非小细胞肺癌治疗展望课件

1、非小细胞肺癌治疗展望,Down to genes,晚期NSCLC一线化疗疗效,Tax:泰素；Gem:健择；Txt: 泰索帝；Vnr:诺维本；Cis:顺铂；Cb:卡铂,非小细胞肺癌治疗的瓶颈,Schiller JH, et al. N Engl J Med. 2002;346:92-98,ECOG 1594: OS,无论使用何种第三代化疗药物的组合，患者的总生存都没有差异,非小细胞肺癌治疗的瓶颈,为什么疗效没有得到提高？是新药物并没有什么大的突破？还是,1. Schiller JH, et al. N Engl J Med 2002; 346:92-98. 2. Scagliotti GV, e

2、t al. J Clin Oncol 2008; 26:3543-3551. 3. Yang CH, et al. Presented at 2010 ESMO. 4. Inoue A, et al. 2011 ASCO Abstract 7519. 5. Mitsudomi T, et al. Lancet Oncol 2009; DOI:10.1016/s1470-2045(09)70364-X,个体化治疗才能解除魔咒,NCCN指南变迁,根据PS评分选择治疗手段,初治的病人进行EGFR突变检测,初治病人要进行EGFR突变和ALK融合基因的检查,What is the next gene,非

3、小细胞肺癌驱动基因的发现之旅,Pao, W Girard, N Lancet Oncol. 2011 Feb;12(2):175-80,肿瘤驱动基因/突变,驱动突变（driver mutation）能提供所在细胞的生长优势，是肿瘤发生的病因因素，能被正选择，驱动正常细胞向增殖癌细胞的转化,Driver mutations confer growth advantage on the cell in which they occur, are causally implicated in cancer development and have therefore been positively

4、selected,Greenman, C Nature 446, 153-158,针对这些驱动基因的治疗药物及手段,Pao, W Girard, N Lancet Oncol. 2011 Feb;12(2):175-80,Massachusetts General Hospitals, data on file,Mitsudomi et al,NSCLC驱动基因在人种上的差别,欧美人群肺腺癌的驱动基因突变情况,Kris MG, et al. ASCO 2011,腺癌不吸烟的人群驱动基因突变情况,Pham D et al. J Clin Oncol 2006;24(11):1700.Stephe

5、ns P et al. Nature 2004;431(7008):525.Shaw AT et al. J Clin Oncol 2009;27(26):4247.Riely GJ et al. Clin Cancer Res 2008;14(18):5731,美国人群,亚洲人群,Chenguang Li et al. PloS ONE 2011;6(11,97%的基因突变互相排斥,Kris MG. et al. ASCO 2011, Abstract # 7506,驱动基因 小结,目前非小细胞肺癌几乎半数的驱动基因已经被发现。 绝大多数情况下，这些驱动基因的突变不会同时出现。 对于已知的靶

6、点，已经有很多上市或在研的药物。他们将会改变现有非小细胞肺癌的治疗策略。 不同的人种，病理类型，吸烟状况，驱动基因的突变状态各异。 其中非吸烟的肺腺癌的驱动基因突变状态已知最全面，且目前可以获得的治疗效果最好,Does dream come true,EGFR TKI 被证实在EGFR 敏感突变的患者中疗效显著,NEJGSG002研究,WJTOG 3405研究,OPTIMAL研究,EURTAC研究,EML4-ALK,Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC,Kwak EL et al. N Engl J

7、 Med 2010;363:1693-703,Median PFS Has Not Been Reached 70% of Patients in Follow-up for PFS,Kwak EL et al. N Engl J Med 2010;363:1693-703,Current Crizotinib Clinical Trials,PRO: NCT00932893; PRO: NCT00932451,Key entry criteria Positive for ALK by central laboratory 1 prior chemotherapy (platinum-bas

8、ed,N=318,PRO,Crizotinib 250 mg BID (N=250) administered on a continuous dosing schedule,Key entry criteria Positive for ALK by central laboratory Progressive disease in Arm B of study A8081007 1 prior chemotherapy,PRO,RANDOMIZE,N=250,Crizotinib 250 mg BID (n=159) administered on a continuous dosing

9、schedule,Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 (n=159) infused on day 1 of a 21-day cycle,MET inhibitor,c-MET as therapeutic target in NSCLC,HGF/MET axis is associated with invasiveness and is regulated in part by the HIF and EGFR pathways MET amplifications are associated with EGFR inhibitor r

10、esistance HGF/MET may promote resistance to VEGF inhibitors,Xu et al, Oncogene, 2010; Engelman et al, Science, 2006; Cascone et al, ASCO 2010,c-MET receptor tyrosine kinase inhibitors Promising therapeutic target in NSCLC,With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502,ARQ-19

11、7, a novel and selective non-ATP competitive inhibitor of c-MET,Cox regression model. With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502,PFS (ITT population,Overall survival (ITT population,HR = 0.81; p = 0.24Adjusted HR = 0.68; p 0.05,HR = 0.81; p = 0.24Adjusted HR = 0.68; p =

12、0.52,ARQ-197 plus erlotinib improves PFS and OS compared with erlotinib alone,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,10,20,30,40,50,Time from randomization (weeks,Erlotinib + ARQ 197 16.1 wks (n = 84)Erlotinib + Placebo 9.7 wks (n = 83,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,10,20,40,60,70,

13、Survival time (weeks,Proportion of patients surviving,Erlotinib + Placebo 29.4 wks (n = 83)Erlotinib + ARQ 197 36.6 wks (n = 84,50,30,Proportion of patients progression free,Cox regression model. With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502,ARQ 197-209: PFS and OS in non-s

14、quamous cell histology patients (n = 117,PFS (investigator assessed,Overall survival,HR = 0.71; p = 0.12Adjusted HR = 0.61; p 0.05,HR = 0.72; p = 0.18Adjusted HR = 0.58; p 0.05,PFS and OS benefits most pronounced in patients with non-squamous cell carcinoma,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,

15、0,10,20,30,40,50,Erlotinib + ARQ 197 18.9 wks (n = 58)Erlotinib + Placebo 9.7 wks (n = 59,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,10,20,40,60,70,Erlotinib + ARQ 197 43.1 wks (n = 58)Erlotinib + Placebo 29.4 wks (n = 59,50,30,Proportion of patients surviving,Proportion of patients progression fre

16、e,Time from randomization (weeks,Time from randomization (weeks,PFS in histologic and molecular subgroups,With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502,0,5.0,0.5,1.0,1.5,2.0,FavorsARQ 197/erlotinib,FavorsErlotinib/placebo,Squamous cell Nonsquamous cell c-MET FISH 4 c-MET FI

17、SH 5 EGFR mutant EGFR wt KRAS mutant KRAS wt,26 / 24 58 / 59 19 / 18 8 / 11 6 / 11 51 / 48 10 / 5 49 / 45,HR=1.05 HR=0.71 HR=0.71 HR=0.45 HR=1.23 HR=0.70 HR=0.18 HR=1.01,13.7 (8.0-18.1) 18.9 (15.0-31.1) 15.4 (8.1-24.4) 24.1 (16.3-NE) 24.1 (8.0-32.1) 13.7 (8.1-18.1) 9.7 (7.9-NE) 15.4 (8.1-18.1,8.4 (7

18、.9-21.0) 9.7 (8.0-16.0) 15.3 (7.1-16.3) 15.6 (7.9-31.4) 21.0 (8.1-36.0) 8.1 (7.9-9.9) 4.3 (1.1-8.0) 9.9 (8.0-16.0,ARQ 197/erlotinib,Placebo/erlotinib,N,Median PFS (95% CI, weeks,Unadjusted HR (95% CI,OAM4558g study design: Randomized Phase II study of erlotinib +/- MetMAb,Spigel. ESMO 2010,Arm A Erl

19、otinib (150 qd-oral) + MetMAb (15 mg/kg IV q3w,Addition of MetMAb,Stratification factors: Tobacco history Performance status Histology,PD,If eligible,Co-primary objectives: PFS in “MET High” patients PFS in overall ITT population Other key objectives: OS in “MET High” patients OS in overall ITT pati

20、ents Overall response rate Safety/tolerability,Key eligibility: Stage IIIB/IV NSCLC 2nd/3rd-line NSCLC Tissue required PS 02,RANDO M IZ A T I O N,1:1,n = 128,n = 64,n = 64,n = 23,Enrollment from 3/2009 to 3/2010 Data cut-off: 8 June 2010,Arm B Erlotinib (150 qd-oral) + placebo (IV q3w,PFS and OS: IT

21、T population,Objective response rates: Erlotinib + placebo n = 3 (4.7%), Erlotinib + MetMAb n = 4 (6.3%) - 23 patients from the erlotinib + placebo arm crossed over to MetMAb,mPFS and mOS are consistent with previously reported findings in a similar disease setting,With permission from Spigel DR et

22、al. ASTRO Thoracic Symposium 2010;Presentation LBPL1,Time to Progression (weeks,Number at Risk,6464,4439,1714,116,63,51,21,01,01,Overall Survival (months,Number at Risk,6464,4438,2013,63,01,00,Erlotinib + placebo,Erlotinib + placebo,Erlotinib + MetMAb,Erlotinib + MetMAb,PFS and OS: MET high populati

23、on,PFS, HR = 0.56,OS, HR = 0.55,MetMAb + erlotinib improves both PFS and OS in MET high NSCLC patients,With permission from Spigel DR et al. ASTRO Thoracic Symposium 2010;Presentation LBPL1,Probability of Progression Free,1.0,0.8,0.6,0.4,0.2,0,0,3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,Time t

24、o Progression (weeks,Median PFS (wk)Hazard ratio95% CILog-rank p-value# Events,6.4,12.4,25,19,0.560.31-1.020.0547,3035,1822,59,35,33,21,21,01,01,Probability of Survival,1.0,0.8,0.6,0.4,0.2,0,0,3,6,9,12,15,Overall Survival (months,Median OS (mo)Hazard ratio95% CILog-rank p-value# Events,7.4,7.7,20,13

25、,0.550.26-1.160.1113,3035,1726,910,33,01,00,Erlotinib +Placebo(n = 30,Erlotinib + placebo,Erlotinib +Placebo(n = 30,Erlotinib + placebo,Erlotinib +MetMAb(n = 35,Erlotinib + MetMAb,Erlotinib +MetMAb(n = 35,Erlotinib + MetMAb,Number at Risk,Number at Risk,PFS and OS: MET low population,PFS, HR = 2.01,

26、OS, HR = 3.02,MET low NSCLC patients do worse with MetMAb + erlotinib,With permission from Spigel DR et al. ASTRO Thoracic Symposium 2010;Presentation LBPL1,Probability of Progression Free,1.0,0.8,0.6,0.4,0.2,0,0,3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,Time to Progression (weeks,11.4,6.0,20,

27、23,2.011.04-3.910.0354,Number at Risk,2927,2215,95,61,20,20,00,00,00,Probability of Survival,1.0,0.8,0.6,0.4,0.2,0,0,3,6,9,12,15,Overall Survival (months,9.2,5.5,9,14,3.021.13-8.110.0212,Number at Risk,2927,2312,93,30,00,00,Erlotinib +Placebo(n = 29,Erlotinib + placebo,Erlotinib +Placebo(n = 29,Erlo

28、tinib + placebo,Erlotinib +MetMAb(n = 27,Erlotinib + MetMAb,Erlotinib +MetMAb(n = 27,Erlotinib + MetMAb,Median PFS (wk)Hazard ratio95% CILog-rank p-value# Events,Median OS (mo)Hazard ratio95% CILog-rank p-value# Events,KRAS- Sorafenib,Primary endpoint: 8-wk disease control rate; 30% assumed,Kim ES,

29、et al. AACR 2010. Abstract LBA1. Reprinted with permission,BATTLE: Phase II NSCLC Biomarker Study,Umbrella protocol,Core biopsy,EGFRKRAS/BRAFVEGFRXR/CyclinD1,Biomarkerprofile,Randomization:Equal Adaptive,ErlotinibEqual (n = 25)Adaptive (n = 33,VandetanibEqual (n = 23)Adaptive (n = 29,Erlotinib + Bex

30、aroteneEqual (n = 21)Adaptive (n = 15,SorafenibEqual (n = 26)Adaptive (n = 72,2006-2012,EGFR and KRAS Mutations: Novel Discovery Findings,ErlotinibVandetanib Erlotinib + bexarotene Sorafenib,Kim ES et al. AACR 2010. Plenary Session LBA #1,Achieved 8 week DC (,N,100 90 80 70 60 50 40 30 20 10 0,29,KR

31、AS Mutation,EGFR Mutation,64,37,56,N,Sornafenib 在KRAS 突变的患者中的治疗结果喜忧参半 57位最后纳入统计的有效病例，其中30（53%）位患者 在6周内没有进展。5位PR，25位SD。 mPFS: 2.3个月，mOS:5.3个月。 II期临床的实验，并不能重复出I期临床的结果,KRAS mutations may effect early disease progression by stimulating cancer cells through more than one signaling pathway, Mellema sugges

32、ted,以上的研究都是集中在肺腺癌，肺鳞癌有什么新突破吗,新发现： 肺鳞状细胞癌细胞样本比其他病理类型的肺癌细胞含有更多的FGFR1的基因表达。 肺腺癌细胞中只有3%出现FGFR1的扩增，而肺鳞癌细胞中有21% 会出现FGFR1的扩增,已近进入临床试验的在研的FGFR抑制剂： Brivanib, dovitinib, BIBF1120, SU-6688,值得关注,2017,2015,使用这些靶向药物的时候选择正确的基因的检测至关重要,案例：EGFR-TKI,不检测 不选择,IHC,FISH,Mutation,直接测序法,血液标本,组织标本,ARMS法,其他,各种方法,选对了样本，选对了检测方法

33、，才能让病人获得最有效的治疗,只有靶向治疗需要进行基因水平的选择吗,虽然我们对于NSCLC很多驱动基因已知，但是没有驱动基因突变的病人还是很多的，他们该如何治疗？ 传统的不经选择的化疗方法疗效局限，且大多数人是在陪靶化疗，没有得到获益，但是还要承受化疗的严重毒副反应。 不同的化疗药物有它特定的优势人群吗？ 虽然我们通过临床特征和病理特征进行选择以后得到了改善。但是并不喜人，化疗也可以通过基因来更加明确的选择吗,Predictive Tests for First Line/ Maintenance Chemotherapy,Platinum Drugs ERCC1 Gemcitabine RR

34、M1 ALIMTA TS (thymidylate synthase,IALT-Bio: ERCC1 Gold = High Expression,RRM1 Expression,ERCC1 Expression,RRM1, ERCC1 与预后,OS N=184 HR=1.8 p=0.02,Zheng, NEJM 356: 800, 2007,如何个体化的制定临床策略,Personalizing the Treatment Matrix,ERCC1 low patients guided to platinum combination,RRM1 low patients guided to g

35、emcitabine combination,High / high patients guided to alternative combination,Feasibility and Efficacy of Molecular Analysis-Directed Individualized Therapy for Advanced NSCLC,Simon G et al. J Clin Oncol 2007,MADeIT,RR 44% (25%) PFS 6.6 months (4 months) Median OS 13.3 months (10 months) 1-year OS 5

36、9% (35,Simon G et al. J Clin Oncol 2007,TS 与力比泰,Mechanism of ALIMTA ALIMTA is an antifolate that inhibits multiple enzymes involved in purine and pyrimidine synthesis TS is the primary target of ALIMTA TS appears to be expressed at much higher levels in squamous lung tumors than adenocarcinomas TS mRNA levels are predictive of response to ALIMTA/gemcitabine chemotherapy2,2Bepler, J Thorac Oncol 3:1112, 2008,Challenges,Multiple methodologies Clinical trials utilized IHC and/or RT-PCR to quan