肺癌驱动基因的研究和EGFRTKI以外的靶向治疗研究进展(施春雷)课件.ppt

1、NSCLCNSCLC治疗已由病理为主转变到病理与治疗已由病理为主转变到病理与驱动基因决定选择的时代驱动基因决定选择的时代Figure:Massachusetts General Hospital,data on file.Horn L,Pao W.J Clin Oncol.2009;26:42324235.KRASEGFRBRAFHER2PIK3CAALKMET Unknown1990Histology-driven selection 2010Targeting oncogenic drivers*Incidence of mutations in adenocarcinoma provid

2、ed as an exampleNon-squamousEvolution of NSCLC treatmentSquamousEGFR WTEGFR MuSquamousEGFR MuKRAS MuALK+Other non-squamous WTSquamous2004TodayCurrent Standard of NSCLC CareLung Cancer Mutation ConsortiumIncidence of Single Driver MutationsDOUBLEMUTANTS 3%AKT1NRASMEK1MET AMPHER2PIK3CABRAF 2%NO MUTATI

3、ONDETECTEDKRAS22%EGFR17%EML4-ALK7%肺腺癌驱动基因肺腺癌驱动基因nEGFR突变：厄洛替尼、吉非替尼、阿法替尼和突变：厄洛替尼、吉非替尼、阿法替尼和PF299804等。等。nKRAS突变：突变：肺腺癌中约为肺腺癌中约为22%25%，肺鳞癌中约为，肺鳞癌中约为7%；索拉非尼、；索拉非尼、GSK1120212、AZD6244和和AS703026。nALK融合：肺腺癌中约融合：肺腺癌中约9.6%。nMET：MET在肺癌中有时突变和（或）扩增；在肺癌中有时突变和（或）扩增；XL184、ARQ-917和和Metmab等。等。n其他：其他：HER2突变或扩增：曲妥珠单抗、拉帕

4、替尼与突变或扩增：曲妥珠单抗、拉帕替尼与PF299804等等PI3K突变或扩增：突变或扩增：GDC-0941、XL-147、XL-765、PX-866、BEZ-235与与BKM120等等FGFR1扩增：扩增：BJG398、AZD4547与与TKI258等。等。GeneEvent TypeFrequencyCDKN2ADeletion/Mutation/Methylation72%PI3KCAMutation16%PTENMutation/Deletion15%FGFR1Amplification15%EGFRAmplification9%PDGFRAAmplification/Mutation

5、9%CCND1Amplification8%DDR2Mutation4%BRAFMutation4%ERBB2Amplification4%FGFR2Mutation3%Therapeutic targets in squamous cell lung carcinomaGovindan R et al.ASCO 2012Pallis AG,et al.EJC 2009;45:2473-2487.靶点靶点类型类型代表药物代表药物EGFR1.TKIn单靶点可逆：单靶点可逆：吉非替尼、厄洛替尼吉非替尼、厄洛替尼n单靶点不可逆：单靶点不可逆：EKB-569、CL-387n多靶点不可逆：多靶点不可逆：

6、HKI-272、卡奈替尼、卡奈替尼、PF-00299804、BIBW 29922.MAB西妥昔单抗西妥昔单抗VEGF1.MAB贝伐单抗贝伐单抗2.RTKI索拉非尼、凡德他尼、舒尼替尼、索拉非尼、凡德他尼、舒尼替尼、Cediranib3.TRAPAVE0005抗血管生抗血管生成成1.Endostatin恩度恩度2.VDAASA404IGF-1RMABFigitumumabmTOR抑制剂抑制剂西罗莫司、依维莫司西罗莫司、依维莫司MET抑制剂抑制剂MetMAb,ARQ197EML4-ALK抑制剂抑制剂Crizotinib免疫调节剂免疫调节剂Ipilimumab蛋白酶体抑制剂蛋白酶体抑制剂硼替佐米硼替

7、佐米HDAC抑制剂抑制剂Vorinostat第一个应用于临床的第一个应用于临床的NSCLC驱动基驱动基因因N-lobeL858Activation loopC-lobeP-loopG719EGFR-MutationEGFR 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)9.56.30.48p0.00121.621.91.00(0.76-1.33)NEJ0022N=19410.85.40.36P0.00127.726.60.89(0.

8、63-1.24)WJTOG34053N=1729.26.30.49P0.000136391.19(0.77-1.83)Erlotinib trialsOPTIMAL4N=15413.74.60.16p0.000122.728.81.04(0.69-1.58)EURTAC5N=17410.45.40.47p0.000119.319.51.04(0.65-1.68)#Afatinib trialLUX-LUNG-3N=34513.66.90.47p2-培美曲塞培美曲塞matuzumab-NRNRPertuzumab243Pertuzumab单药：单药：840mg/m2诱导剂量：诱导剂量：420mg

9、/m2,q3周周0/20.9 SD6.1 周周NR荟萃分析：荟萃分析：OSLung Cancer.2010 Oct;70(1):57-62.0.50.71.0 1.32.0风险比风险比化疗化疗+/-西妥昔单抗受益西妥昔单抗受益单独化疗受益单独化疗受益化疗化疗+/-西妥昔单抗西妥昔单抗FLEXN=1125Pirker et al顺铂顺铂/长春瑞滨长春瑞滨BMS-099N=676Lynch et al卡铂卡铂/多西他赛多西他赛或卡铂或卡铂/紫杉醇紫杉醇BMS-100N=131Butts et al卡铂卡铂/吉西他滨吉西他滨或顺铂或顺铂/吉西他滨吉西他滨LUCASN=86Rosell et al顺铂

10、顺铂/长春瑞滨长春瑞滨OS的荟萃分析的荟萃分析N=2018HR95%CI0.8710.7620.9960.8900.7541.0510.8390.5541.2710.7120.4511.1240.878 0.7950.969 P=0.010荟萃分析：荟萃分析：PFS0.50.71.0 1.32.0风险比风险比化疗化疗+/-西妥昔单抗受益西妥昔单抗受益单独化疗受益单独化疗受益化疗化疗+/-西妥昔单抗西妥昔单抗FLEXN=1125Pirker et al顺铂顺铂/长春瑞滨长春瑞滨BMS-099N=676Lynch et al卡铂卡铂/多西他赛或多西他赛或卡铂卡铂/紫杉醇紫杉醇BMS-100N=13

11、1Butts et al卡铂卡铂/吉西他滨吉西他滨或顺铂或顺铂/吉西他滨吉西他滨LUCASN=86Rosell et al顺铂顺铂/长春瑞滨长春瑞滨PFS的荟萃分析的荟萃分析N=2018HR95%CI0.9430.8261.0770.9020.7611.0690.8020.5531.1640.7080.4131.2140.899 0.8140.993 P=0.036Lung Cancer.2010 Oct;70(1):57-62.Pallis AG,et al.EJC 2009;45:2473-2487.靶点靶点类型类型代表药物代表药物EGFR1.TKIn单靶点可逆：单靶点可逆：吉非替尼、厄洛

12、替尼吉非替尼、厄洛替尼n单靶点不可逆：单靶点不可逆：EKB-569、CL-387n多靶点不可逆：多靶点不可逆：HKI-272、卡奈替尼、卡奈替尼、PF-00299804、BIBW 29922.MAB西妥昔单抗西妥昔单抗VEGF1.MAB贝伐单抗贝伐单抗2.RTKI索拉非尼、凡德他尼、舒尼替尼、索拉非尼、凡德他尼、舒尼替尼、Cediranib3.TRAPAVE0005抗血管生抗血管生成成1.Endostatin恩度恩度2.VDAASA404IGF-1RMABFigitumumabmTOR抑制剂抑制剂西罗莫司、依维莫司西罗莫司、依维莫司MET抑制剂抑制剂MetMAb,ARQ197EML4-ALK抑

13、制剂抑制剂Crizotinib免疫调节剂免疫调节剂Ipilimumab蛋白酶体抑制剂蛋白酶体抑制剂硼替佐米硼替佐米HDAC抑制剂抑制剂Vorinostatn重组的人源化单克隆抗体，包含重组的人源化单克隆抗体，包含93%的人源性片段和的人源性片段和7%的鼠源性结构的鼠源性结构n可与所有可与所有VEGF结合，从而阻止结合，从而阻止VEGF受体信号转导受体信号转导贝伐单抗两项重要的贝伐单抗两项重要的III期临床研究期临床研究Pallis AG,et al.EJC 2009;45:2473-2487.研究研究治疗治疗NORR(%)PFS(mo)OS(mo)ECOG 4599CMT444154.510.

14、3CMT+BEV(15MG/KG)434356.212.3P0.001P0.001P=0.003AVAiLCMT347206.113.1CMT+Bev(7.5 mg/kg)345346.7(p=0.002)13.6(p=0.42)CMT+Bev(15 mg/kg)351306.5(p=0.03)13.4(p=0.761)CMT ECOG 4599：紫杉醇：紫杉醇+卡铂；卡铂；CMT AVAiL:顺铂顺铂+吉西他滨吉西他滨0369121518210.00.20.40.60.81.0HR=0.722(0.592-0.881)Log-rank P=0.0012无进展生存期(月)无进展概率贝伐单抗+安

15、慰剂(n=373)贝伐单抗+厄洛替尼(n=370)Miller VA et al,ASCO 2009;Abstract No:LBA8002.2010年罗氏年罗氏 半年报告：半年报告：2009 年探索性分析显示年探索性分析显示OS没有统计学上差异没有统计学上差异药物药物靶点靶点研究期别研究期别索拉非尼索拉非尼VEGF R2/3,C-RAF,PDGFR-,c-kitIII凡德他尼凡德他尼Erb-1,VEGFR2III舒尼替尼舒尼替尼VEGF R1/2/3,FLT PDGFR-,c-kitIICediranib(AZD2171)VEGF R1/2/3,PDGFR-,c-kitIIVatalanib

16、(PTK787)VEGF R1/2/3,C-Fms PDGFR-,c-kitII阿西替尼阿西替尼VEGF R1/2/3,PDGFR-,c-kitII帕唑帕尼帕唑帕尼VEGF R1/2/3,PDGFR-/,c-kitIIMotesanibVEGF R1/2/3,PDGF,c-kitII/IIICP-547,632VEGF R-2I/IIBIBF1120VEGF R1/2/3,PDGFR,FGFRI/IIXL647EGFR,HER2,EphB4,VEGFR-2IIAEE788EGFR,HER2,VEGFR-2IKRN951VEGF R1/2,PDGF,c-kitIABT-869VEGF R1/2/

17、3,PDGFRIIOSI-930Kinase insert domain receptor,c-kitIBMS-690514VEGFR,Pan-ErbIPallis AG,et al.EJC 2009;45:2473-2487.Flanigan J,et al.Biologics:Targets&Therapy 2010;4:237-243.研究研究/既往化疗既往化疗次数次数设计设计RR(%)PFSOS(m)ZEST1240/1-21.V 300mg2.厄洛替尼厄洛替尼121211.3 周周8.9 周周HR 0.98.P=0.7216.97.8NSZEAL534/11.培美曲塞培美曲塞+V 1

18、00mg2.培美曲塞培美曲塞19817.6 周周11.9 周周HR 0.86.P=0.10810.59.2NSZODLAC139/11.多西他赛多西他赛+V 100mg2.多西他赛多西他赛17104 月月3.2月月HR 0.79.P50%I期临床调整期临床调整为入选为入选AKL+NSCLCALK+NSCLC患患者的者的III期期临床开始临床开始在在NEJM首次发表首次发表Crizotinib治疗治疗ALK+NSCLC的的临床数据临床数据美国美国Crizotinib被批准用于治被批准用于治疗疗ALK+的的NSCLC患者患者EML4EML4ALK variant 1HELP1496981WDBas

19、ic14961059110581620TMKinaseALKEML4ALK变体变体 1激酶ALK 融合基因驱动融合基因驱动EGFR突变驱动突变驱动临床临床&病理特征：病理特征：ALK融合融合 vs EGFR突变突变特征特征EGFREML4/ALK组织学组织学腺癌腺癌 TTF1+腺癌腺癌TTF1+亚型亚型非粘液型非粘液型粘液型粘液型吸烟状态吸烟状态不吸烟不吸烟不吸烟不吸烟人种人种东亚东亚所有人种所有人种发病年龄发病年龄66y52y性别性别女性女性男男女女 与与EGFR突变患者相比，突变患者相比，ALK阳性阳性NSCLC患者发病年龄更轻，患者发病年龄更轻，更偏重于男性更偏重于男性A T.Shaw,

20、et al.J Clin Oncol.2009;27:4247-4253CharacteristicALK(n=19)EGFR(n=31)WT/WT(n=91)PNo.%No.%No.%ALK v EGFRALK v WT/WTAge,yearsMedianRange5229-766636-906429-87.001.005Sex Male Female1185842823267429623268.036.039Smoking history Never smoker Light smoker Smoker1450742602164681913241552261657.36610%的肿瘤细胞中

21、含的肿瘤细胞中含大量粘液成分大量粘液成分ALKALK 阳性阳性 vs ALK 阴性阴性Yang P,et al.J Thorac Oncol.2012;7:9097Years since diagnosisPFS/RFS曲线FISH(positive)versus FISH(negative)Years since diagnosisPFS/RFS曲线IHC3(positive)versus IHC0/1(negative)ALK阳性阳性EGFR突变突变驱动基因驱动基因ALK融合基因融合基因EGFR突变突变临床临床&病理特征病理特征年轻、腺癌（粘液型）、年轻、腺癌（粘液型）、不吸烟不吸烟东亚裔

22、、腺癌（非粘东亚裔、腺癌（非粘液型）、不吸烟液型）、不吸烟患者预后患者预后差差好好治疗方法治疗方法克唑替尼克唑替尼EGFR-TKIs 专家组推荐命名：专家组推荐命名：根据专家的讨论，从检测方法学角度考虑到根据专家的讨论，从检测方法学角度考虑到ALK融融合型肺癌不仅是基因序列层面的改变，合型肺癌不仅是基因序列层面的改变，ALK融合蛋融合蛋白也是该类疾病中的重要变异，因此将此类疾病统称白也是该类疾病中的重要变异，因此将此类疾病统称为为ALK阳性阳性非小细胞肺癌非小细胞肺癌 专家组推荐定义：专家组推荐定义：ALK阳性阳性非小细胞肺癌非小细胞肺癌：是指包括是指包括ALK FISH检测阳性、检测阳性、A

23、LK序列融合变异或序列融合变异或ALK融合蛋白表达阳性的肺癌，肿瘤细胞中存在融合蛋白表达阳性的肺癌，肿瘤细胞中存在ALK融合基因表达，是非小细胞肺癌的一个分子亚融合基因表达，是非小细胞肺癌的一个分子亚型，常见于腺癌，该类患者通常可从型，常见于腺癌，该类患者通常可从ALK抑制剂治抑制剂治疗中获益疗中获益。PRO:Crizotinib vs Chemotherapy(2nd/3rd line therapy)Key entry criteria ALK+by central FISH testing Stage IIIB/IV NSCLC 1 prior chemotherapy(platinum

24、-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)PRO:NCT00932893Endpoints Primary PFS(RECIST 1.1,independent radiology review)Secondary ORR,DCR,DR OS Safety Pati

25、ent reported outcomes(EORTC QLQ-C30,LC13)RANDOMIZECROSSOVER TO CRIZOTINIB ON PROaStratification factors:ECOG PS(0/1 vs 2),brain metastases(present/absent),and prior EGFR TKI(yes/no)aShaw et al.ESMO 2012aRECIST v1.1ORRa by Independent Radiologic Review65.319.5ORR(%)ORR ratio:3.4(95%CI:2.5 to 4.7);P0.

26、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 Population)Probability of survival without progression(%)1008060402000510152025Time(months)17393381120174

27、4915410No.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 2012 Crizotinib(n=172a)Pemetrexed(n=99a)Docetaxel(n=72a)Events,n(%)100(58)72(73)54(75)Median,mo7.74.22.6HRb(95%CI)0

28、.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)17293381120 993612310 7213 310No.at riskCrizotinibPemetrexedDocetaxelaAs-treated population:excludes 1 patient in crizotinib arm

29、 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 patients3470.49(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-As

30、ian1900.45(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 120.12(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(0.3

31、00.60)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)and tumor histology(n=7)Shaw et al.ESMO 2012Phase III PRO(n=334)Phase III PRO(n=334)ALK-positive locally advanced/metastatic non-squamous NSCLC No prio

32、r treatment for advanced diseaseR RA AN ND DOOMMI IS SE ECrizotinib 250 mg BID(nCrizotinib 250 mg BID(n=167)167)continuouscontinuousPemetrexed/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 PROPh

33、ase III PRO2929(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(nCrizotinib 250 mg BID(n=167)167)continuouscontinuousPemetrexed/cisplatin orpemetrexed/carboplatin(n=167)infused on day 1 of a

34、 21-day cycle150 patients China and 50 from 2-3 150 patients China and 50 from 2-3 other Asian countriesother Asian countriesCrossover on PDGlobalAsiaNSCLC的个体化治疗时代已经到来EGFR厄洛替尼厄洛替尼(获批获批)易瑞沙易瑞沙(获批获批)PF299804阿法替尼阿法替尼(BIBW2992)ALK克唑替尼克唑替尼(获批获批)LDK378AP26113AF802ROS1克唑替尼克唑替尼HER2PF299804阿法替尼阿法替尼(BIBW2992)

35、PGFRBGJ398FP1039(HGS1036)Ponatinib(AP24534)GGFR/PDGFRA/VEGFRBIBF1120帕唑帕尼帕唑帕尼Lenvatinib(E7080)Brivanib(BMS-582,664)多韦替尼多韦替尼(TKI258)PDGFRAMEDI575IMC-3G3PI3KBKM120PX-866GDC-0941SAR245408PI3K/MTORGDC-0980BEZ235SAR245409MEKMEK162GDC-0973GSK1120212MSC1936369BSTAT3OPB51602AKTMK2206Heist RS,et al.Cancer Cel

36、l 2012;21:448.EGFR=表皮生长因子受体；NOS=未确定组织学类型；PS=体能状态评分a See Principles of Pathologic Review(NSCL-A).b In patients with squamous cell carcinoma,the observed incidence is 2.7%with a confidence that the true incidence of mutations is 3.6%in patients with squamous cell carcinoma.This frequency of EGFR mutat

37、ions does not justify routine testing of all tumor specimens.Forbes et al.Curr Protoc Hum Genet 2008;chapter 10:unit 10.11.c Maemondo et al.N Engl J Med 2010;362(25):2380-2388.Mitsudomi et al.Lancet Oncol 2010;11(2):121-128.d For PS 0-4.e In areas of the world where gefitinib is available,it may be

38、used in place of erlotinib.f Janne et al.J Clin Oncol 2010;28(Suppl 15):abstract 7503.g Cappuzzo et al.Lancet Oncol 2010;11(6):521-529.Note:All recommendations are category 2A unless otherwise indicated.Clinical Trials:NCCN believes that the best management of any cancer patient is in a clinical tri

39、al.Participation in clinical trials is especially encouraged.Adapted from:NCCN.复发或转移后治疗复发或转移后治疗一线治疗一线治疗确定组织确定组织分型分型a 腺癌腺癌 大细胞大细胞 非小细胞肺癌非小细胞肺癌 NOS鳞癌鳞癌不建议常规进行不建议常规进行EGFR突变检测突变检测b EGFR突变检测突变检测a(1类类)ALK检测检测aEGFR突变、突变、或或 ALK阴性、阴性、或未知或未知EGFR 突突变阳性变阳性ALK阳性阳性一线化疗前发现一线化疗前发现EGFR突变突变一线化疗中发现一线化疗中发现EGFR突变突变厄洛替尼厄洛替尼c,d,e克唑替尼克唑替尼 进展进展切换维持切换维持:厄洛替厄洛替尼尼、或加入厄洛、或加入厄洛替尼替尼f,g 到当前化到当前化疗疗(2B类类)进展进展 进展进展参见参见 一线治疗一线治疗(NSCL-14)参见一线治疗参见一线治疗(NSCL-15)参见二线治疗参见二线治疗(NSCL-16)参见二线治疗参见二线治疗(NSCL-16)参见二线治疗参见二线治疗(NSCL-16)