肺癌驱动基因研究总结

1、非小细胞肺癌驱动基因研究非小细胞肺癌驱动基因研究吴一龙广东省肺癌研究所广东省人民医院广东省医学科学院2Treatment selection is moving from histology-based to targeting oncogenic driversFigure: Massachusetts General Hospital, data on file. Horn L, Pao W. J Clin Oncol. 2009;26:42324235.KRASEGFRBRAFHER2PIK3CAALKMET Unknown1999Histology-driven selection 2

2、010Targeting oncogenic drivers* *Incidence of mutations in adenocarcinoma provided as an exampleNon-squamousEvolution of NSCLC treatmentSquamousEGFR WTEGFR MuSquamousEGFR MuKRAS MuALK+Other non-squamous WTSquamous2008TodayCurrent Standard of NSCLC CareAdenocarcinomaSquamous-cell carcinomaLarge cell

3、carcinomaNSCLC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.K-rasEGFRB-rafHer2PIK3CAALKMET UnknownUnknown2010： ：7类肿类肿瘤瘤驱动驱动基因，基因，未知未知55%NRASMEK1HER2PIK3CAMET AM

4、PNo mutation detectedKRAS (22%)EGFR (17%)EML4-ALK (7%)Double mutants (3%)BRAF (2%)AKT12011： ：10类肿类肿瘤瘤驱动驱动基因，未知基因，未知46%Frequency of driver genes in subgroups of NSCLC in ChineseAn SJ, Wu YL. PLoS One June 2012Frequency of driver genes in subgroups of NSCLC in ChineseAn SJ, Wu YL. PLoS One June 201291

5、%抗肿瘤药物的敏感性与基因变异相关分析了分析了130种抗种抗肿肿瘤瘤药药物与物与肿肿瘤基因瘤基因变变异异之之间间的关系，的关系，证实证实91% (118/130)的抗的抗肿肿瘤瘤药药物敏感性与至物敏感性与至少一种基因少一种基因变变异相关异相关Garnett MJ, et al. Nature 2012; 483:570-577.Significantly Mutated Genes in Squamous Cell Lung CancerGovindan et al. The Cancer Genome Atlas (TCGA) Project . 2012 ASCO178/500鳞癌完成分析

6、GeneEvent TypeFrequencyCDKN2ADeletion/Mutation/Methylation72%PI3KCAMutation16%PTENMutation/Deletion15%FGFR1Amplification15%EGFRAmplification9%PDGFRAAmplification/Mutation9%CCND1Amplification8%DDR2Mutation4%BRAFMutation4%ERBB2Amplification4%FGFR2Mutation3%Therapeutic targets in squamous cell lung car

7、cinomaGovindan R et al. ASCO 2012第一个有临床意义的NSCLC驱动基因：EGFREGFR mutant 1st line trials : PFS and OSPFSOSEGFR TKI组组化疗组化疗组HREGFR TKI组组化疗组化疗组HRGefitinib trials IPASS*1 (n= 261)8p0.00121.621.91.00(0.76-1.33)NEJ0022N=1946P0.00127.726.60.89(0.63-1.24)WJTOG34053N=179P0.000136391.1

8、9(0.77-1.83)Erlotinib trialsOPTIMAL4N= 1546p0.000122.728.81.04(0.69-1.58)EURTAC5N=1747p0.000119.319.51.04(0.65-1.68)# Afatinib trialLUX-LUNG- 3N=3457p0.0001PlaceboErlotinib 150mg/dayPreviously untreated stage IIIB/IV NSCLC, PS 0/1(n=451)RPDGemcitabine 1,250mg/m2 (d1, 8)

9、 + 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/day (d1528); q4wks x 6 cycles GC-erlotinib (n=226)PDStudy treatmentMaintenance phaseScreeningErlotinib 1

10、50mg/dayPrimary endpoint: PFS with IRC confirmationSecondary endpoints: subgroup analyses, OS in all patients and subgroups, ORR, duration of response, TTP, NPR at 16 weeks, safety, QoLFASTACT-2 (MO22201; CTONG0902) study designNSCLC = non-small cell lung cancer; PS = performance status; PD = diseas

11、e 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 life1:1; stratified by stage, histology, smoking status and chemo regime

12、nPFS according to IRCPFS probabilityTime (months)0222426281816126201410842Patients remaining225Placebo12351341951791792001.00.207.410.0HR=0.58 (0.460.72)Log-rank p0.0001226Erlotinib4376151599311417720011731032914110Erlotinib (n=226)Placebo (n=225)Mok, Wu et al. ASCO 2012PFS and OS in EGFR M

13、ut+ subgroup (22 Jun 2012)1.00.20Time (months)PFS probability1.00.20bTime (months)OS probability048121620242832048121620242832366.916.820.631.4Erlotinib (n=49)Placebo (n=48)HR=0.48 (0.270.84)p=0.0092Erlotinib (n=49)Placebo (n=48)HR=0.25 (0.160.39)p0.0001PFSOSE4946423325191160P48351

14、6542210E 494846454133241530P 48484336262414600Mok, ESMO 2012CTONG 9021.00.20PFS and OS in patients with EGFR WT and ERCC1 IHC+ status (22 Jun 2012)Time (months)PFS probability1.00.20Time (months)PFSOSOS probability04824329.518.4Erlotinib (n=20)Placebo (n=17)HR=0.32 (0.140.69)p=0.00

15、24Erlotinib (n=20)Placebo (n=17)HR=0.55 (0.271.12)p=0.0941016284.6 7.54812242012162028E 2013732210P 178200000E 20161515138630PTONG 902Mok, ESMO 2012OS in ITT population (22 Jun 2012)15.218.3Erlotinib (n=226)Placebo (n=225)HR=0.79 (95% CI 0.640.99) p=0.0420OS probabilityTime (months)1.00

16、.003836343230282624222018161412108642E 226 219 202 191 176 165 154 138 129 114 988568523923961 0 P 225 218 206 185 168 156 138 120 103 92786853372413640 0Mok, ESMO 2012Mok, ESMO 2012Tarceva T790M present (n=21)Tarceva T790M absent (n=43)Chemotherapy T790M present (n=26)Chemotherapy T790M a

17、bsent (n=33)EURTAC Results: PFS by baseline T790M statusPFS probability1.00.20Time (months)03691215182124273033364.5 6.3 8.812.1Rosell R, et al. J Clin Oncol 2012;30 (Suppl. 15 Pt I):485s (Abs. 7522)Nature Medicine 18(8):521, 2012EURTAC Biomarker Study 95 patients from EURTAC (EGFR Mutation

18、) with available samples Biomarkers: ELM4 ALK, T790M, TP53, BIM16% detected by PCR38% detected24% mutation31% high BEAM levelBest survival in EGFR mutants receiving erlotinib:T790M +ive and BIM high: 40+months疗效持续时间：基线到首次疗效持续时间：基线到首次PD时间；时间；肿瘤负荷：靶病灶倍增时间肿瘤负荷：靶病灶倍增时间 和非靶病灶评分（和非靶病灶评分（4分）：病变进展、新出现胸内病变、新

19、出现胸外分）：病变进展、新出现胸内病变、新出现胸外 病病 变、恶性胸腔积液变、恶性胸腔积液症状评分：无症状（症状评分：无症状（0）、原有症状稳定（）、原有症状稳定（1）、症状恶化（）、症状恶化（2）Yang JJ, Chen HJ, Wu YL ,et al. Lung Cancer On Line 17 Oct 2012NSCLC驱动基因EML4-ALK融合基因融合基因PROFILE 1007: Crizotinib vs Chemotherapy (2nd/3rd line therapy)Key entry criteria ALK+ by central FISH testing St

20、age IIIB/IV NSCLC 1 prior chemotherapy (platinum-based) ECOG PS 02 Measurable disease Treated brain metastases allowedN=318Crizotinib 250 mg BID PO, 21-day cycle(n=159)Pemetrexed 500 mg/m2 orDocetaxel 75 mg/m2 IV, day 1, 21-day cycle(n=159)PROFILE 1007: NCT00932893Endpoints Primary PFS (RECIST 1.1,

21、independent radiology review) Secondary ORR, DCR, DR OS Safety Patient reported outcomes (EORTC QLQ-C30, LC13)RANDOMIZECROSSOVER TO CRIZOTINIB ON PROFILE 1005aStratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (yes/no)aShaw et al. ESMO 2012aRECIST v1.1O

22、RRa by Independent Radiologic Review65.319.5ORR (%)ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P0.001 Crizotinib (n=173)PEM/DOC (n=174)806040200Treatment65.729.36.9Crizotinib (n=172)PEM (n=99)DOC (n=72)Treatment806040200Shaw et al. ESMO 2012Primary Endpoint: PFS by Independent Radiologic Review (ITT Popula

23、tion)Probability of survival without progression (%)1008060402000510152025Time (months)173933811201744915410No. at riskCrizotinibPEM/DOC Crizotinib(n=173)PEM/DOC(n=174)Events, n (%)100 (58)127 (73)Median, mo7.73.0HR (95% CI)0.49 (0.37 to 0.64)P 0.001PEM/DOC, pemetrexed/docetaxel Shaw et al. ESMO 201

24、2 Crizotinib(n=172a)Pemetrexed(n=99a)Docetaxel(n=72a)Events, n (%)100 (58)72 (73)54 (75)Median, moHRb (95% CI)0.59 (0.43 to 0.80) 0.30 (0.21 to 0.43)P0.00040.0001PFS of Crizotinib vs Pemetrexed or DocetaxelProbability of survival without progression (%)1008060402000510152025Time (months)172

25、93381120 993612310 7213 310No. at riskCrizotinibPemetrexedDocetaxelaAs-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 AnalysisSubgroupnaHR (95% CI)All pat

26、ients3470.49 (0.370.64)Age 65 years 500.54 (0.271.08)Age 65 years2970.49 (0.370.65)Male1530.52 (0.340.77)Female1940.48 (0.340.68)Non-Asian1900.45 (0.300.66)Asian1570.53 (0.360.76)Non-smoker2190.45 (0.320.63)Smoker or ex-smoker1270.53 (0.340.83)Adenocarcinoma3280.50 (0.380.66)Non-adenocarcinoma 120.1

27、2 (0.011.02)ECOG PS 0/13130.48 (0.360.63)ECOG PS 2 340.31 (0.120.86)Brain metastases present1200.67 (0.441.03)Brain metastases absent2270.43 (0.300.60)Prior EGFR TKI 410.48 (0.221.03)No prior EGFR TKI3060.49 (0.370.66)012HRFavors chemotherapyFavors crizotinibaData missing for smoking status (n=1) an

28、d tumor histology (n=7)Shaw et al. ESMO 2012 Crizotinib(n=173)Chemotherapya(n=174)Events, n (%)49 (28)47 (27)Median, mo20.3 22.8 HR (95% CI)1.02 (0.68 to 1.54)bP 0.5394Interim Analysis of OSa111 patients crossed over to crizotinib outside PROFILE 1007bHR adjusted for crossover using rank-preserving

29、structural failure time method: 0.83 (0.36 to 1.35)173129833711101741298434100No. at riskCrizotinibChemotherapyProbability of survival (%)100806040200051015202530Time (months)EML4-ALK阳性患者二阳性患者二线标准治疗线标准治疗Phase III PROFILE 1014 (n=334)Phase III PROFILE 1014 (n=334)ALK-positive locally advanced/ metast

30、atic non-squamous NSCLC No prior treatment for advanced diseaseR RA AN ND DOOMMI IS SE ECrizotinib 250 mg BID (n=167)continuousPemetrexed/cisplatin orpemetrexed/carboplatin (n=167)infused on day 1 of a 21-day cycleCrossover on PDCrossover on PD克唑替尼一线治疗克唑替尼一线治疗ALKALK +肺癌的临床试验肺癌的临床试验Phase III PROFILE

31、101Phase III PROFILE 1012929 (n= (n=200200) )ALK-positive locally advanced/ metastatic non-squamous NSCLC No prior treatment for advanced diseaseR RA AN ND DOOMMI IS SE ECrizotinib 250 mg BID (n=167)continuousPemetrexed/cisplatin orpemetrexed/carboplatin (n=167)infused on day 1 of a 21-day cycle150

32、patients China and 50 from 2-3 150 patients China and 50 from 2-3 other Asian countriesother Asian countriesCrossover on PDGlobalAsiaPh-I: LDK378 is active in ALK+ NSCLC High response rate in crizotinib relapsed patientsuPR or PRPRDose 400 mgn (evaluable) = 12103All dose levelsn (evaluable) = 15103

33、Prior crizotinibCrizotinib naiveuPR or PRPRDose 400 mgn (evaluable) = 411All dose levelsn (evaluable) = 922Andrew BoralNSCLC驱动基因ROS1融合基因融合基因ROS1临床病例l 31岁，男性，非吸烟岁，男性，非吸烟l EGFR 野生型；野生型；ALK()l 一线吉非替尼治疗无效一线吉非替尼治疗无效l 口服口服Crizotinib 8周后高度周后高度PR ROS fusion: FISHROS fusion: IHCBergethon K, et al. J Clin Onc

34、ol 2012; 30:863-870.肺腺癌，肺腺癌，发发生率生率1%ALKinhibitor有效有效CrizotinibCrizotinib在在ROS1 NSCLCROS1 NSCLC中的临床活性中的临床活性Abstract No. 7508 , 2012 ASCOLan et al, Nat Gen 2012NSCLC驱动基因KRASCR, complete response; PR, partial response; SD, stable diseasePD, progressive disease; DoR, duration of response; APF6, alive an

35、d progression-free at 6 monthsFishers exact 2-sided mid p value 1-sided p value*11 confirmed, 5 unconfirmedOne patient was classed as non-evaluable due to non evaluable non-target lesions and would have had a partial response according to RECIST 1.1 criteriap0.0001p=0.0158%Selumetinib + docetaxel N=

36、44Placebo + docetaxelN=43Best objective response (RECIST 1.0), number (%)CR00PR16 (37.2)*0SD 6 weeks19 (44.2)20 (50.0)PD8 (18.6)18 (45.0)Not evaluable02 (5.0)Median DoR, days182-Selumetinib for KRAS mutationJanne et al ESMO 20120Median PFSSelumetinib + docetaxel, N=435.3 moPlacebo + docetaxel, N=402

37、.1 moHR 0.58; 80% CI 0.42, 0.79; 1-sided p=0.0138*Progression Free SurvivalThere was a statistically and clinically significant improvement in PFS71/83 events (85.5%): selumetinib + docetaxel 35/43, placebo + docetaxel 36/40 Symbols represent censored observations*Analysis was performed using a Cox

38、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 patientsDays0 50 100 150 200 250 300 350 400 450 1.00.20.0Number at risk4340342128122391261054222111NSCLC驱动基因其他其他l 33岁，非

39、吸烟，岁，非吸烟，EGFR&KRAS&ALK均均(-)l 新发现存在新发现存在KIF5B-RET融合基因表达融合基因表达l RETinhibitor有效有效Ju YS, et al. Genome Res 2012; 22(3):436-445.肺腺癌，肺腺癌，发发生率生率2%三阴性三阴性NSCLC， ，6.3%RET inhibitor有效？有效？KIF5B-RETDDR2突变鳞癌患者突变鳞癌患者Dasatinib治疗有效治疗有效化化疗疗前前化化疗疗后后PD，开始，开始Dasatinib+erlotinib治治疗疗Dasatinib+erlotinib治治疗疗后后2月，月，疗

40、疗效效PR鳞鳞癌，癌，DDR2 S768R突突变变Hammerman PS, et al. Cancer Discovery 2011; 1:78-89.Mutation identifiedSTOP Enrollmentto n=25Screening & EnrollmentStage 1Stage 23 of 12 respond by stratumStudy treatment: dasatinib, 140 mg po QD until progression or unacceptable toxicity in all strata & both stages

41、of enrollmentFollow up for progression and survivalnoyesStudy 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，非吸烟腺癌癌已有已有94.2的的患者可明确其患者可明确其肿肿瘤瘤驱动驱动基因基因Li F, et al. Cell Research 2012; 22:928-931.EGFR突突变变KRAS突突变变HER2突突变变EML4-ALKROS1融合融合RET融合融合未知未知A Novel Classification of Lung Cancer into Molecular SubtypesWest L, et al. PLoS ONE 2012; 7(2):e31906.基因基因通路通路可能的相关治疗可