肺癌驱动基因研究总结ppt课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,厦门,CSCO 2009,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,1,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,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.,KRAS,EGFR,BRAF,HER2,PIK3CA,ALK,MET,Unknown,1999,Histology-driven,selection,2010,Targeting oncogenic,drivers*,*Incidence of mutations in adenocarcinoma provided as an example,Non-squamous,Evolution of NSCLC treatment,Squamous,EGFR,WT,EGFR,Mu,Squamous,EGFR,Mu,KRAS,Mu,ALK,+,Other non-squamous WT,Squamous,2008,Today,Current Standard of NSCLC Care,Adenocarcinoma,Squamous-cell carcinoma,Large cell carcinoma,Treatment selection is moving,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;,26:4232,423,5,.,K-ras,EGFR,B-raf,Her2,PIK3CA,ALK,MET,Unknown,Unknown,2010,：,7,类肿瘤驱动基因，,未知,55%,NRAS,MEK1,HER2,PIK3CA,MET AMP,No mutation detected,KRAS (22%),EGFR (17%),EML4-ALK (7%),Double mutants (3%),BRAF (2%),AKT1,2011,：,10,类肿瘤驱动基因，未知,46%,NSCLC肿瘤驱动基因Kris MG, et al. ASC,Frequency of driver genes in subgroups of NSCLC in Chinese,An SJ, Wu YL. PLoS One June 2012,Frequency of driver genes in s,Frequency of driver genes in subgroups of NSCLC in Chinese,An SJ, Wu YL. PLoS One June 2012,Frequency of driver genes in s,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.,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,Significantly 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,Significantly Mutated Genes in,Gene,Event Type,Frequency,CDKN2A,Deletion/Mutation/Methylation,72%,PI3KCA,Mutation,16%,PTEN,Mutation/Deletion,15%,FGFR1,Amplification,15%,EGFR,Amplification,9%,PDGFRA,Amplification/Mutation,9%,CCND1,Amplification,8%,DDR2,Mutation,4%,BRAF,Mutation,4%,ERBB2,Amplification,4%,FGFR2,Mutation,3%,Therapeutic targets in squamous cell lung carcinoma,Govindan R et al. ASCO 2012,GeneEvent TypeFrequencyCDKN2AD,第一个有临床意义的,NSCLC,驱动基因：,EGFR,第一个有临床意义的NSCLC驱动基因：EGFR,EGFR mutant 1,st,line trials : PFS and OS,PFS,OS,EGFR TKI,组,化疗组,HR,EGFR TKI,组,化疗组,HR,Gefitinib trials,IPASS*,1,(n= 261),9.5,6.3,0.48,p0.001,21.6,21.9,1.00(0.76-1.33),NEJ002,2,N=194,10.8,5.4,0.36,P0.001,27.7,26.6,0.89(0.63-1.24),WJTOG3405,3,N=172,9.2,6.3,0.49,P0.0001,36,39,1.19(0.77-1.83),Erlotinib trials,OPTIMAL,4,N= 154,13.7,4.6,0.16,p0.0001,22.7,28.8,1.04(0.69-1.58),EURTAC,5,N=174,10.4,5.4,0.47,p0.0001,19.3,19.5,1.04(0.65-1.68),#,Afatinib trial,LUX-LUNG- 3,N=345,13.6,6.9,0.47,p0.0001,EGFR mutant 1st line trials :,Placebo,Erlotinib 150mg/day,Previously untreated stage IIIB/IV NSCLC, PS 0/1,(n=451),R,PD,Gemcitabine,1,250mg/m,2,(d1, 8),+ carboplatin AUC=5 or cisplatin 75mg/m,2,(d1) + placebo (d1528);,q4wks x,6 cycles,GC-placebo (n=225),Gemcitabine,1,250mg/m,2,(d1, 8),+ carboplatin AUC=5 or cisplatin 75mg/m,2,(d1) + erlotinib 150mg/day (d1528); q4wks x,6 cycles,GC-erlotinib (n=226),PD,Study treatment,Maintenance phase,Screening,Erlotinib 150mg/day,Primary endpoint:,PFS with IRC confirmation,Secondary endpoints:,subgroup analyses, OS in all patients and subgroups, ORR, duration of response, TTP, NPR at 16 weeks, safety, QoL,FASTACT-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 = non-progression rate; QoL = quality of life,1:1; s,tratified by,stage, histology, smoking status and chemo regimen,PlaceboErlotinib 150mg/dayPrev,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=0.58 (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 according to IRCPFS probab,PFS and OS in,EGFR,Mut+,subgroup (22 Jun 2012),1.0,0.8,0.6,0.4,0.2,0,Time (months),PFS probability,1.0,0.8,0.6,0.4,0.2,0b,Time (months),OS probability,0,4,8,12,16,20,24,28,32,0,4,8,12,16,20,24,28,32,36,6.9,16.8,20.6,31.4,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,E4946423325191160,P483516542210,E 494846454133241530,P 48484336262414600,Mok, ESMO 2012,CTONG 902,PFS and OS in EGFR Mut+ subgro,1.0,0.8,0.6,0.4,0.2,0,PFS and OS in patients,with,EGFR,WT,and,ERCC1 IHC+,status (22 Jun 2012),Time (months),PFS probability,1.0,0.8,0.6,0.4,0.2,0,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=0.0941,0,16,28,4.6,7.5,4,8,12,24,20,12,16,20,28,E 2013732210,P 178200000,E 20161515138630,P 17139631000,CTONG 902,Mok, ESMO 2012,1.0PFS and OS in patients with,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),1.0,0.8,0.6,0.4,0.2,0,0,38,36,34,32,30,28,26,24,22,20,18,16,14,12,10,8,6,4,2,E 226219202191176165154138129114988568523923961 0 P 22521820618516815613812010392786853372413640 0,Mok, ESMO 2012,Mok, ESMO 2012,OS in ITT population (22 Jun 2,Tarceva T790M present (n=21),Tarceva T790M absent (n=43),Chemotherapy T790M present (n=26),Chemotherapy T790M absent (n=33),EURTAC Results: PFS by baseline T790M status,PFS probability,1.0,0.8,0.6,0.4,0.2,0,Time (months),0369121518212427303336,4.5,6.3,8.8,12.1,Rosell R, et al. J Clin Oncol 2012;30 (Suppl. 15 Pt I):485s (Abs. 7522),Tarceva T790M present (n=21)Ta,Nature Medicine 18(8):521, 2012,Nature Medicine 18(8):521, 201,EURTAC Biomarker Study,95 patients from EURTAC (EGFR Mutation) with available samples,Biomarkers: ELM4 ALK, T790M, TP53, BIM,16% detected by PCR,38% detected,24% mutation,31% high BEAM level,Best survival in EGFR mutants receiving erlotinib:,T790M +ive and BIM high: 40+months,EURTAC Biomarker Study95 patie,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,疗效持续时间：基线到首次PD时间；Yang JJ, Chen,NSCLC,驱动基因,EML4-ALK,融合基因,NSCLC驱动基因EML4-ALK融合基因,PROFILE 1007: Crizotinib vs Chemotherapy (2,nd,/3,rd,line therapy),Key entry criteria,ALK+,by central FISH testing,Stage IIIB/IV NSCLC,1 prior chemotherapy (platinum-based),ECOG PS 02,Measurable disease,Treated brain metastases allowed,N=318,Crizotinib 250 mg BID,PO, 21-day cycle,(n=159),Pemetrexed,500 mg/m,2,or,Docetaxel 75 mg/m,2,IV, day 1, 21-day cycle,(n=159),PROFILE 1007: NCT00932893,Endpoints,Primary,PFS (RECIST 1.1, independent radiology review),Secondary,ORR, DCR, DR,OS,Safety,Patient reported outcomes (EORTC QLQ-C30, LC13),RANDOMIZE,CROSSOVER TO CRIZOTINIB,ON PROFILE 1005,a,Stratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (yes/no),a,Shaw et al. ESMO 2012,PROFILE 1007: Crizotinib vs Ch,a,RECIST v1.1,ORR,a,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,65.7,29.3,6.9,Crizotinib (n=172),PEM (n=99),DOC (n=72),Treatment,80,60,40,20,0,Shaw et al. ESMO 2012,aRECIST v1.1ORRa by Independen,Primary Endpoint: PFS by Independent Radiologic Review (ITT Population),Probability of survival without progression (%),100,80,60,40,20,0,0510152025,Time (months),17393381120,1744915410,No. at risk,Crizotinib,PEM/DOC,Crizotinib,(n=173),PEM/DOC,(n=174),Events, n (%),100 (58),127 (73),Median, mo,7.7,3.0,HR (95% CI),0.49 (0.37 to 0.64),P,0.001,PEM/DOC, pemetrexed/docetaxel,Shaw et al. ESMO 2012,Primary Endpoint: PFS by Indep,Crizotinib(n=172,a,),Pemetrexed(n=99,a,),Docetaxel(n=72,a,),Events, n (%),100 (58),72 (73),54 (75),Median, mo,7.7,4.2,2.6,HR,b,(95% CI),0.59 (0.43 to 0.80,),0.30 (0.21 to 0.43,),P,0.0004,0.0001,PFS of Crizotinib vs Pemetrexed or Docetaxel,Probability of survival without progression (%),100,80,60,40,20,0,0510152025,Time (months),17293381120 993612310 7213 310,No. at risk,Crizotinib,Pemetrexed,Docetaxel,a,As-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;,b,vs crizotinib,Crizotinib(n=172a)Pemetrexed,PFS Subgroup Analysis,Subgroup,n,a,HR (95% CI),All patients,347,0.49 (0.370.64),Age 65 years,50,0.54 (0.271.08),Age 65 years,297,0.49 (0.370.65),Male,153,0.52 (0.340.77),Female,194,0.48 (0.340.68),Non-Asian,190,0.45 (0.300.66),Asian,157,0.53 (0.360.76),Non-smoker,219,0.45 (0.320.63),Smoker or ex-smoker,127,0.53 (0.340.83),Adenocarcinoma,328,0.50 (0.380.66),Non-adenocarcinoma,12,0.12 (0.011.02),ECOG PS 0/1,313,0.48 (0.360.63),ECOG PS 2,34,0.31 (0.120.86),Brain metastases present,120,0.67 (0.441.03),Brain metastases absent,227,0.43 (0.300.60),Prior EGFR TKI,41,0.48 (0.221.03),No prior EGFR TKI,306,0.49 (0.370.66),012,HR,Favors chemotherapy,Favors crizotinib,a,Data missing for smoking status (n=1) and tumor histology (n=7),Shaw et al. ESMO 2012,PFS Subgroup AnalysisSubgroupn,Crizotinib,(n=173),Chemotherapy,a,(n=174),Events, n (%),49 (28),47 (27),Median, mo,20.3,22.8,HR (95% CI),1.02 (0.68 to 1.54),b,P,0.5394,Interim Analysis of OS,a,111 patients crossed over to crizotinib outside PROFILE 1007,b,HR adjusted for crossover using rank-preserving structural failure time method: 0.83 (0.36 to 1.35),17312983371110,1741298434100,No. at risk,Crizotinib,Chemotherapy,Probability of survival (%),100,80,60,40,20,0,051015202530,Time (months),EML4-ALK,阳性患者二线标准治疗,CrizotinibChemotherapyaEvents,Phase III PROFILE 1014 (n=334),ALK-,positive locally advanced/ metastatic non-squamous NSCLC,No prior treatment for advanced disease,RANDOMISE,Crizotinib 250 mg BID (n,=,167),continuous,Pemetrexed/cisplatin orpemetrexed/carboplatin (n,=,167),infused on day 1 of a 21-day cycle,Crossover on PD,Crossover on PD,克唑替尼一线治疗,ALK,+,肺癌的临床试验,Phase III PROFILE 101,29,(n=,200,),ALK-,positive locally advanced/ metastatic non-squamous NSCLC,No prior treatment for advanced disease,RANDOMISE,Crizotinib 250 mg BID (n,=,167),continuous,Pemetrexed/cisplatin orpemetrexed/carboplatin (n,=,167),infused on day 1 of a 21-day cycle,150 patients China and 50 from 2-3 other Asian countries,Crossover on PD,Global,Asia,Phase III PROFILE 1014 (n=334),Ph-I: LDK378 is active in ALK+ NSCLC,High response rate in crizotinib relapsed patients,uPR or PR,PR,Dose 400 mgn (evaluable) = 12,10,3,All dose levelsn (evaluable) = 15,10,3,Prior crizotinib,Crizotinib naive,uPR or PR,PR,Dose 400 mgn (evaluable) = 4,1,1,All dose levelsn (evaluable) = 9,2,2,Andrew Boral,Ph-I: LDK378 is active in ALK+,NSCLC,驱动基因,ROS1,融合基因,NSCLC驱动基因ROS1融合基因,ROS1,临床病例,31,岁，男性，非吸烟,EGFR,野生型；,ALK(),一线吉非替尼治疗无效,口服,Crizotinib 8,周后高度,PR,ROS fusion: FISH,ROS fusion: IHC,Bergethon K, et al. J Clin Oncol 2012; 30:863-870.,肺腺癌，发生率,1%,ALKinhibitor,有效,ROS1临床病例31岁，男性，非吸烟ROS fusion:,Crizotinib,在,ROS1 NSCLC,中的临床活性,Abstract No. 7508 , 2012 ASCO,Lan et al, Nat Gen 2012,Crizotinib在ROS1 NSCLC中的临床活性Abs,NSCLC,驱动基因,KRAS,NSCLC驱动基因KRAS,CR, complete response; PR, partial response; SD, stable diseasePD, progressive disease; DoR, duration of response;,APF6, alive and progression-free at 6 months,Fisher,s exact 2-sided mid p value,1-sided p value,*11 confirmed, 5 unconfirmed,One patient was classed as non-evaluable due to nonevaluable non-target lesions and would have had a partial response according to RECIST 1.1 criteria,p0.0001,p=0.0158,%,Selumetinib + docetaxel,N=44,Placebo + docetaxel,N=43,Best objective response (RECIST 1.0), number (%),CR,0,0,PR,16 (37.2)*,0,SD 6 weeks,19 (44.2),20 (50.0),PD,8 (18.6),18 (45.0),Not evaluable,0,2 (5.0),Median DoR, days,182,-,Selumetinib for KRAS mutation,Janne et al ESMO 2012,0,CR, complete response; PR, par,Median PFS,Selumetinib + docetaxel,N=43,5.3 mo,Placebo + docetaxel,N=40,2.1 mo,HR 0.58; 80% CI 0.42, 0.79; 1-sided p=0.0138*,Progression Free Survival,There was a,statistically and clinically significant improvement in PFS,71/83 events (85.5%): selumetinib + docetaxel 35/43, placebo + docetaxel 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 50 100 150 200 250 300 350 400 450,1.0,0.8,0.6,0.4,0.2,0.0,Number at risk,43,40,34,21,28,12,23,9,12,6,10,5,4,2,2,2,1,1,1,Median PFSSelumetinib + doceta,NSCLC,驱动基因,其他,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,33岁，非吸烟，EGFR&KRAS&ALK均(-)Ju YS,DDR2,突变鳞癌患者,Dasatinib,治疗有效,化疗前,化疗后,PD,，开始,Dasatinib+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.,DDR2突变鳞癌患者Dasatinib治疗有效化疗前化疗后P,Mutation identified,STOP,Enrollment,to n=25,Screening & Enrollment,Stage 1,Stage 2,Study treatment: dasatinib, 140 mg po QD until progression or unacceptable toxicity,in all strata & both stages of enrollment,Follow up for progression and survival,no,yes,Study Schematic (DDR2 Inhibitor),Mutation identifiedSTOP Enroll,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.,EGFR,突变,KRAS,突变,HER2,突变,EML4-ALK,ROS1,融合,RET,融合,未知,2012 NSCLC肿瘤驱动基因的加速发现What abou,A Novel Classification of Lung Cancer into Molecular,Subtypes,West L, et al. PLoS ONE 2012; 7(2):e31906.,基因,通路,可能的相关治疗,相关,组织学亚型,临床应用,证据强度,EGFR sensitive mut,EGFR,TKIs & Chemo,腺癌,高,EGFR,resistant mut(,包括,T790M),EGFR,EGFR/HER2dualTKI,，,c-METinhibitor,+/- EGFR TKIs,，,Hsp90 inhibitor,，,MET/VEGFR2dualinhibitor,，,Chk1inhibitor,腺癌,高,K-ras,mut,K-ras,MAPK & AKT/PI3K,dual inhibitor,，,Hsp90 inhibitor,腺癌,高,EML4-ALK,EML4-ALK,ALKinhibitor,，,Hsp90 inhibitor,腺癌,高,c-MET,over expression,c-MET,c-METinhibitor,，,Met/VEGFR2dualinhibitor,，,ALK/METinhibitor,，,c-MET,Mab,腺癌，,小细胞癌，鳞癌,中,c-MET,mut,c-MET,c-METinhibitor,，,Met/VEGFR2dualinhibitor,，,ALK/METinhibitor,，,c-MET,Mab,腺癌，鳞癌，大细胞癌，小细胞癌,低,PI3KCA,amp, mut,AKT/PI3K,PI3K,，,AKT,，,mTORinhibitor,腺癌,低,PTEN del/mel,AKT/PI3K,PI3K,，,AKT,，,mTORinhibitor,腺癌,低,VEGFR,over expresion,VEGFR,VEGFRinhibitor,小细胞癌,低,ROS1,translocation,ROS-1,ROS1 inhibitor,腺癌,(1.5%),中,IGF,abnormal,IGF,IGF1R Mab,，,IGF1R TKIs,腺癌，鳞癌，,SCLC,-,A Novel Classification of Lung,非鳞癌,鳞癌,含铂双药,+ bevacizumab,含铂双药,含铂双药,完成一线治疗,Clinical,Bevacizumab,EGFR TKIs,或培美曲塞,特罗凯,Bevacizumab,敏感,Bevacizumab,不敏感,病理分型,进展,驱动基因检测,EGFR,突变,EML4-ALK,ROS1,KRAS,cMET,.,TKIs,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 3,rd,line,必须包括,EGFRTKIs,和化疗,P,优选,P,方案,培美曲塞或多西他赛（依据既往治疗）,3,L,治疗选择,治疗选择：,根据耐药机制,局部治疗不可缺少,鼓励参加临床试验,非鳞癌鳞癌含铂双药 + bevacizumab 含铂双药,谢谢,Thanks!,谢谢Thanks!,