非小細(xì)胞肺癌內(nèi)科治療進展周彩存同濟大學(xué)附屬上海市肺科醫(yī)院編輯ppt化療進展早期術(shù)后輔助化療：個體化？局部晚期

同步化放療，AP未超越EP鱗癌：白蛋白紫杉醇>普通紫杉醇;

ND優(yōu)于DP非鱗癌

分子靶向治療

貝伐單化療優(yōu)于化療

培美優(yōu)于健擇

連續(xù)維持治療改善總體生存免疫治療編輯ppt輔助治療的必要性編輯ppt輔助化療是淋巴結(jié)陽性完全切除早期NSCLC的標(biāo)準(zhǔn)治療在淋巴結(jié)陰性病人,仍存在爭議順鉑為基礎(chǔ)方案是標(biāo)準(zhǔn)卡鉑為基礎(chǔ)方案未得到批準(zhǔn),但經(jīng)常使用證據(jù)最多的是NPECOG1505允許所有未批準(zhǔn)的方案編輯pptBRCA1水平和含鉑藥物化療的相關(guān)性YangYetal.JExpClinCancerRes,2013編輯pptCustomizedBRCA1AdjuvantTreatmentinStageII-IINSCLC(SCAT)PresentedByMarkSocinskiat2015ASCOAnnualMeetingResectedNSCLCR0pN1/pN21..3CONTROLEXPERIMENTALDocetaxel/CisT1BRCA1T2BRCA1T3BRCA1Gem/CisDocetaxel/CisDocetaxelEudract:2007-000067-15NCTgov:00478699Statificationfactors:-Stage:N1vs.N2-Age≤65vs>65y-Histology:Non-SCCvs.SCC-Typeofresection:LobectomyvsPneumonectomyPlannednumberofpatients:432(amended)CTshouldbestartedbefore8weeksaftersurgeryPORTinN2patientsSLIDESARETHEPROPERTYOFTHEAUTHOR.PERMISSIONREQUIREDFORREUSE.編輯pptPresentedByMarkSocinskiat2015ASCOAnnualMeetingCustomizedBRCA1AdjuvantTreatmentinStageII-IINSCLC(SCAT)ResectedNSCLCR0pN1/pN21..3CONTROLEXPERIMENTALDocetaxel/CisT1BRCA1T2BRCA1T3BRCA1Gem/CisDocetaxel/CisDocetaxelEudract:2007-000067-15NCTgov:00478699PrimaryEndpoint:OS5yrOS45%→65%SLIDESARETHEPROPERTYOFTHEAUTHOR.PERMISSIONREQUIREDFORREUSE.編輯ppt實驗組的OSBRCA1低水平BRCA1中等水平BRCA1高水平1.00.80.60.40.20.001020304050607080時間(月)OSHR低水平vs高水平：0.84中等水平vs高水平：0.95編輯pptMassutiB,etal.2015ASCOAbstract7507.BRCA1高水平患者DFS和OS1.00.80.60.40.20.001020304050607080試驗組對照組HR=1.87(0.83-4.19)時間(月)DFS1.00.80.60.40.20.001020304050607080試驗組對照組HR=1.24(0.59-2.59)時間(月)OSBRCA1高表達(dá)者未顯示順鉑耐藥。編輯pptMassutiB,etal.2015ASCOAbstract7507.BRCA1低表達(dá)患者DFS和OS1.00.80.60.40.20.0010203040506070801.00.80.60.40.20.001020304050607080試驗組對照組HR=0.64(0.38-1.09)試驗組對照組HR=0.50(0.28-0.88)P=0.016時間(月)DFS時間(月)OSBRCA1低表達(dá)者多見于腺癌、非吸煙和女性患者。編輯ppt分子學(xué)分析指導(dǎo)下的晚期NSCLC患者全球III期研究：研究設(shè)計分層因素：PS、性別、既往(新)輔助治療治療：6周期、無維持治療、無貝伐單抗主要入組條件：IIIB(濕性)/IV期NSCLC，PS0-1，可測量疾病，F(xiàn)FPE組織塊并有蛋白表達(dá)數(shù)據(jù)計劃入組：267例(254個事件)BeplerG,etal.2013ASCOAbstract8001.招募：運輸組織塊，篩選符合條件受試者主要終點：無進展生存AQUA測定RRM1及ERCC1隨機分組低RRM1≤40.5高RRM1低RRM1≤40.5高RRM1低ERCC1≤66.0吉西他濱+卡鉑多西他賽+卡鉑低ERCC1≤66.0吉西他濱+卡鉑高ERCC1吉西他濱+多西他賽多西他賽+長春瑞濱高ERCC12:1N=275編輯ppt研究結(jié)果：PFS和OS1.00.80.60.40.20.006121824303642對照組(n=92)中位PFS：6.9個月6個月PFS：56.5%研究組(n=183)中位PFS：6.1個月6個月PFS：52.0%Log-rankP=0.181PFS時間(月)1.00.80.60.40.20.00612182430364248對照組(n=92)中位OS：11.3個月12個月OS：46.6%研究組(n=183)中位OS：11.0個月12個月OS：46.1%Log-rankP=0.656時間(月)OSBeplerG,etal.2013ASCOAbstract8001.OS編輯pptSowhatcanweconcludefromthisstudyand

whataretheissues?PresentedByMarkSocinskiat2015ASCOAnnualMeetingBRCA1doesnotappeartobearobustbiomarkerinthissmall4-armtrialRT-PCR-isitavalidmethodtoquantitateBRCA1function?Threedifferenttreatmentsgiven-howdoyouseparatethetreatmenteffectsfromthebiology?TercileswerenotbalancedforknownprognosticfactorsRaisesthehypothesisthatdifferentcisplatin-baseddoubletsmayhavedifferingeffectsindifferentsubsetsCompliancetotherapyimportant(butreasonsfornon-compliancenotdelineated)編輯ppt化療進展早期術(shù)后輔助化療：個體化？局部晚期

同步化放療，AP未超越EP鱗癌：白蛋白紫杉醇>普通紫杉醇;

ND優(yōu)于DP非鱗癌

分子靶向治療

貝伐單化療優(yōu)于化療

培美優(yōu)于健擇

連續(xù)維持治療改善總體生存免疫治療編輯pptUnresectableStageIIINSCLCPresentedByMarkSocinskiat2015ASCOAnnualMeetingChemoradiationestablishedasthestandardofcareoveradecadeagoConcurrentsuperiortosequentialchemoradiationOptimalchemotherapyregimen/strategystillunclearFull-doseaswellaslow-dosestrategiesacceptedasastandardofcareCommonfull-doseregimens-cisplatin+etoposide,vinorelbine,vinblastine,docetaxelCommonlow-doseregimen–weeklycarboplatin/paclitaxel編輯ppt除了EP同步化放為2B證據(jù)外，其他都為2A級證據(jù)。編輯ppt不可手術(shù)的III期NSCLC過去10年,III期臨床研究所致力解決的問題:誘導(dǎo)治療的作用；鞏固治療的作用；新藥

vs.

老藥；放療的劑量（60vs.74Gy);Cetuximab的作用；Tecemotide的作用；編輯pptIsCisPem“worthy”ofaPhaseIIITrialinstageIIINSCLC?PresentedByMarkSocinskiat2015ASCOAnnualMeetingPre-clinicalsynergismofpemetrexedwithRT11phItrialswitheithercisplatinorcarboplatinallusingRTdosesof40-70Gy(mostcommon66Gy)8phIItrialsofvariousstrategiesshowedhighORR(46-86%)andmedOSof18-34monthsAIIphI/IItrialsused"systemic"dosesPhIItrialsreportedratesofgr3-4esophagitisandpnemonitisof0-16%and3-23%,respectively編輯pptPROCLAIM:StudyDesignPresentedByMarkSocinskiat2015ASCOAnnualMeetingPrimaryEndpoint:OS(superiority)*Stratifiedfor.ECOGPS(0vs1);PETscanstaging(yesvsno);gender,anddiseasestage(IIIAvsIIIB).↑AJCCCancerStagingManual(ed6),2002.?Folicacid,vitaminB12,anddexamethasoneadministeredinArmATRT=thoracicradiotherapy.PreviouslyuntreatedstageIIIA-IIIB*nonsquamousNSCLCPS0/1R↑Pemetrexed:?500mg/m2

Cisplatin:75mg/m2,q3wTRT:66Gy,2Gy/fxdaily3CYCLESEtoposide:50mg/m2

D1-5,q4wCisplatin:50mg/m2

D1.8,q4wTRT:66Gy,2Gy/fxdaily2CYCLESPemetrexed:?

500mg/m2,q3w

4CYCLESInvestigator’schoice:Etoposide-Cisplatin:(samedosing/schedule)orVinorelbine-Cisplatin:Vin:30mg/m2iv,D1.8,q3wCis:75mg/m2D1,q3worPaclitaxel-Carboplatin:Pac:200mg/m2iv,q3wCar.AUC=6iv,q3w2CYCLESArmAArmBPR/CR/SDPerRECISTConcurrentPhaseRecoveryPeriod(3-5wks)ConsolidationPhaseTwovariables編輯pptPresentedByMarkSocinskiat2015ASCOAnnualMeetingPrimaryEndpoint:OS(superiority)*Stratifiedfor.ECOGPS(0vs1);PETscanstaging(yesvsno);gender,anddiseasestage(IIIAvsIIIB).↑AJCCCancerStagingManual(ed6),2002.?Folicacid,vitaminB12,anddexamethasoneadministeredinArmATRT=thoracicradiotherapy.PreviouslyuntreatedstageIIIA-IIIB*nonsquamousNSCLCPS0/1R↑Pemetrexed:?500mg/m2

Cisplatin:75mg/m2,q3wTRT:66Gy,2Gy/fxdaily3CYCLESEtoposide:50mg/m2

D1-5,q4wCisplatin:50mg/m2

D1.8,q4wTRT:66Gy,2Gy/fxdaily2CYCLESPemetrexed:?

500mg/m2,q3w

4CYCLESInvestigator’schoice:Etoposide-Cisplatin:(samedosing/schedule)orVinorelbine-Cisplatin:Vin:30mg/m2iv,D1.8,q3wCis:75mg/m2D1,q3worPaclitaxel-Carboplatin:Pac:200mg/m2iv,q3wCar.AUC=6iv,q3w2CYCLESArmAArmBPR/CR/SDPerRECISTConcurrentPhaseRecoveryPeriod(3-5wks)ConsolidationPhase~24weeks~15weeksPROCLAIM:StudyDesign編輯pptPROCLAIM:PrimaryEndpoint,OSPresentedByMarkSocinskiat2015ASCOAnnualMeetingHR(95%CI):0.98(0.79,1.20)Lag-rankp=0.831MedianOS(95%CI),mosPem-Cis:26.8(20.4,30.9)Eto-Cis:25.0(22.2,29.8)Medianfollow-uptimes(mos-[range])Allpatients:Pem-Cis,22.2(0.1-66.6)Eto-Cis,22.6(0.0-71.4)Patientsalive:Pem-Cis,32.9(0.1-66.6)Eto-Cis,35.7(0.0-71.4)Totalevents:357Pem-Cis:177events/301patientsEto-Cis:180events/297patients編輯pptPROCLAIMinthewakeofRTOG0617PresentedByMarkSocinskiat2015ASCOAnnualMeetingEP(n=297)CisPem(n=301)CbP/60Gy*(n=217)MedOS,mos25.026.828.72-yrOS,%525257.6MedPFS,mos9.811.411.8Infieldfailure45.837.330.7Distantfailure45.85046.6Gr3-4esophagitis(%)18.815.57Gr3-4F/N,(%)5.39.6NRAllgrpneumonitis,(%)10.71710*p<0.05,includes2gr5events;

+BradleyJDetal.LancetOncol16:187-99,2015PETStaging-82%PROCLAIM,~90%inRTOG0617編輯ppt化療進展早期術(shù)后輔助化療：個體化？局部晚期

同步化放療，AP未超越EP鱗癌：白蛋白紫杉醇>普通紫杉醇;

ND優(yōu)于DP非鱗癌

分子靶向治療

貝伐單化療優(yōu)于化療

培美優(yōu)于健擇

連續(xù)維持治療改善總體生存免疫治療編輯pptWJOG5208L:StudydesignPresentedByTakehitoShukuyaat2015ASCOAnnualMeeting主要終點：OS;次人終點:

PFS,

RR,

AEs初期樣本大小250例；

修改后樣本350例，power由80%變?yōu)?0%WJOC

5208L:比較nedaplatin與順鉑聯(lián)合多烯紫杉醇一線治療晚期或復(fù)發(fā)肺鱗癌Chemo-naivePS0-1Age20-74StageIIIb/IVorrecurrentSqLCN:350Docetaxel60mg/m2dlNedaplatin100mg/m2dlq3w,4-6cyclesN=175Docetaxel60mg/m2dlCisplatin80mg/m2dlq3w,4-6cyclesN=1751:1Stratificationfactors:Stage(IIIb,IVorrecurrent)GenderInstitutions編輯pptBaselinecharacteristicsPresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(N=177)CD(N=172)AgeMedian(years)Range(years)≥70years<70years64.037-7433(18.6%)144(81.4%)65.041-7431(18.0%)141(82.0%)GenderMaleFemale157(88.7%)20(11.3%)153(89.0%)19(11.0%)SmokingstatusNeversmokerCurrentorformersmoker5(2.8%)172(97.2%)10(5.8%)162(94.2%)PS0181(45.8%)96(54.2%)63(36.6%)109(63.4%)StageatscreeningIIIBIVPostoperativerecurrence56(31.6%)107(60.5%)14(7.9%)56(32.6%)106(61.6%)10(5.8%)編輯pptPrimaryendpoint:OverallsurvivalPresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(N=177)CD(N=172)Median,months13.611.41year,%55.943.52year,%27.118.1HR(90%CI)0.81(0.67-0.98)p*0.037編輯pptProgression-freesurvivalPresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(N=177)CD(N=172)Median,months4.94.56months,%35.627.9HR(90%CI)0.83(0.69-1.00)p*0.050編輯pptObjectivetumorresponsePresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(N=172)CD(N=168)*pvalueCR3(1.7%)1(0.6%)_PR93(54.1%)88(52.4%)_SD50(29.1%)47(28.0%)_PD24(14.0%)27(16.1%)_NE2(1.2%)5(3.0%)_ORR55.8%53.0%0.663DCR84.9%81.0%0.387RECISTver.1.1*Fisher’sexacttest編輯pptTreatmentexposurePresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(N=177)*CD(N=172)*Cyclesreceived

≤

3456median,(range)48(27.1%)68(38.4%)20(11.3%)40(22.6%)4(1-6)64(37.2%)72(41.9%)11(6.4%)23(13.4%)4(1-6)Relativedoseintensity(%),medianNedaplatinCisplatinDocetaxel93.3—93.8—92.394.6*Oneand2patientswithdrewbeforestudytreatmentinNDandCD,respectively編輯pptPost-StudySystemicTherapyPresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(N=177)(%)CD(N=172)(%)2ndlinetherapyGemcitabineS-1Carboplatin+paclitaxelGemcitabine+vinorelbineGemcitabine+S-1Carboplatin+gemcitabineCarboplatin+S-1DocetaxelVinorelbineErlotinibOthers78.013.614.711.94.05.62.83.44.51.11.714.776.714.012.26.47.02.35.23.52.33.52.917.43rdlinetherapy53.740.14thlinetherapy27.725.0編輯pptCA031試驗設(shè)計初次化療PS0-1Ⅲb/Ⅳ期NSCLCN=1,0501：1白蛋白結(jié)合型紫杉醇：100mg/m2

，第1、8、15天卡鉑：AUC6，第1天無預(yù)處理N=525溶劑型紫杉醇：

200mg/m2

，第1天卡鉑：AUC6，第1天地塞米松+抗組胺藥預(yù)處理N=525分層因素：分期(Ⅲb或Ⅳ期)年齡(＜70或＞70)性別組織學(xué)(鱗狀細(xì)胞\非鱗狀細(xì)胞)區(qū)域三周重復(fù)Abstract#LBA7511,2010ASCO編輯ppt主要終點ORR--所有組織學(xué)類型RR=1.31(1.082-1.593)P=0.00533%25%緩解率獨立影像學(xué)評價Nab-P/C(n=521)P/C(n=531)37%30%研究者評價RR=1.26(1.060-1.496)P=0.008Abstract#LBA7511,2010ASCO編輯ppt主要終點ORR--組織學(xué)分層鱗癌Nab-P/CP/C非鱗癌Abstract#LBA7511,2010ASCO41%24%26%25%P<0.001P=0.808n=228n=221n=292n=310獨立影像學(xué)評價緩解率編輯ppt化療方案的選擇JMDB研究：力比泰/順鉑對非鱗癌患者的療效更優(yōu)ScagliottiGV,etal.JClinOncol.2008;26(21):3543-51OS(非鱗癌)OS(鱗癌)編輯ppt化療方案的選擇PujolJL,etal.Oralabstractpresentedat2012ESMO.Vienna,Austria.中性粒細(xì)胞減少p<0.001貧血(血紅蛋白)P=0.001血小板減少(血小板)P<0.001白細(xì)胞減少P=0.019患者(%)惡心P=0.004嘔吐p=1.0脫水(任何分級)P=0.075脫發(fā)

(任何分級)P<0.001疲乏P=0.143發(fā)熱性中性粒細(xì)胞減少P=0.002患者(%)3/4級非血液學(xué)毒性反應(yīng)3/4級血液學(xué)毒性反應(yīng)力比泰/順鉑一線治療非鱗癌耐受性優(yōu)勢顯著編輯ppt化療方案的選擇晚期NSCLC非鱗癌（尤其EGFR突變狀態(tài)未知）患者：優(yōu)選力比泰NSCLC組織學(xué)分組一線治療Pem/Cisvs.Gem/Cis維持治療Pemvs.Placebo二線治療Pemvs.DocPem+CisGem+CisPemPlaceboPemDoc非鱗癌*N=618N=634N=325N=156N=205N=194

mOS(月)11.010.115.510.39.38.0校對的HR(95%CI)P值0.84(0.74,0.96)0.0110.70(0.56,0.88)0.0020.78(0.61,1.00)0.048鱗癌N=244N=229N=116N=66N=78N=94

mOS(月)9.410.89.910.86.27.4校對的HR(95%CI)P值1.23(1.00,1.51)0.0501.07(0.77,1.50)0.6781.56(1.08,2.26)0.018*非鱗癌包括：腺癌、大細(xì)胞癌和其他未確定類型的NSCLCScagliottiG.etal.JThoracOncol.2011;6(1):64-70.編輯pptPARAMOUNT研究：力比泰同藥維持治療顯著延長非鱗癌(EGFR突變狀態(tài)未知)患者PFS力比泰同藥維持：顯著降低患者疾病進展風(fēng)險40%Paz-AresL,etal.JClinOncol.

2013Aug10;31(23):2895-902.

ScagliottiGV,etal.LungCancer.2014Sep;85(3):408-14.

HR=0.60(0.50-0.73)p<0.001時間(月)03691215PFS0.00.10.20.30.40.50.60.70.80.91.0力比泰(n=359)：中位4.4個月安慰劑(n-180)：中位2.8個月PFS（維持治療階段）時間(月)0369121518PFS0.00.10.20.30.40.50.60.70.80.91.0力比泰(n=359)：中位7.50個月安慰劑(n-180)：中位5.60個月PFS（自誘導(dǎo)開始）HR=0.60(0.50-0.73)p<0.001編輯pptPARAMOUNT研究：力比泰同藥維持治療顯著延長非鱗癌(EGFR突變狀態(tài)未知)患者OS力比泰同藥維持：顯著降低患者死亡風(fēng)險22%HR=0.78(0.64-0.96)P=0.01951.00.80.60.40.20.0061218243036力比泰(n=359)：中位13.9個月安慰劑(n-180)：中位11.0個月OS時間(月)OS（維持治療階段）1.00.80.60.40.20.0061218243036力比泰(n=359)：中位16.9個月安慰劑(n-180)：中位14.0個月OS時間(月)HR=0.78(0.64-0.96)P=0.0191OS（自誘導(dǎo)開始）Paz-AresL,etal.JClinOncol.

2013Aug10;31(23):2895-902.

編輯pptSingle-agentPlBEYONDstudydesignSecondaryendpoints:OS,ORR,durationofresponse,safety,plasmabiomarkers(VEGF-A,VEGFR-2)Exploratorybiomarkers:tissueandplasmaEGFRmutationstatusStratificationfactors:gender,smokingstatus,ageChinesepatientswithpreviouslyuntreated,advanced,stageIIIB/IVnon-squamousNSCLCn=276Bevacizumab(B)15mg/kgd1Carboplatin(C)AUC6d1Paclitaxel(P)175mg/m2d13-weeklycycle,n=1386cyclesRPDCP+Placebo(Pl)Allond13-weeklycycle,n=1381:1PDPrimaryendpoint:PFStoconfirmefficacyinChinesepopulationthroughconsistencywithE4599(HRthreshold≤0.83)**Optionalenrolmentinpost-progressionphaseofopen-labelB+approved2nd-/3rd-linetreatmentforB+CParmonlyPD=diseaseprogression;R=randomised;ORR=objectiveresponserate;HR=hazardratio;VEGF-A=vascularendothelialgrowthfactor-AVEGFR-2=vascularendothelialgrowthfactorreceptor-2;EGFR=epidermalgrowthfactorreceptorSingle-agentB編輯pptExploratoryEGFRbiomarkeranalysis:PFSAtotalof152patientsprovidedtissueforbiomarkeranalysis(n=85B+CP;n=67Pl+CP)EGFRmutation-positiveratewas27%inB+CPand25%inPl+CPpatientsNocorrelationwasobservedbetweenEGFRmutationstatusandbevacizumabefficacyasimilardegreeoftreatmentbenefitwasseenformutationpositiveandwild-typegroups(mutation-positiveHR0.27,95%CI0.12–0.63;wild-typeHR0.33,95%CI0.21–0.53AnalysesofEGFRplasmadataareongoingMut+=mutation-positive;WT=wildtypePFS(primaryendpoint)Datacut-off27Jan201317 11 1 0 050 25 0 0 023 17 8 2 062 49 20 1 0B+CP:EGFRMut+natriskPl+CP:EGFRMut+Pl+CP:EGFRWTB+CP:EGFRWTStudyMonth0 5 10 15 201.00.80.60.40.20.0ArmbyEGFRstatusPI+CP:EGFRMut+(median7.9months)PI+CP:EGFR

WT(median5.6months)B+CP:EGFRMut+(median12.4months)B+CP:EGFRWT(median8.3months)編輯pptMedianOSwas24.3vs27.5monthsforB+CPvsPl+CPintheEGFRmutation-positivesubgroup(HR0.90)IntheEGFRwild-typesubgroup,medianOSwas20.3vs13.8monthsforB+CPvsPl+CP(HR0.57)ExploratoryEGFRbiomarkeranalysis:OSDatacut-off30Apr2014ArmbyEGFRstatusPI+CP:EGFRMut+(median27.5months)PI+CP:EGFR

WT(median13.8months)B+CP:EGFRMut+(median24.3months)B+CP:EGFRWT(median20.3months)1.00.80.60.40.20.00 5 10 15 20 25 30 35OverallSurvival17 16

15

11

10 9 1 049 45

29

19

13 9 1 023

23

21

17

15 8 3 062 57

46

41

31 21 5 0StudyMonthB+CP:EGFRMut+natriskPl+CP:EGFRMut+Pl+CP:EGFRWTB+CP:EGFRWT編輯pptPlasmasampleswereavailablefrom274patientsPlasmaVEGF-AandVEGFR-2baselinelevels(highversuslowcomparedtomedianlevels)didnotcorrelatewithbevacizumabefficacyforPFSorOSPlasmaVEGFbiomarkeranalysisDatacut-off27Jan2013forPFS;30Apr2014forOS Baseline ≤median 131 0.26 0.40 1.62 Baseline ≤median 137 0.24 0.37 0.56PFS All All 274 0.29 0.40 0.54 VEGF-A >median 131 0.22 0.34 0.53 ≤P25 66 0.2 0.46 0.83 >P25-P50 65 0.18 0.36 1.71 >P50-P75 69 0.17 0.33 0.64 >P75 65 0.22 0.39 0.72 VEGFR-2 >median 137 0.26 0.40 0.62 ≤P25 69 0.18 0.34 0.63 >P25-P50 68 0.23 0.40 0.71 >P50-P75 66 0.16 0.30 0.56 >P75 68 0.25 0.46 0.83 0.2 0.4 0.6 1 Lower Upper Category Subgroup N limit Est. limit confidence confidenceHazardRatioOS All All 274 0.50 0.68 0.93 Baseline ≤median 131 0.41 0.64 1.00 VEGF-A >median 131 0.40 0.62 0.96 ≤P25 66 0.27 0.53 1.03 >P25-P50 65 0.49 0.89 1.60 >P50-P75 69 0.28 0.53 1.01 >P75 65 0.41 0.76 1.39 Baseline ≤median 137 0.42 0.64 0.97 VEGFR-2 >median 137 0.40 0.63 0.98 ≤P25 69 0.30 0.53 0.94 >P25-P50 68 0.42 0.77 1.41 >P50-P75 66 0.25 0.48 0.91 >P75 68 0.38 0.71 1.35 0.2 0.4 0.6 1 2 3 Lower Upper Category Subgroup N limit Est. limit confidence confidenceHazardRatio編輯ppt化療進展早期術(shù)后輔助化療：個體化？局部晚期

同步化放療，AP未超越EP鱗癌：白蛋白紫杉醇>普通紫杉醇;

ND優(yōu)于DP非鱗癌

分子靶向治療

貝伐單化療優(yōu)于化療

培美優(yōu)于健擇

連續(xù)維持治療改善總體生存免疫治療編輯pptMutationalheterogeneityincancerPresentedByLauraChowat2014ASCOAnnualMeeting編輯ppt適應(yīng)性免疫應(yīng)答可以預(yù)測預(yù)后GalonJ,et.al,Science,2006,313:1960-1964編輯ppt克服免疫逃逸的根本—解除T細(xì)胞的抑制T細(xì)胞效應(yīng)功能受到宿主和腫瘤微環(huán)境的影響而抑制

-對于Treg細(xì)胞增多的患者，抗CTLA-4和PD-1是一種有效的方式

-阻斷T細(xì)胞正常表達(dá)的CTLA-4，PD-L1，或LAG3可減少它們的抗原應(yīng)答

-僅僅通過抑制CTLA-4和PD-1對CD8+T細(xì)胞增殖和生存是不夠的，加入LAG3抑制劑可進一步增強T細(xì)胞的增殖和激活

-對于具有MDSCs或調(diào)節(jié)性B細(xì)胞表型的患者，或腫瘤微環(huán)境相關(guān)的先天性免疫應(yīng)答缺陷的患者，另一種免疫檢測點抑制劑可能有效，比如OX40或ICOSLucasCL,etal.Blood.2011;117:5532-5540Twyman-SaintVictorC,etal.Nature.2015;520:373-377編輯pptTargetAgentClassRegulatoryStatusinUnitedStates(March2015)CTLA4IpilimumabFullyhumanimmunoglobulinG1ApprovedinadvancedmelanomaTremelimumabFullyhumanimmunoglobulinG2Indevelopment/investigationalPD-1NivolumabHumanizedmonoclonalimmunoglobulinG4Approvedinunresectableormetastaticmelanoma;approvedinmetastaticsquamousNSCLCPembrolizumabApprovedinmelanomaafterfailureofipilimumabtherapytopalian,Drake,Pardoll,CurrOpinImmunol2012美國FDA批準(zhǔn)的免疫檢測點抑制劑編輯ppt免疫檢查點及其抗體腫瘤免疫逃避是腫瘤局部事件

TILs

IFN-γ誘導(dǎo)腫瘤細(xì)胞表達(dá)PD-L1免疫檢查點抗體

適用于多種腫瘤

大腫瘤有效

較長的反應(yīng)維持時間

不良反應(yīng)輕編輯ppt生存優(yōu)勢能否持續(xù)？Nivolumab二線治療肺鱗癌的III期臨床研究CheckMate017IIIb/IV期鱗狀NSCLC既往接受過1次含鉑雙