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1、Treatment selection is moving from histology-based to targeting oncogenic drivers,Figure: Massachusetts General Hospital, data on file. Horn L, Pao W. J Clin Oncol. 2009;26:42324235.,1999Histology-driven selection,2010Targeting oncogenic drivers*,*Incidence of mutations in adenocarcinoma provided as
2、 an example,Non-squamous,Evolution of NSCLC treatment,2008,Today,Current Standard of NSCLC Care,NSCLC肿瘤驱动基因,Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01.Massachusetts General Hospital, data on file; Horn L, Pao W. J Clin Oncol 2009; 26:42324235.,Frequency o
3、f driver genes in subgroups of NSCLC in Chinese,An SJ, Wu YL. PLoS One June 2012,Frequency of driver genes in subgroups of NSCLC in Chinese,An SJ, Wu YL. PLoS One June 2012,91%抗肿瘤药物的敏感性与基因变异相关,分析了130种抗肿瘤药物与肿瘤基因变异之间的关系，证实91% (118/130)的抗肿瘤药物敏感性与至少一种基因变异相关,Garnett MJ, et al. Nature 2012; 483:570-577.,S
4、ignificantly Mutated Genes in Squamous Cell Lung Cancer,Govindan et al. The Cancer Genome Atlas (TCGA) Project . 2012 ASCO,178/500鳞癌完成分析,Therapeutic targets in squamous cell lung carcinoma,Govindan R et al. ASCO 2012,第一个有临床意义的NSCLC驱动基因：,EGFR,EGFR mutant 1st line trials : PFS and OS,Placebo,Erlotinib
5、 150mg/day,Previously untreated stage IIIB/IV NSCLC, PS 0/1(n=451),R,PD,Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2 (d1) + placebo (d1528); q4wks x 6 cycles GC-placebo (n=225),Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2 (d1) + erlotinib 150mg/d
6、ay (d1528); q4wks x 6 cycles GC-erlotinib (n=226),PD,Study treatment,Maintenance phase,Screening,Erlotinib 150mg/day,Primary endpoint: PFS with IRC confirmationSecondary endpoints: subgroup analyses, OS in all patients and subgroups, ORR, duration of response, TTP, NPR at 16 weeks, safety, QoL,FASTA
7、CT-2 (MO22201; CTONG0902) study design,NSCLC = non-small cell lung cancer; PS = performance status; PD = disease progression; AUC = area under the curve; q4wks = every 4 weeks; IRC = independent review committee; OS = overall survival; ORR = objective response rate; TTP = time to progression; NPR =
8、non-progression rate; QoL = quality of life,1:1; stratified by stage, histology, smoking status and chemo regimen,PFS according to IRC,PFS probability,Time (months),0,22,24,26,28,18,16,12,6,20,14,10,8,4,2,Patients remaining,225,Placebo,12,35,134,19,51,79,179,200,1.0,0.8,0.6,0.4,0.2,0,7.4,10.0,HR=0.5
9、8 (0.460.72)Log-rank p0.0001,226,Erlotinib,43,76,151,59,93,1,14,177,200,1,1,7,3,1,0,3,29,14,1,1,0,Erlotinib (n=226),Placebo (n=225),Mok, Wu et al. ASCO 2012,PFS and OS in EGFR Mut+ subgroup (22 Jun 2012),1.00.80.60.40.20,Time (months),PFS probability,1.00.80.60.40.20b,Time (months),OS probability,0,
10、4,8,12,16,20,24,28,32,0,4,8,12,16,20,24,28,32,36,6.9,16.8,20.6,31.4,Erlotinib (n=49),Placebo (n=48),HR=0.48 (0.270.84)p=0.0092,Erlotinib (n=49),Placebo (n=48),HR=0.25 (0.160.39)p0.0001,PFS,OS,E4946423325191160P483516542210,E 494846454133241530P 48484336262414600,Mok, ESMO 2012,CTONG 902,1.00.80.60.4
11、0.20,PFS and OS in patients with EGFR WT and ERCC1 IHC+ status (22 Jun 2012),Time (months),PFS probability,1.00.80.60.40.20,Time (months),PFS,OS,OS probability,0,4,8,24,32,9.5,18.4,Erlotinib (n=20),Placebo (n=17),HR=0.32 (0.140.69)p=0.0024,Erlotinib (n=20),Placebo (n=17),HR=0.55 (0.271.12)p=0.0941,0
12、,16,28,4.6,7.5,4,8,12,24,20,12,16,20,28,E 2013732210P 178200000,E 20161515138630P 17139631000,CTONG 902,Mok, ESMO 2012,OS in ITT population (22 Jun 2012),15.2,18.3,Erlotinib (n=226),Placebo (n=225),HR=0.79 (95% CI 0.640.99) p=0.0420,OS probability,Time (months),1.0,0.8,0.6,0.4,0.2,0,0,38,36,34,32,30
13、,28,26,24,22,20,18,16,14,12,10,8,6,4,2,E 226219202191176165154138129114988568523923961 0 P 22521820618516815613812010392786853372413640 0,Mok, ESMO 2012,Mok, ESMO 2012,EURTAC Results: PFS by baseline T790M status,PFS probability,1.0,0.8,0.6,0.4,0.2,0,Time (months),0369121518212427303336,4.5,6.3,8.8,
14、12.1,Rosell R, et al. J Clin Oncol 2012;30 (Suppl. 15 Pt I):485s (Abs. 7522),Nature Medicine 18(8):521, 2012,EURTAC Biomarker Study,95 patients from EURTAC (EGFR Mutation) with available samplesBiomarkers: ELM4 ALK, T790M, TP53, BIM,16% detected by PCR,38% detected,24% mutation,31% high BEAM level,B
15、est survival in EGFR mutants receiving erlotinib:T790M +ive and BIM high: 40+months,疗效持续时间：基线到首次PD时间；肿瘤负荷：靶病灶倍增时间 和非靶病灶评分（4分）：病变进展、新出现胸内病变、新出现胸外 病 变、恶性胸腔积液症状评分：无症状（0）、原有症状稳定（1）、症状恶化（2）,Yang JJ, Chen HJ, Wu YL ,et al. Lung Cancer On Line 17 Oct 2012,NSCLC驱动基因,EML4-ALK融合基因,PROFILE 1007: Crizotinib vs
16、Chemotherapy (2nd/3rd line therapy),Key entry criteriaALK+ by central FISH testingStage IIIB/IV NSCLC1 prior chemotherapy (platinum-based)ECOG PS 02Measurable diseaseTreated brain metastases allowed,N=318,Crizotinib 250 mg BID PO, 21-day cycle(n=159),Pemetrexed 500 mg/m2 orDocetaxel 75 mg/m2 IV, day
17、 1, 21-day cycle(n=159),PROFILE 1007: NCT00932893,EndpointsPrimaryPFS (RECIST 1.1, independent radiology review)SecondaryORR, DCR, DROSSafety Patient reported outcomes (EORTC QLQ-C30, LC13),RANDOMIZE,aStratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (
18、yes/no),a,Shaw et al. ESMO 2012,aRECIST v1.1,ORRa by Independent Radiologic Review,65.3,19.5,ORR (%),ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P0.001,Crizotinib (n=173),PEM/DOC (n=174),80,60,40,20,0,Treatment,Shaw et al. ESMO 2012,Primary Endpoint: PFS by Independent Radiologic Review (ITT Population),Pr
19、obability of survival without progression (%),100,80,60,40,20,0,0510152025,Time (months),173933811201744915410,No. at riskCrizotinibPEM/DOC,PEM/DOC, pemetrexed/docetaxel,Shaw et al. ESMO 2012,PFS of Crizotinib vs Pemetrexed or Docetaxel,Probability of survival without progression (%),100,80,60,40,20
20、,0,0510152025,Time (months),17293381120 993612310 7213 310,No. at riskCrizotinibPemetrexedDocetaxel,aAs-treated population: excludes 1 patient in crizotinib arm who did not receive study treatment and 3 patients in chemotherapy arm who did not receive study treatment; bvs crizotinib,PFS Subgroup Ana
21、lysis,012,HR,Favors chemotherapy,Favors crizotinib,aData missing for smoking status (n=1) and tumor histology (n=7),Shaw et al. ESMO 2012,Interim Analysis of OS,a111 patients crossed over to crizotinib outside PROFILE 1007bHR adjusted for crossover using rank-preserving structural failure time metho
22、d: 0.83 (0.36 to 1.35),173129833711101741298434100,No. at riskCrizotinibChemotherapy,EML4-ALK阳性患者二线标准治疗,Crossover on PD,Crossover on PD,克唑替尼一线治疗ALK +肺癌的临床试验,150 patients China and 50 from 2-3 other Asian countries,Crossover on PD,Global,Asia,Ph-I: LDK378 is active in ALK+ NSCLC High response rate in
23、 crizotinib relapsed patients,Prior crizotinib,Crizotinib naive,Andrew Boral,NSCLC驱动基因,ROS1融合基因,ROS1临床病例,Bergethon K, et al. J Clin Oncol 2012; 30:863-870.,肺腺癌，发生率1%ALKinhibitor有效,Crizotinib在ROS1 NSCLC中的临床活性,Abstract No. 7508 , 2012 ASCO,Lan et al, Nat Gen 2012,NSCLC驱动基因,KRAS,CR, complete response;
24、PR, partial response; SD, stable diseasePD, progressive disease; DoR, duration of response; APF6, alive and progression-free at 6 months,Fishers exact 2-sided mid p value 1-sided p value*11 confirmed, 5 unconfirmedOne patient was classed as non-evaluable due to nonevaluable non-target lesions and wo
25、uld have had a partial response according to RECIST 1.1 criteria,p0.0001,p=0.0158,%,Selumetinib for KRAS mutation,Janne et al ESMO 2012,0,Progression Free Survival,There was a statistically and clinically significant improvement in PFS71/83 events (85.5%): selumetinib + docetaxel 35/43, placebo + do
26、cetaxel 36/40,Symbols represent censored observations,*Analysis was performed using a Cox proportional hazards model; The model allows for the effect of treatment and included terms for WHO PS, gender, histology and smoking status.,Proportion of progressionfree patients,Days,0 50 100 150 200 250 300
27、 350 400 450,1.0,0.8,0.6,0.4,0.2,0.0,Number at risk,4340,3421,2812,239,126,105,42,22,11,1,NSCLC驱动基因,其他,33岁，非吸烟，EGFR&KRAS&ALK均(-)新发现存在KIF5B-RET融合基因表达RETinhibitor有效,Ju YS, et al. Genome Res 2012; 22(3):436-445.,肺腺癌，发生率2%三阴性NSCLC，6.3%RET inhibitor有效？,KIF5B-RET,DDR2突变鳞癌患者Dasatinib治疗有效,化疗前,化疗后PD，开始Dasati
28、nib+erlotinib治疗,Dasatinib+erlotinib治疗后2月，疗效PR,鳞癌，DDR2 S768R突变,Hammerman PS, et al. Cancer Discovery 2011; 1:78-89.,Mutation identified,STOP,Enrollmentto n=25,Screening & Enrollment,Stage 1,Stage 2,Study treatment: dasatinib, 140 mg po QD until progression or unacceptable toxicity in all strata & bot
29、h stages of enrollment,Follow up for progression and survival,no,yes,Study Schematic (DDR2 Inhibitor),2012 NSCLC肿瘤驱动基因的加速发现,What about 2013，2014.,2012，非吸烟腺癌已有94.2的患者可明确其肿瘤驱动基因,Li F, et al. Cell Research 2012; 22:928-931.,A Novel Classification of Lung Cancer into Molecular Subtypes,West L, et al. PLoS ONE 2012; 7(2):e31906.,进展,驱动基因检测,治疗指南,1L,1LM,2L,野生型/未知,PS差,特罗凯（依据既往治疗）,特罗凯或易瑞沙或培美曲塞或多西他赛（依据既往治疗）,PS良好,晚期NSCLC未来3年可能的治疗模式,Adapted from Gandara, et al. Clin Lung Cancer 2009,化疗（单药）/ 特罗凯,EGFR TKIs 3rd line,培美曲塞或多西他赛（依据既往治疗）,3L,鼓励参加临床试验,谢谢,Thanks!,
