1、非小細胞肺癌驅(qū)動基因研究,吳一龍 廣東省肺癌研究所 廣東省人民醫(yī)院 廣東省醫(yī)學科學院,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.,1999 Histology-driven selection,2010 Targeting oncogenic drivers*,*Inciden

2、ce of mutations in adenocarcinoma provided as an example,Non-squamous,Evolution of NSCLC treatment,2008,Today,Current Standard of NSCLC Care,NSCLC腫瘤驅(qū)動基因,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

3、W. J Clin Oncol 2009; 26:42324235.,Frequency of 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%抗腫瘤藥物的敏感性與基因變異相關(guān),分析了130種抗腫瘤藥物與腫瘤基因變異之間的關(guān)系，證實91% (118/130)的抗腫瘤藥物敏感性與至少一種基因變異相關(guān),

4、Garnett MJ, et al. Nature 2012; 483:570-577.,Significantly Mutated Genes in Squamous Cell Lung Cancer,Govindan et al. The Cancer Genome Atlas (TCGA) Project . 2012 ASCO,178/500鱗癌完成分析,Therapeutic targets in squamous cell lung carcinoma,Govindan R et al. ASCO 2012,第一個有臨床意義的NSCLC驅(qū)動基因：,EGFR,EGFR mutant

5、1st line trials : PFS and OS,Placebo,Erlotinib 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=

6、5 or cisplatin 75mg/m2 (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 r

7、esponse, 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

8、response rate; TTP = time to progression; NPR = 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,

9、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 and OS in EGFR Mut+ subgroup (22 Jun 2012),1.0 0.8 0.6 0.4 0.2 0,Time (months),PFS probabi

10、lity,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 4948464541332

11、41530 P 48484336262414600,Mok, ESMO 2012,CTONG 902,1.0 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

12、.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 PCTONG 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)

13、 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,EURTAC Results: PFS by baseline T790M status,PFS probab

14、ility,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),Nature Medicine 18(8):521, 2012,EURTAC Biomarker Study,95 patients from EURTAC (EGFR Mutation) with available samples Biomarkers: ELM4 ALK, T790M,

15、 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,療效持續(xù)時間：基線到首次PD時間； 腫瘤負荷：靶病灶倍增時間 和非靶病灶評分（4分）：病變進展、新出現(xiàn)胸內(nèi)病變、新出現(xiàn)胸外 病 變、惡性胸腔積液 癥狀評分：無癥狀（0）、原有癥狀穩(wěn)定（1）、癥狀惡化（2）,Yang JJ, Chen HJ, Wu YL ,et al. Lu

16、ng Cancer On Line 17 Oct 2012,NSCLC驅(qū)動基因,EML4-ALK融合基因,PROFILE 1007: Crizotinib vs Chemotherapy (2nd/3rd 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,Crizotin

17、ib 250 mg BID PO, 21-day cycle (n=159),Pemetrexed 500 mg/m2 or Docetaxel 75 mg/m2 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,CROS

18、SOVER TO CRIZOTINIB ON PROFILE 1005,aStratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (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),

19、PEM/DOC (n=174),80,60,40,20,0,Treatment,Shaw et al. ESMO 2012,Primary Endpoint: PFS by Independent Radiologic Review (ITT Population),Probability of survival without progression (%),100,80,60,40,20,0,0510152025,Time (months)1744915410,No. at risk Crizotinib PEM/DOC,PEM/DOC, pemetrexed/d

20、ocetaxel,Shaw et al. ESMO 2012,PFS of Crizotinib vs Pemetrexed or Docetaxel,Probability of survival without progression (%),100,80,60,40,20,0,0510152025,Time (months)993612310 7213 310,No. at risk Crizotinib Pemetrexed Docetaxel,aAs-treated population: excludes 1 patient in crizotinib a

21、rm who did not receive study treatment and 3 patients in chemotherapy arm who did not receive study treatment; bvs crizotinib,PFS Subgroup Analysis,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

22、OS,a111 patients crossed over to crizotinib outside PROFILE 1007bHR adjusted for crossover using rank-preserving structural failure time method: 0.83 (0.36 to 1.35),17312983371110 1741298434100,No. at risk Crizotinib Chemotherapy,EML4-ALK陽性患者二線標準治療,Crossover on PD,Crossover on PD,克唑替尼一線治療ALK +肺癌的臨床試

23、驗,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 crizotinib relapsed patients,Prior crizotinib,Crizotinib naive,Andrew Boral,NSCLC驅(qū)動基因,ROS1融合基因,ROS1臨床病例,Bergethon K, et al. J Clin Oncol 2012; 30:863-870.

24、,肺腺癌，發(fā)生率1% ALKinhibitor有效,Crizotinib在ROS1 NSCLC中的臨床活性,Abstract No. 7508 , 2012 ASCO,Lan et al, Nat Gen 2012,NSCLC驅(qū)動基因,KRAS,CR, complete response; PR, partial response; SD, stable diseasePD, progressive disease; DoR, duration of response; APF6, alive and progression-free at 6 months,Fishers exact 2-s

25、ided 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 for KRAS mutation,Janne et al ESMO 2012,0,Progression Fr

26、ee 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 include