晚期非小細(xì)胞肺癌的精準(zhǔn)治療

周彩存周彩存，醫(yī)學(xué)博士，博士生導(dǎo)師，主任醫(yī)師，教授；上海市領(lǐng)軍人才，享受國(guó)務(wù)院特殊津貼

現(xiàn)任同濟(jì)大學(xué)附屬上海市肺科醫(yī)院腫瘤科主任，醫(yī)學(xué)院腫瘤研究所所長(zhǎng)

中國(guó)醫(yī)促會(huì)胸部腫瘤分會(huì)主委，中國(guó)抗癌協(xié)會(huì)肺癌專業(yè)委員會(huì)常委，上海市抗癌協(xié)會(huì)肺癌分子靶向和免疫治療專業(yè)委員會(huì)主委，中國(guó)抗癌協(xié)會(huì)腫瘤藥物臨床研究專業(yè)委員會(huì)副主任委員，上海市醫(yī)學(xué)會(huì)分子診斷專委會(huì)副主任委員，中國(guó)醫(yī)師協(xié)會(huì)腫瘤分會(huì)常委，上海市醫(yī)師協(xié)會(huì)腫瘤分會(huì)副會(huì)長(zhǎng)

晚期非小細(xì)胞肺癌的精準(zhǔn)治療CaicunZhouShanghaiPulmonaryHospital,ShanghaiTongjiUniversity,P.R.China肺癌是我國(guó)發(fā)病率和死亡率最高的惡性腫瘤，5年生存率僅為16％發(fā)病率和死亡率仍在上升肺癌對(duì)患者、家庭、國(guó)家都是一種災(zāi)難生存期短過度治療無效治療患者家庭國(guó)家失去家庭成員的巨大痛苦高昂治療費(fèi)用的壓力治與不治的艱難選擇不斷增加的高昂醫(yī)療負(fù)擔(dān)高加索肺腺癌驅(qū)動(dòng)基因圖譜亞裔肺腺癌驅(qū)動(dòng)基因圖譜ShollLM,etal.JThoracOncol.2015;10(5):768-777SeoJS,GenomeRes.2012,22(11):2109-2119肺癌驅(qū)動(dòng)基因譜明確，精準(zhǔn)治療條件最成熟KRAS25%無已知的腫瘤驅(qū)動(dòng)基因36%EGFR23%ALK7.9%MEK10.3%ERBB2

2.7%BRAF

2.6%PIK3CA

0.8%NRAS0.7%MET0.7%融合基因點(diǎn)突變未知肺腺癌（n=200）外顯子跳躍精準(zhǔn)治療，路在何方？PrecisionMedicineinAdvancedNSCLCClinicalLungCancerGenomeProjectandNetworkGenomicMedicine,ScienceTransl.Med.2013Targettherapy

(1st,2nd,and3rdgeneration)Newtargets

Increaseofbiomarkertesting

Immunotherapy

ＰＤ－Ｌ1ＴＰＳ>50%

Mutationload>200

SquamousCarcinoma

SmokingadenocarcinomaNoactionabledrivermutationAvastin＋Chemo

Non-squamousNSCLC

AdenoCaSquamousCa.SCLCNOSLargecell

USLungCancerMutationalConsortium(LCMC)Collaborationof14USCancerCentersMultiplexgenotypingof1007adenocarcinomas(fullgenotyping733)CloselinktoclinicaltrialplatformKrisetal.,ASCO2011,#7506,Krisetal.,JAMA2014LCMC:BenefitinoverallsurvivalforpersonalizedtreatmentKrisetal.,ASCO2011,#7506,Krisetal.,JAMA2014

IPASS開啟了EGFR-TKI的肺癌精準(zhǔn)醫(yī)學(xué)時(shí)代048121620240.00.20.40.60.81.0GefitinibEGFRM+(n=132)

GefitinibEGFRM-(n=91)

Carboplatin/paclitaxelEGFRM+(n=129)Carboplatin/paclitaxelEGFRM-(n=85)Probability

ofPFSEGFRM+HR(95%CI)0.48(0.36,0.64),p<0.0001EGFRM-HR(95%CI)2.85(2.05,3.98),p<0.0001PrimaryCoxanalysiswithcovariates;ITTpopulation;HR<1impliesalowerriskofprogressionongefitinibTreatmentbysubgroupinteractiontest,p<0.0001Moketal2009Timefromrandomisation(months)九項(xiàng)臨床研究驗(yàn)證TKI是EGFR突變陽(yáng)性患者一線治療的最佳選擇ROSsiA,etal.CancerTreatmentReviews2013;39:489-497.ZhouCC,etal.LancetOncol2011;12:735–42.WuYL,etal.AuunalofOnco2015.HanJY,etal.JClinOncol2012;30:1122-1128.研究分組N

(EGFRm+)ORR(%)ORRP值中位PFS(月)PFSP值IPASS易瑞沙卡鉑/紫杉醇13212971.247.30.00019.5

6.30.0001First-SIGNAL易瑞沙順鉑/吉西他濱261684.637.50.0028.06.30.086WJOG3405易瑞沙順鉑/多西他賽868662.132.10.00019.66.60.001NEJ002易瑞沙卡鉑/紫杉醇11411473.730.70.00110.85.40.001OPTIMAL厄洛替尼卡鉑/吉西他濱827283360.000113.14.60.0001ENSURE厄洛替尼順鉑/吉西他濱11010762.733.60.000111.05.50.0001EURTAC厄洛替尼含鉑兩藥86875815NA9.75.20.0001CONVINEC凱美納培美＋鉑14814864.833.8ＮＡ9.77.20.001NCCN指南明確單藥TKI是目前EGFR突變陽(yáng)性患者標(biāo)準(zhǔn)治療阿法替尼40mg/天*易瑞沙250mg/天病理學(xué)證實(shí)診斷為IIIB期或IV期肺腺癌之前未接受過化療之前未接受過EGFR抑制劑腫瘤組織中有證實(shí)激活性EGFR突變（Del19和/或L858R）ECOGPS0–1(n=319)R主要研究終點(diǎn)無進(jìn)展生存期(PFS)

-獨(dú)立評(píng)估治療失敗時(shí)間(TTF)總生存期(OS)次要研究終點(diǎn)客觀緩解率(ORR)至客觀緩解的時(shí)間客觀緩解持續(xù)時(shí)間疾病控制持續(xù)時(shí)間腫瘤縮小健康相關(guān)生活質(zhì)量評(píng)估（HRQoL)分層因素：突變類型（19/21);是否有腦轉(zhuǎn)移如果研究者認(rèn)為有獲益則允許進(jìn)展后持續(xù)治療第4、8、隨后每8周直至第64周、隨后每12周評(píng)估療效(RECIST)入組：2011年12月-2013年8月中位PFS隨訪時(shí)間：27.3個(gè)月ParkK,etal.2015ESMOAsia.*Del19和/或L858R(腫瘤組織)，local或central檢測(cè)a根據(jù)處方信息，允許劑量調(diào)整為50,30,20mgLUX-Lung7研究：對(duì)于EGFR突變陽(yáng)性患者的新一代EGFR-TKI探索以易瑞沙為基礎(chǔ)對(duì)照進(jìn)行

LUX-Lung7:PFS(獨(dú)立評(píng)估)ParkK,etal.2015ESMOAsia.阿法替尼(N=160)易瑞沙(N=159)中位PFS(月)11.010.9HR(95%Cl)0.73(0.57-0.95)P值0.01651.00.80.60.40.2003691215182124273033363942時(shí)間(月)PFSAZD9291用于經(jīng)治T790M+的NSCLC：

AURA2(II期研究)主要終點(diǎn)：評(píng)估AZD9291療效（ORR）

關(guān)鍵入組標(biāo)準(zhǔn)：年齡≥18歲(日本≥20歲)確認(rèn)EGFRm+至少有一個(gè)可重復(fù)評(píng)估病灶PS：0/1臟器功能可接受允許有穩(wěn)定腦轉(zhuǎn)移不符合入組條件既往接受過EGFR-TKI治療出現(xiàn)進(jìn)展或轉(zhuǎn)移的患者經(jīng)中心確認(rèn)EGFRm+疾病進(jìn)展時(shí)再次活檢經(jīng)中心檢測(cè)確認(rèn)T790M+T790M+(n=210)T790M-AZD929180mg,QDTetsuyaMitsudomi,etal.2015WCLCMINI16.08獨(dú)立中心評(píng)估療效T790M陽(yáng)性患者ORR，%（95%CI）71（64，77）中位DOR，月（95%CI）7.8（7.1，NC）（成熟度27%）中位PFS，月（95%CI）8.6（8.3，9.7）（成熟度38%）AURA17研究：AZD9291中國(guó)注冊(cè)臨床研究AZD929180mg每日一次

(n=175)每6周進(jìn)行RECIST1.1評(píng)估指導(dǎo)出現(xiàn)疾病進(jìn)展基于最近一次治療后進(jìn)展的腫瘤標(biāo)本經(jīng)中心實(shí)驗(yàn)室檢測(cè)出T790M突變陽(yáng)性EGFRm+的局部晚期或轉(zhuǎn)移性NSCLC患者，且T790M突變陽(yáng)性作為2線治療508作為3線或以上治療10017中國(guó)患者(n=150)非中國(guó)患者(n=25)依據(jù)既往治療分入兩個(gè)隊(duì)列設(shè)計(jì)：本研究預(yù)計(jì)入組225例患者，其中包括180例中國(guó)患者（占總?cè)虢M人數(shù)80%）主要終點(diǎn):ORR次要終點(diǎn):PFS,OSConfidentialforAZD9291.InternalUseonly.Notforinternalorexternaldistribution期待2016WCLC結(jié)果！AZD9291一線治療EGFR突變NSCLC數(shù)據(jù)令人期待注：數(shù)據(jù)錄入截止時(shí)間：2015年8月1日對(duì)距最后一次評(píng)估14周以內(nèi)的疾病進(jìn)展事件進(jìn)行監(jiān)察反應(yīng)持續(xù)時(shí)間是距離第一次有記錄的反應(yīng)到Recist評(píng)估出現(xiàn)進(jìn)展或死亡的時(shí)間SureshS.,etal.2015WCLCMINI16.07AZD9291，對(duì)比吉非替尼或厄洛替尼治療EGFR-TKI敏感突變的初治晚期NSCLC的隨機(jī)III期臨床研究(FLAURA)局部晚期或轉(zhuǎn)移性NSCLC病理學(xué)證實(shí)為肺腺癌既往未接受過治療腫瘤組織存在19DEL或21L858R突變或合并其他EGFR突變WHOPS0-1按以下因素分層：亞洲/非亞洲19DEL/21L858RAZD929180mgqd吉非替尼250mgqd或厄洛替尼150mgqd按照RECIST1.1標(biāo)準(zhǔn)每6周評(píng)估一次直到進(jìn)展進(jìn)展后病人可以隨機(jī)分到AZD9291組1:1隨機(jī)分組主要終點(diǎn)：PFS次要終點(diǎn)：PFS(亞組分析)ORR，緩解持續(xù)時(shí)間，DCR研究者評(píng)估的緩解程度，OS安全性和耐受性，藥物代謝動(dòng)力學(xué)疾病相關(guān)癥狀和HRQoL主要排除標(biāo)準(zhǔn)：既往接受過任何抗腫瘤治療既往接受過EGFR-TKI手術(shù)后至第一次治療時(shí)間間隔小于4周間質(zhì)性肺病脊髓壓迫和有癥狀的腦轉(zhuǎn)移GFR檢測(cè)由中心實(shí)驗(yàn)室評(píng)估檢測(cè)方法：cobas檢測(cè)PFS2：從隨機(jī)入組到疾病二次進(jìn)展RamalingamSS,etal.2015ASCOAbstract8102.2016年ASCO公布肺癌最新液態(tài)活檢數(shù)據(jù)（II/II）組織、血漿、尿液中T790M陽(yáng)性患者對(duì)CO-1686的應(yīng)答率比較接近，在預(yù)測(cè)療效上有著相同的功能。PresentedbyDavid

at2016ASCOSlide8PresentedByJacobChabonat2016ASCOAnnualMeetingPhaseIIItrialscomparingcrizotinibwithchemotherapyin<br/>ALK+lungcancer(PROFILE1007and1014)PresentedByTetsuyaMitsudomiat2016ASCOAnnualMeetingALK陽(yáng)性病人：ALK抑制劑LimitationsofcrizotinibPresentedByTetsuyaMitsudomiat2016ASCOAnnualMeetingJ-ALEX:StudyDesignPresentedByShirishGadgeelat2016ASCOAnnualMeetingPrimaryEndpoint:PFSbyIRF(ITTPopulation)PresentedByShirishGadgeelat2016ASCOAnnualMeetingEfficacyresultsforALK+patientsPresentedByTetsuyaMitsudomiat2016ASCOAnnualMeeting3rdGenerationALKi:Loratinib如何優(yōu)化？使用順序：一代與新的TKI群體的選擇及其治療策略優(yōu)化Bim

豐度

其它基因的改變PrecisionMedicineinAdvancedNSCLCClinicalLungCancerGenomeProjectandNetworkGenomicMedicine,ScienceTransl.Med.2013Targettherapy

(1st,2nd,and3rdgeneration)Newtargets

Increaseofbiomarkertesting

Immunotherapy

ＰＤ－Ｌ1ＴＰＳ>50%

Mutationload>200

SquamousCarcinoma

SmokingadenocarcinomaNoactionabledrivermutationAvastin＋Chemo

Non-squamousNSCLC

AdenoCaSquamousCa.SCLCNOSLargecell

E4599：貝伐珠單抗一線聯(lián)合卡鉑/紫杉醇

顯著延長(zhǎng)PFS、OS及ORRECOG4599HR=0.66,p<0.001(95%CI:0.57–0.77)

06121824304.56.21.00.80.60.40.20PFS貝伐珠單抗+卡鉑/紫杉醇卡鉑/紫杉醇

109876543210 06121824 303642OSHR=0.79(0.67–0.92)P=0.00312.310.3貝伐珠單抗+卡鉑/紫杉醇卡鉑/紫杉醇

Sandler,etal.NEnglJMed2006貝伐聯(lián)合卡鉑紫杉醇卡鉑紫杉醇HRP中位PFS(月)6.24.50.66<0.0016個(gè)月PFS55%33%1年P(guān)FS15%6%中位OS(月)12.310.30.790.003ORR35%15%BEYOND：貝伐珠單抗在中國(guó)人群療效的驗(yàn)證安慰劑單藥中國(guó)IIIB/IV期非小細(xì)胞肺癌患者既往未接受治療組織學(xué)或細(xì)胞學(xué)證實(shí)為非鱗癌年齡≥18歲ECOGPS0-1n=276貝伐珠單抗15mg/kgd1卡鉑AUC6d1

紫杉醇175mg/m2d13周方案,n=1386個(gè)周期R進(jìn)展*安慰劑d1+紫杉醇/卡鉑3周方案,n=1381:1進(jìn)展貝伐珠單抗單藥主要終點(diǎn)：PFS：證實(shí)在中國(guó)人群中的療效與E4599研究療效一致(HR臨界

≤0.83)次要終點(diǎn)：OS，ORR，疾病緩解時(shí)間，安全性，血漿生物標(biāo)志物(VEGF-A，VEGFR-2)ZhouC,etal.JClinOncol2015;33:2197-2204.主要基線特征Bev+CP(n=138)Pl+CP(n=138)ECOGPS,n(%)034(25)27(20)1104(75)111(80)組織學(xué),n(%)

腺癌137(99)136(98)疾病分期,n(%)

復(fù)發(fā)

4(3)3(2)IIIB8(6)9(7)IV126(91)125(91)

未知0(0.0)1(1)EGFR突變狀態(tài)*,n(%)8566EGFR突變陽(yáng)性,n(%)23(27)17(26)EGFR野生型,n(%)62(73)50(74)研究設(shè)計(jì)*進(jìn)展揭盲后,僅貝伐珠單抗組可選擇使用貝伐珠單抗聯(lián)合已被批準(zhǔn)的二、三線治療BEYOND：

貝伐珠單抗聯(lián)合卡鉑/紫杉醇顯著延長(zhǎng)PFS及OSPFS(主要終點(diǎn))中位PFS9.2月

vs6.5月HR0.40(95%CI0.29–0.54)p<0.0011.00.80.60.40.206121824貝伐珠單抗+卡鉑紫杉醇(n=138)卡鉑+紫杉醇(n=138)時(shí)間(月)9.2月

6.5月進(jìn)展風(fēng)險(xiǎn)60%2.7時(shí)間

(月)1.00.80.60.40.2061218243036總生存貝伐珠單抗+卡鉑紫杉醇(n=138)卡鉑+紫杉醇(n=138)中位

OS24.3月vs6.5月HR0.68(95%CI0.50–0.93)p=0.0154死亡風(fēng)險(xiǎn)32%24.3月17.7月6.6數(shù)據(jù)截止時(shí)間2013年1月27日Z(yǔ)houC,etal.JClinOncol2015;33:2197-2204.研究終點(diǎn)Bev+CP(n=136)Pl+CP(n=133)ORR,%(95%CI)54(45.4–62.9)26(19.2–34.8)P值<0.0001DCR,%(95%CI)95(89.3–97.7)89(81.8–93.3)中位緩解持續(xù)時(shí)間,月(95%CI)8.0(6.9–9.4)5.3(4.4–6.0)PrecisionMedicineinAdvancedNSCLCClinicalLungCancerGenomeProjectandNetworkGenomicMedicine,ScienceTransl.Med.2013Targettherapy

(1st,2nd,and3rdgeneration)Newtargets

Increaseofbiomarkertesting

Immunotherapy

ＰＤ－Ｌ1ＴＰＳ>50%

Mutationload>200

SquamousCarcinoma

SmokingadenocarcinomaNoactionabledrivermutationAvastin＋Chemo

Non-squamousNSCLC

AdenoCaSquamousCa.SCLCNOSLargecell

ActivityinpretreatedpatientsNivolumabPembrolizumabAtezolizumabDurvalumabAvelumabN129475175228184RR鱗癌非鱗癌17%18%23.5%19%27%21%21%13%14%藥物相關(guān)AE所有級(jí)別?級(jí)41%4.7%71%9.5%66%11%50%8%77%12%RRPDL-1陽(yáng)性PDL-1陰性16%13%42%(>50%)10%(<1%)34%IC2/3orTC2/3(halfif3used)GettingerS,JClinOncol2015;33:2004-2012;HerbstR,Nature2014;515:563-7;SoriaJC,ESMO2013;GaronE,NEJM2015;372:2018-28;RizviN,ASCO2015;GuleyLJ,ASCO2015NivolumabvsdocetaxelinadvancedNSCLC

Overallsurvival

Sqamous AdenocarcinomaHR0.59(95%CI0.44-0.79) HR0.73(95%CI0.59-0.89)P<0.001 p=0.002

BrahmerJetal.NEJM2015,373,123 BorghaeiHetal.NEJM2015Pembrolizumab(2or10mg/kg)versusdocetaxel

inadvancedNSCLC:OverallSurvival

HerbstRetal.LancetOncology2015,onlineDecember18

PD-L150%ormore Pembrolizumab10mg/kgevery3weeks:HR0.50(95%CI0.36-0.70)p<0.0001Pembrolizumab2mg/kgevery3weeks:HR0.54(95%CI0.38-0.77)p=0.0002

TotalPembrolizumab10mg/kgevery3weeks:HR0.61(95%CI0.49-0.75)p=0.0001Pembrolizumab2mg/kgevery3weeks:HR0.71(95%CI0.58-0.88)p=0.0008

Slide16PresentedByGideonBlumenthalat2016ASCOAnnualMeeting探索性匯總無進(jìn)展生存K-M曲線Slide17PresentedByGideonBlumenthalat2016ASCOAnnualMeeting探索性匯總總生存K-M曲線一線策略？MonotherapyHighPD-L1expressionIncombinationwithchemotherapyLowPD-L1expressionIncombinationwithotheragents

Targetedtherapies？BevacizumabImmunecheckpointinhibitorsOtherimmunotherapies免疫治療一線研發(fā)策略Primaryendpoint:Progression-freesurvival(independentradiologyreviewcommittee)inpatientswithstronglyPD-L1positivetumors535patientsNivolumab3mg/kgi.v.every2weeks(untildiseaseprogression,unacceptabletoxicity,withdrawalofconsentorstudyclosure)Chemotherapy(investigator'schoice,upto6cycles)vsPembrolizumabasfirst-linetherapy

inpatientswithhighlevelsofPD-L1

KEYNOTE-024Merck‘sKEYTRUDA?(pembrolizumab)demonstratessuperior-progression-freesurvivalandoverallsurvivalcomparedtochemotherapyasfirst-linetherapyinpatientswithadvancednon-smallcelllungcance.rPressrelease,Thursday,June16,20166:45amEDT34%ofPatientswereTPS＜1%KEYNOTE-021(phaseⅠ/Ⅱ):studydesignStageIIIB/IVNSCLCNosystemictherapyforrecurrentdiseaseECOGPS0-1(n=308)CohortA:Pembrolizumab+carboplatin+paclitaxel(n=25)CohortB:Pembrolizumab+carboplatin+paclitaxel+bevacizumab(n=25)CohortC:Pembrolizumab+carboplatin+pemetrexed(n=25)MaintenancepembrolizumabMaintenancepembrolizumab+bevacizumabMaintenancepembrolizumab+pemetrexedPembrolizumabdose:2or10mg/kgi.v.q3w;Carboplatindose:AUC6i.v.(cohortAandB),AUC5i.v.(cohortC);Paclitaxeldose:200mg/m2i.v.q3w;Bevacizumabdose:15mg/kgi.v.q3w;Pemetrexeddose:500mg/m2i.v.q3wPrimaryendpointORRSecondaryendpointOSPFSDoRGadgeel,etat.ASCO2016KEYNOTE-021:ResponseCohortA:Pembrolizumab+carboplatin+paclitaxel(n=25)CohortB:Pembrolizumab+carboplatin+paclitaxel+bevacizumab(n=25)CohortC:Pembrolizumab+carboplatin+pemetrexed(n=25)*ParientswithTPS≥50%Gadgeel,etat.ASCO2016KEYNOTE-021:OSKEYNOTE-021:OSNR=notreachedGadgeel,etat.ASCO2016CheckMate012StudyDesign:NivolumabPlusIpilimumabinFirst-lineNSCLCPrimaryendpoint:safetyandtolerabilitySecondaryendpoints:ORR(RECISTv1.1)andPFSrateat24wksExploratoryendpoints:OS;efficacybyPD-L1expressionStageIIIB/IVNSCLC(anyhistology);nopriorchemotherapyforadvanceddisease;ECOGPS0or1Nivo3mg/kgIVQ2WuntildiseaseprogressionorunacceptabletoxicityaNivo1mg/kgIVQ3Wx4+Ipi1mg/kgIVQ3Wx4Nivo1mg/kgIVQ2W+Ipi1mg/kgIVQ6WNivo3mg/kgIVQ2W+Ipi1mg/kgIVQ12WNivo3mg/kgIVQ2W+Ipi1mg/kgIVQ6WUntildiseaseprogressionorunacceptabletoxicityaHere,wereportresultsfromnewcohortsexploredtopermitsynergisticactivityandacceptablesafetyprofileofcombinationtreatmentwithnivolumabandipilimumabaPatientstoleratingstudytreatmentpermittedtocontinuetreatmen