain. Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51Scagliotti GV, et al. J Clin Oncol. 2008;26(21)

11、:3543-51ALIMTA Summary of Product Characteristics. Eli Lilly and Co; approved April 8, 2008.ALIMTA Summary of Product Characteristics. Eli Lilly and Co; approved April 8, 2008.Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51a 列出的是至少在一组中发生率3%的毒性Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3

12、543-51ESA=erythropoiesis-stimulating agent; G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte-macrophage colony-stimulating factorScagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51a 列出的是至少在一组中发生率3%的毒性Scagliotti GV, et al. J Cl

13、in Oncol. 2008;26(21):3543-51Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-51Smith IE et al. JCO 2001: 1336-1343. Socinski MA, JCO 2002: 1335-1343.Paclitaxel 100 mg/m2 weekly for 3 of 4 wks + Carboplatin (AUC=6) on day 1Paclitaxel 100 mg/m2 Carboplatin (AUC=2) weekly For 3 of 4 wksPaclitaxel

14、150 mg/m2 cycle 1 and 100 mg/m2 cycle 2 and Carboplatin (AUC=2) weekly for 6 of 8 wksRweekly paclitaxel 70mg/m2, 3 of 4 wks; (n=65)observation (n=65)RResponded (n=130) at week 16N=400Belani CP, et al. J Clin Oncol 2003;21:2933-2939.维持治疗生存期安全性: 维持治疗阶段，86%紫杉醇组报告至少1次不良事件，45%报告至少一次3或4级。p=0.124P=0.243紫杉醇

15、单药维持与紫杉醇单药维持与BSC相比，疗效没有显著性优势但相比，疗效没有显著性优势但3,4级毒副作用相应明显增加级毒副作用相应明显增加Westeel V, et al. J Natl Cancer Inst 2005;97:499-506.长春瑞滨维持化疗不能增加对长春瑞滨维持化疗不能增加对MIC诱导治疗有效的诱导治疗有效的晚期晚期NSCLC的生存期，但毒性反应显著增加的生存期，但毒性反应显著增加N/AN/AN/AASCO 2007 - Fidias P et al., Abstract # LBA7516RecruitmentNSCLC stage IIIB/IVChemo-naiveECO

16、G PS = 0-2No brain metaGC induction n=552G 1000 mg/m2,d1, 8C AUC 5，d1 q 3w/4wksRDoc IM 75 mg/m2 day 1, q3w till PD or max.6 cyclesDoc DL or BSC start till PD75 mg/m2 d1, q3w till PD or max. 6 cyclesDCRN=307OSPFS和缓解率立即给药组显著优于延迟治疗组和缓解率立即给药组显著优于延迟治疗组两组严重药物不良反应发生率相似两组严重药物不良反应发生率相似Brodowicz T. et al, Lun

17、g Cancer, 2006:52, 155-163.健择健择联合顺铂一线化疗后，继以健择联合顺铂一线化疗后，继以健择单药维持化疗可显著改善单药维持化疗可显著改善TTP对于体力状态好的患者，健择对于体力状态好的患者，健择单药维持化疗可显著改善总生存期单药维持化疗可显著改善总生存期维持治疗对症状改善和生活质量改善有积极意义维持治疗对症状改善和生活质量改善有积极意义Ciuleanu TE et al; J Clin Oncol 2008, 26: (suppl. Abs. No. 8011) 研究设计研究设计 多中心、双盲、安慰剂对照多中心、双盲、安慰剂对照期临床研究期临床研究47B/期期NSCL

18、C患者患者ECOG PS 0-1既往接受既往接受4周周期含铂诱导化期含铂诱导化疗未进展疗未进展2:1比例比例随机化随机化*BSC: 所有患者均接受所有患者均接受VB12、叶酸和地塞米松、叶酸和地塞米松ASCO 2009 Belani et al., Abstract # CRA800047 首要终点：首要终点：PFS 次要终点：次要终点：OS客观反应率客观反应率(CR+PR)疾病控制率疾病控制率(CR+PR+SD)安全性和毒性反应安全性和毒性反应48ASCO 2009 Belani et al., Abstract # CRA8000研究终点研究终点48研究结果研究结果PFS 力比泰力比泰维持

19、治疗可显著延长维持治疗可显著延长ITT人群的人群的PFS494950研究结果不同组织学类型的研究结果不同组织学类型的PFS 力比泰力比泰维持治疗对非鳞癌患者的维持治疗对非鳞癌患者的PFS改善更显著改善更显著50研究结果研究结果OS51力比泰力比泰维持治疗可显著延长维持治疗可显著延长ITT人群的人群的OS51研究结果不同组织学类型的研究结果不同组织学类型的OS52力比泰力比泰维持治疗对非鳞癌患者的维持治疗对非鳞癌患者的OS改善更显著改善更显著52研究结果客观反应率和疾病控制率研究结果客观反应率和疾病控制率53CR+PR(RR)*,%CR+PR+SD(DCR)*%力比泰力比泰安慰剂安慰剂P值值力比

20、泰力比泰安慰剂安慰剂P值值ITT人群人群N=66401*tumor response based on independently review population(N=581)53 毒性反应毒性反应54ASCO 2009 Belani et al., Abstract # CRA8000 级级 AEs (%)力比泰力比泰n= 441安慰剂安慰剂 n = 222中性粒细胞减少中性粒细胞减少 30贫血贫血31白细胞减少白细胞减少21乏力乏力51食欲不振食欲不振20感染感染10腹泻腹泻10恶心恶心11呕吐呕吐10感觉神经病变感觉神经病变10粘膜炎粘膜炎

21、/口腔炎口腔炎10P0.05 for grade 3/4 rates of neutropenia and fatigue研究结果研究结果54 这是第一项证明维持治疗可显著延长这是第一项证明维持治疗可显著延长NSCLC患者患者OS的随机、的随机、双盲、安慰剂对照研究，也证明了力比泰双盲、安慰剂对照研究，也证明了力比泰维持治疗的疗效维持治疗的疗效 非鳞癌组织类型可作为力比泰非鳞癌组织类型可作为力比泰治疗治疗NSCLC疗效的预测指标疗效的预测指标 力比泰力比泰在维持治疗应用中具有良好的安全性和耐受性在维持治疗应用中具有良好的安全性和耐受性 基于基于JMEN良好的疗效和安全性结果，力比泰良好的疗效和

22、安全性结果，力比泰已经于已经于7月被月被美国美国FDA批准用于非小细胞肺癌的维持治疗，成为第一个批准用于非小细胞肺癌的维持治疗，成为第一个同时被批准非小细胞肺癌一线、二线和维持治疗的药物！同时被批准非小细胞肺癌一线、二线和维持治疗的药物！55ASCO 2009 Belani et al., Abstract # CRA8000研究结论研究结论551.Shepherd et al. N Engl J Med. 2005;353:123-132. 2.Shepherd et al. J Clin Oncol. 2000;18:2095-2103. 3.Fossella et al. J Clin

23、Oncol. 2000;18:2354-2362. 4.Thatcher et al. Lancet. 2005;366:1522-1537. 5.Gridelli et al. Br J Cancer. 2004;91:1996-2004. 6.Camps et al. Ann Oncol. 2006;17:467-472. 7.Ramlav et al. J Clin Oncol. 2006;24:2800-2807. 8.Douillard et al; Data presented at WCLC 2007 in Seoul, Korea. * Not including placeb

24、o, BSC, or control arm.q3wk. N=49. N=125.qwk. qd.# qd, Days 1-5. NR=not reported1.Shepherd et al. N Engl J Med. 2005;353:123-132. 2.Shepherd et al. J Clin Oncol. 2000;18:2095-2103. 3.Fossella et al. J Clin Oncol. 2000;18:2354-2362. 4.Thatcher et al. Lancet. 2005;366:1522-1537. 5.Gridelli et al. Br J

25、 Cancer. 2004;91:1996-2004. 6.Camps et al. Ann Oncol. 2006;17:467-472. 7.Ramlav et al. J Clin Oncol. 2006;24:2800-2807. * Not including placebo, BSC, or control arm.q3wk. N=49. N=125.qwk. qd.# qd, Days 1-5. NR=not reportedHanna et al. J Clin Oncol 2004;22:1589-1597.随机分组力比泰力比泰500 mg/m2 IV q21d (n=283

26、)(叶酸 350-1000 g qd + 维生素 B12 1000 g q 9wk + 地塞米松 4 mg bid on d-1, d0, d+1)多西他赛多西他赛 75 mg/m2 iv q21d (n=288)(地塞米松 8 mg bid on d-1, d0, d+1)Hanna et al. J Clin Oncol 2004;22:1589-1597.Hanna et al. J Clin Oncol 2004;22:1589-1597.Hanna et al. J Clin Oncol 2004;22:1589-1597.Hanna et al. J Clin Oncol 2004

27、;22:1589-1597.Hanna et al. J Clin Oncol 2004;22:1589-1597.* 新辅助或辅助化疗不计入* 优效性和10%的非劣效性检验均无统计学显著性差异MST: 8.3 mos1-yr OS: 29.7%MST: 7.9 mos1-yr OS: 29.7%HR 0.9995% CI of HR (0.82, 1.20*)ALIMTA (N=265)Docetaxel (N=276)Survival distribution functionSurvival time (mos)Hanna et al. J Clin Oncol 2004;22:1589

28、-1597.BSC=best supportive care.Paoletti. Presented at Oncology Drugs Advisory Committee meeting, July 27, 2004. Available at:/ohrms/dockets/ac/04/slides/2004-4060S1_01_Lilly-Core-Presentation_files/frame.htm. Accessed March 13, 2007.Sourced from: Hanna et al. J Clin Oncol. 2004;22:1

29、589-1597.1.Shepherd et al. J Clin Oncol. 2000;18:2095-2103.Survival time (mos)Cumulative probabilityTAX 317 BSC (N=49)TAX 317 Docetaxel 75 mg/m2 (N=55)HR (ALIMTA vs BSC) 0.5595% CI: 0.33, 0.90p-value=0.019JMEI ALIMTA 500 mg/m2 (N=265)JMEI Docetaxel 75 mg/m2 (N=276)TAX 317 BSC (N=49) TAX 317 Docetaxe

30、l 75 mg/m2 (N=55)Survival time (mos)Cumulative probabilityBSC=best supportive care.Paoletti. Presented at Oncology Drugs Advisory Committee meeting, July 27, 2004. Available at:/ohrms/dockets/ac/04/slides/2004-4060S1_01_Lilly-Core-Presentation_files/frame.htm. Accessed March 13, 200

31、7.Sourced from: Hanna et al. J Clin Oncol. 2004;22:1589-1597.1.Shepherd et al. J Clin Oncol. 2000;18:2095-2103.9.1%(CI 5.9, 13.2)8.8% (CI 5.7, 12.8)45.8%(CI 39.7, 52.1)46.4%(CI 40.3, 52.5)ALIMTA (N=265)Docetaxel (N=276)Hanna et al. J Clin Oncol 2004;22:1589-1597.HR 0.9795% CI of HR (0.82, 1.16)MPFS=

32、2.9 mosMPFS=2.9 mosSurvival distributionALIMTA 500 mg/m2 (N=283)Docetaxel 75 mg/m2 (N=288)Survival time (mos)Hanna et al. J Clin Oncol 2004;22:1589-1597.* 实际接受治疗的患者 ALIMTA N=265; docetaxel N=276. 意向性分析Hanna et al. J Clin Oncol 2004;22:1589-1597.Weiss et al. J Clin Oncol. 2006;24:4405-4411.Peterson P

33、, et al. Eur J Cancer Suppl. 2007;5:363-364.Treatment-by-histology interaction was statistically significant (p0.001)Hanna et al. J Clin Oncol 2004;22:1589-1597. Hanna et al. J Clin Oncol 2004;22:1589-1597.多西他赛组因中性粒细胞减少而入院治疗的比例显著高出力比泰多西他赛组因中性粒细胞减少而入院治疗的比例显著高出力比泰 6 倍！倍！N/A=not applicable; NS=not sign

34、ificant.脱发脱发6NA38NA.001谷丙转氨酶升高谷丙转氨酶升高8210.00.028Hanna et al. J Clin Oncol 2004;22:1589-1597.Bhalla S et al. World Conference on Lung Cancer, 2005. Poster PD-066.Grade 1Grade 2Grade 3Grade 427623816013910288No adverse eventsNo adverse eventsGrade 1Grade 226523915313610090周期数周期数力比泰力比泰多西他赛多西他赛Percent o

35、f patientsGrade 4Grade 3Grade 2Grade 1None任何化疗周期内，力比泰任何化疗周期内，力比泰 3/4度不良反应发生率均显著少于多西他赛度不良反应发生率均显著少于多西他赛Pujol et al. European Society for Medical Oncology. 2004. Poster 705.HR 0.6095% CI of HR (0.50-0.72)p-value 0.0001Docetaxel (N=276)Med 0.4 mos1年无毒性生存率: 6.1%ALIMTA (N=265)Med 1.2 mos1年无毒性生存率: 12.2%Survival without toxicity (mos)Survival distribution functionALIMTA (N=265)Docetaxel (N=276)1年无毒性生存率，力比泰年无毒性生存率，力比泰比多西他赛显著延长比多西他赛显著延长 1 倍！倍！Hanna et al. J Clin Oncol 2004;22:1589-1597.Hanna et al. J Clin Oncol 2004;22:1589-1597. 2.Shepherd et al. N Engl