肺癌内科治疗进展

非小细胞肺癌内科治疗进展周彩存同济大学附属上海市肺科医院化疗进展早期术后辅助化疗：个体化？局部晚期

同步化放疗，AP未超越EP鳞癌：白蛋白紫杉醇>普通紫杉醇;ND优于DP非鳞癌

分子靶向治疗

贝伐单化疗优于化疗

培美优于健择

连续维持治疗改善总体生存免疫治疗辅助治疗的必要性辅助化疗是淋巴结阳性完全切除早期NSCLC的标准治疗在淋巴结阴性病人,仍存在争议顺铂为基础方案是标准卡铂为基础方案未得到批准,但经常使用证据最多的是NPECOG1505允许所有未批准的方案BRCA1水平和含铂药物化疗的相关性YangYetal.JExpClinCancerRes,2013CustomizedBRCA1AdjuvantTreatmentinStageII-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.PresentedByMarkSocinskiat2015ASCOAnnualMeetingCustomizedBRCA1AdjuvantTreatmentinStageII-IINSCLC(SCAT)ResectedNSCLCR0pN1/pN21..3CONTROLEXPERIMENTALDocetaxel/CisT1BRCA1T2BRCA1T3BRCA1Gem/CisDocetaxel/CisDocetaxelEudract:2007-000067-15NCTgov:00478699PrimaryEndpoint:OS5yrOS45%→65%SLIDESARETHEPROPERTYOFTHEAUTHOR.PERMISSIONREQUIREDFORREUSE.实验组的OSBRCA1低水平BRCA1中等水平BRCA1高水平1.00.80.60.40.20.001020304050607080时间(月)OSHR低水平vs高水平：0.84中等水平vs高水平：0.95MassutiB,etal.2015ASCOAbstract7507.BRCA1高水平患者DFS和OS1.00.80.60.40.20.001020304050607080试验组对照组HR=1.87(0.83-4.19)时间(月)DFS1.00.80.60.40.20.001020304050607080试验组对照组HR=1.24(0.59-2.59)时间(月)OSBRCA1高表达者未显示顺铂耐药。MassutiB,etal.2015ASCOAbstract7507.BRCA1低表达患者DFS和OS1.00.80.60.40.20.0010203040506070801.00.80.60.40.20.001020304050607080试验组对照组HR=0.64(0.38-1.09)试验组对照组HR=0.50(0.28-0.88)P=0.016时间(月)DFS时间(月)OSBRCA1低表达者多见于腺癌、非吸烟和女性患者。分子学分析指导下的晚期NSCLC患者全球III期研究：研究设计分层因素：PS、性别、既往(新)辅助治疗治疗：6周期、无维持治疗、无贝伐单抗主要入组条件：IIIB(湿性)/IV期NSCLC，PS0-1，可测量疾病，FFPE组织块并有蛋白表达数据计划入组：267例(254个事件)BeplerG,etal.2013ASCOAbstract8001.招募：运输组织块，筛选符合条件受试者主要终点：无进展生存AQUA测定RRM1及ERCC1随机分组低RRM1≤40.5高RRM1低RRM1≤40.5高RRM1低ERCC1≤66.0吉西他滨+卡铂多西他赛+卡铂低ERCC1≤66.0吉西他滨+卡铂高ERCC1吉西他滨+多西他赛多西他赛+长春瑞滨高ERCC12:1N=275研究结果：PFS和OS1.00.80.60.40.20.006121824303642对照组(n=92)中位PFS：6.9个月6个月PFS：56.5%研究组(n=183)中位PFS：6.1个月6个月PFS：52.0%Log-rankP=0.181PFS时间(月)1.00.80.60.40.20.00612182430364248对照组(n=92)中位OS：11.3个月12个月OS：46.6%研究组(n=183)中位OS：11.0个月12个月OS：46.1%Log-rankP=0.656时间(月)OSBeplerG,etal.2013ASCOAbstract8001.OSSowhatcanweconcludefromthisstudyand

whataretheissues?PresentedByMarkSocinskiat2015ASCOAnnualMeetingBRCA1doesnotappeartobearobustbiomarkerinthissmall4-armtrialRT-PCR-isitavalidmethodtoquantitateBRCA1function?Threedifferenttreatmentsgiven-howdoyouseparatethetreatmenteffectsfromthebiology?TercileswerenotbalancedforknownprognosticfactorsRaisesthehypothesisthatdifferentcisplatin-baseddoubletsmayhavedifferingeffectsindifferentsubsetsCompliancetotherapyimportant(butreasonsfornon-compliancenotdelineated)化疗进展早期术后辅助化疗：个体化？局部晚期

同步化放疗，AP未超越EP鳞癌：白蛋白紫杉醇>普通紫杉醇;ND优于DP非鳞癌

分子靶向治疗

贝伐单化疗优于化疗

培美优于健择

连续维持治疗改善总体生存免疫治疗UnresectableStageIIINSCLCPresentedByMarkSocinskiat2015ASCOAnnualMeetingChemoradiationestablishedasthestandardofcareoveradecadeagoConcurrentsuperiortosequentialchemoradiationOptimalchemotherapyregimen/strategystillunclearFull-doseaswellaslow-dosestrategiesacceptedasastandardofcareCommonfull-doseregimens-cisplatin+etoposide,vinorelbine,vinblastine,docetaxelCommonlow-doseregimen–weeklycarboplatin/paclitaxel除了EP同步化放为2B证据外，其他都为2A级证据。不可手术的III期NSCLC过去10年,III期临床研究所致力解决的问题:诱导治疗的作用；巩固治疗的作用；新药

vs.

老药；放疗的剂量（60vs.74Gy);Cetuximab的作用；Tecemotide的作用；IsCisPem“worthy”ofaPhaseIIITrialinstageIIINSCLC?PresentedByMarkSocinskiat2015ASCOAnnualMeetingPre-clinicalsynergismofpemetrexedwithRT11phItrialswitheithercisplatinorcarboplatinallusingRTdosesof40-70Gy(mostcommon66Gy)8phIItrialsofvariousstrategiesshowedhighORR(46-86%)andmedOSof18-34monthsAIIphI/IItrialsused"systemic"dosesPhIItrialsreportedratesofgr3-4esophagitisandpnemonitisof0-16%and3-23%,respectivelyPROCLAIM: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)ConsolidationPhaseTwovariablesPresentedByMarkSocinskiat2015ASCOAnnualMeetingPrimaryEndpoint: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:StudyDesignPROCLAIM: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/297patientsPROCLAIMinthewakeofRTOG0617PresentedByMarkSocinskiat2015ASCOAnnualMeetingEP(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化疗进展早期术后辅助化疗：个体化？局部晚期

同步化放疗，AP未超越EP鳞癌：白蛋白紫杉醇>普通紫杉醇;ND优于DP非鳞癌

分子靶向治疗

贝伐单化疗优于化疗

培美优于健择

连续维持治疗改善总体生存免疫治疗WJOG5208L:StudydesignPresentedByTakehitoShukuyaat2015ASCOAnnualMeeting主要终点：OS;次人终点:

PFS,

RR,

AEs初期样本大小250例；

修改后样本350例，power由80%变为90%WJOC

5208L:比较nedaplatin与顺铂联合多烯紫杉醇一线治疗晚期或复发肺鳞癌Chemo-naivePS0-1Age20-74StageIIIb/IVorrecurrentSqLCN:350Docetaxel60mg/m2dlNedaplatin100mg/m2dlq3w,4-6cyclesN=175Docetaxel60mg/m2dlCisplatin80mg/m2dlq3w,4-6cyclesN=1751:1Stratificationfactors:Stage(IIIb,IVorrecurrent)GenderInstitutionsBaselinecharacteristicsPresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(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%)Primaryendpoint: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*0.037Progression-freesurvivalPresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(N=177)CD(N=172)Median,months4.94.56months,%35.627.9HR(90%CI)0.83(0.69-1.00)p*0.050ObjectivetumorresponsePresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(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’sexacttestTreatmentexposurePresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(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,respectivelyPost-StudySystemicTherapyPresentedByTakehitoShukuyaat2015ASCOAnnualMeetingND(N=177)(%)CD(N=172)(%)2ndlinetherapyGemcitabineS-1Carboplatin+paclitaxelGemcitabine+vinorelbineGemcitabine+S-1Carboplatin+gemcitabineCarboplatin+S-1DocetaxelVinorelbineErlotinibOthers78.013