不一樣的時(shí)代ALK陽性非小細(xì)胞肺癌全程管理

不一樣的時(shí)代ALK+非小細(xì)胞肺癌患者全程管理馬學(xué)真青島市中心醫(yī)院ALK陽性晚期NSCLCSodaetal.,Nature,448,561-6(2007)ResponseratetoSOCALK+(n=15)EGFRmt(n=25)WT/WT(n=49)Chemo(Ptdoublet)EGFR-TKI25%0%50%70%35%13%Leeetal.Cancer,118,3579-86(2012)Shawetal.J.Clin.Oncol.,27,4247-4253(2009)KRASBRAFV600EGeneticalterationsinNSCLC(DFCI:2002~2014)ALKOthersROS1EGFRSacheretal.,JAMAoncol,2,313-20(2016)(5%)DriveroncogenesKinasedomainALK抑制劑問世前，化療方案效果不好ALK+患者的OS較短ALK通路及藥物發(fā)展簡史1.Dearden,etal.AnnOncol2013;2.Gridelli,etal.CancerTreatRev20143.Hallberg,etal.NatRevCancer2013;4.Rikova,etal.Cell2007;5.Soda,etal.Nature2007;6.AmericanCancerSociety20137.Torre,etal.CACancerJClin2015;8.Perez,etal.LungCancer;9/Lancet.2016;388(10048):1012-24.2011(Aug)Crizotinib,approvedforadvancedALK+NSCLC2014(Jul)AlectinibapprovedinJapan2013(Jun)FDAgrantedAlectinibBTDforALK+NSCLCpatientswhohaveprogressedoncrizotinib2007EML4–ALKfusiondiscoveredinNSCLC2015(Dec)AlectinibFDAapprovalforALK-positiveNSCLCprogressingon/orintoleranttocrizitinib2016(Sep)FDAgrantedAlecensa2ndBTDfor1LALK+NSCLC2017(Feb)AlectinibapprovedinEU(Crizotinibfailure)2017(May)CeritinibFDA1Lapproval2014(Apr)CertinibFDAapprovedforALK-positive,crizotinibresistantNSCLCCrizotinibAlectinibCertinib2017(Nov)AlectinibFDA1Lapproval(Dec)AlectinibEMA1Lapproval2018(Jun)CeritinibCFDA2Lapproval2013(Jan)Crizotinib,approvedinChina2017(Apr)BrigatinibFDAAccelarateapprovalforALK-positiveNSCLCprogressingon/orintoleranttocrizitinibBrigatinib2018(Aug)AlectinibCFDAapproval三代ALK抑制劑發(fā)展之路CeritinibCrizotinib不同的酪氨酸激酶域結(jié)合模式

對(duì)ALK耐藥突變的敏感性AlectinibKodamaetal.MolCancerTher(2014)Lorlatinib促進(jìn)ALK結(jié)合活性脂溶性增加，促進(jìn)CNS暴露對(duì)二代耐藥突變有效Brigatinib指南推薦的一線治療藥物（NCCN2018v3）細(xì)胞信號(hào)激酶ALKKDRSRCINSREGFR2ABLIGF1RPDFGRβMETRONEGFRHER2KITCDK1PKAMEK1PKCαRaf-1AKT1PKCβ1AuroraAJAK1CDK2PKCβ2ROS1RETIC50(nM)10,0001,000100101CeritinibROS1IGF1RALKKDRSRCINSRFGFR2ABLIGF1RPDFGRβMETRONEGFRHER2KITCDK1PKAMEK1PKCαRaf-1AKT1PKCβ1AuroraAJAK1CDK2PKCβ2ROS1RETIC50(nM)AKT2AKT310,0001,000100101AlectinibALKKDRSRCINSREGFR2ABLIGF1RPDFGRβMETRONEGFRHER2KITCDK1PKAMEK1PKCαRaf-1AKT1PKCβ1AuroraAJAK1CDK2PKCβ2ROS1RETIC50(nM)10,0001,000100101METROS1Crizotinib首個(gè)在頭對(duì)頭III期研究中證實(shí)優(yōu)于另一種TKI藥物的靶向治療藥物CrizotinibCeritinibAlectinibIII期研究PROFILE1014、1029克唑替尼優(yōu)于化療ASCEND4Ceritinib優(yōu)于化療ALEX、J-ALEXAlectinib優(yōu)于克唑替尼CFDA適應(yīng)癥2013年1月（全線）2018年6月1日2018年8月17日高效選擇性ALK抑制劑PROFILE1014:克唑替尼對(duì)比化療的三期臨床研究

AE=adverseevent;PFS=progression-freesurvival;GI=gastrointestinal;HR=hazardratioSolomon,etal.NEnglJMed20146HR=0.45(95%CI:0.35–0.60)p<0.001Crizotinib(n=172)Chemotherapy(n=171)PFSprobabilityTime(months)102030515257.010.90.80.60.40.201.0035Efficacy與化療相比，克唑替尼表現(xiàn)出了高有效性和安全性，視覺障礙和消化道的副反應(yīng)是克唑替尼最常見的AEsVision

disordersDiarrhoeaOedemaVomitingConstipationAST

increasedSafety%ofpatientswithAEs克唑替尼對(duì)比化療的PFSSoc=StandardofcareSolomon,etal.NEnglJMed20147MedianPFS(months)克唑替尼

(PROFILE10141)

化療

(PROFILE10141)7.010.9PFS*克唑替尼通過PROFILE1014的研究成功取代了化療，成為ALK陽性非小細(xì)胞肺癌一線標(biāo)準(zhǔn)治療方案塞瑞替尼(n=115)化療

(n=116)HR=0.49(0.36–0.67)p<0.001ASCEND-5:塞瑞替尼治療克唑失敗之后的ALK+患者1.00.80.60.40.200時(shí)間(月)PFS24612181.6Shaw,etal.LancetOncol2017培美曲塞或多西他賽

i.v.q3wR1:1塞瑞替尼

750mg/dayIIIB/IV期NSCLCFISH檢測ALK+曾接受過克唑替尼和含鉑雙藥方案治療)據(jù)RECIST1.1標(biāo)準(zhǔn)，≥1個(gè)可測量病灶(n=236)5.4ASCEND-4:塞瑞替尼對(duì)比化療的三期臨床研究

ALT=alaninetransaminase;AST=aspartatetransaminase;GGT=gamma-glutamyltransferase;

GI=gastro-intestinalSoria,etal.LancetOncol20179Ceritinib(n=189)Chemotherapy(n=187)HR=0.55(95%CI:0.42–0.73)Log-rankp<0.000011.00.80.60.40.200Time(months)PFSestimate961824331521303122716.68.136Efficacy塞瑞替尼相比化療同樣表現(xiàn)出了非常好的療效但是塞瑞替尼具有較高的胃腸道副反應(yīng)以及較強(qiáng)的肝毒性SafetyDiarrhoeaNauseaVomitingALT

increaseAST

increaseGGT

increase%ofpatientswithAEsALK+NSCLC患者的1L治療現(xiàn)狀*AdaptedandupdatedfromFerreraetal,20183.Forillustrationpurposesonly;notethatcross-trialcomparisonsshouldbeinterpretedwithcautionduetodifferencesinstudydesign,size,patientpopulationanddatamaturity1.Solomon,etal.NEnglJMed2014;2.Soria,etal.LancetOncol2017

4.Ferrara,etal.JThorac.Oncol201810克唑替尼

(PROFILE10141)塞瑞替尼

(ASCEND-42)MedianPFS(months)

塞瑞替尼為ALK+NSCLC提供了另一個(gè)一線治療的可選方案塞瑞替尼在與化療的對(duì)比的臨床研究中體現(xiàn)出了更長的PFS值化療

(PROFILE10141)7.0

化療

(ASCEND-42)8.110.916.6PFS*

Ceritinib

(ASCEND-5)25.4Brigatinib：

克唑替尼治療失敗患者的II期研究（ALTA）局部晚期或轉(zhuǎn)移性ALK+NSCLC既往克唑替尼失敗腦轉(zhuǎn)移患者可入組ECOGPS0–2(n=222)R

1:1ArmA

Brigatinib90mgQD*

(n=112)ArmB

Brigatinib180mgQD§

(n=110)Brigatinib:180mgQD*

(n=110)Brigatinib:90mgQD

(n=112)ProbabilityofPFS(%)100806040200012636Time(months)1824309.2(7.4–11.1)15.6(11.1–19.4)HR=0.64(0.45–0.91)首要研究終點(diǎn)ORR（研究者評(píng)估）：46%

vs.55%ALTA-1L研究（III期，ALK初治vs克唑替尼）進(jìn)行中

Ahn,etal.WCLC2017目前FDA批準(zhǔn)的所有ALK抑制劑臨床研究結(jié)果

*AdaptedandupdatedfromFerreraetal,20187.Forillustrationpurposesonly;notethatcross-trialcomparisonsshouldbeinterpretedwithcautionduetodifferencesinstudydesign,size,patientpopulationanddatamaturity

NR=notreached*BrigatinibnotyetappriovedinEU1.Solomon,etal.NEngJMed2014;2.Shaw,etal.Lancet2017

3.Novello,etal.AnnOncol2018;4.Huber,etal.ASCO2018

5.Soria,etal.LancetOncol2017;6.Camidge,etal.ASCO2018

7.Ferrara,etal.JThorac.Oncol201812PFS:1LALKiPFS:2LALKiCrizotinib

(PROFILE10141)10.95.410.9Alectinib

(ALUR)39.610.9Brigatinib*

(ALTA-2)415.6塞瑞替尼

(ASCEND-45)16.6MedianPFS(months)

5.4Ceritinib

(ASCEND-5)2Brigatinib已經(jīng)在ALKTKI的二線治療中體現(xiàn)出了非常好的療效一線治療的效果值得期待

化療

(PROFILE10141)7.0ALK+NSCLC患者有更多切實(shí)的需求13阿來替尼是否能給患者更多。。。?！?更高的有效率.…更好的安全性和耐受性….對(duì)于腦轉(zhuǎn)移病灶更好的療效ALEX研究

阿來替尼對(duì)比克唑替尼III期臨床研究阿來替尼600mgBID克唑替尼250mgBIDR1:1關(guān)鍵入選標(biāo)準(zhǔn)晚期或轉(zhuǎn)移性ALK+NSCLCALK+中心實(shí)驗(yàn)室IHC檢測初治ECOGPS0?2可測量病灶允許無癥狀腦轉(zhuǎn)移（n=303）直至PD*、

無法耐受的副作用、退出研究，或死亡主要終點(diǎn)PFS（研究者評(píng)估）12分層因素

基線是否存在CNS轉(zhuǎn)移（是vs否）亞裔vs非亞裔ECOG(0–1vs2)次要終點(diǎn)ORRDoROSPFS(IRC)CNSORR安全性至CNS進(jìn)展時(shí)間(IRC)

*孤立性無癥狀性CNS進(jìn)展患者，允許繼續(xù)治療至出現(xiàn)全身性或癥狀性CNS進(jìn)展BID=每天兩次;DoR=緩解持續(xù)時(shí)間IHC=免疫組化;IRC獨(dú)立評(píng)審委員會(huì);ORR=客觀緩解率;OS=總生存期Peters,etal.NEnglJMed2017療效突破

阿來替尼中位PFS達(dá)到空前的34.8個(gè)月，且顯著降低進(jìn)展風(fēng)險(xiǎn)達(dá)57%阿來替尼(n=152)克唑替尼(n=151)34.8(17.7–NE)10.9(9.1–12.9)020406080100061218243036時(shí)間（月）預(yù)估PFS(%)克唑替尼(N=151)阿來替尼

(N=152)PFS事件數(shù),n(%)116(77)72(47)中位PFS,months

(95%CI)10.9(9.1–12.9)34.8(17.7–NR)數(shù)據(jù)截至2017.12.1進(jìn)展風(fēng)險(xiǎn)降低57%HR=0.43(95%CI0.32-0.58)INV主要終點(diǎn)：PFS數(shù)據(jù)截止日期：2017年12月1日NE：不可評(píng)估Takiguchi,etal.ASCO2017；Petersetal,NEJM2017Camidge,etal.ASCO2018Posternumber:9043ALEX研究：阿來替尼緩解率達(dá)82.9%，且有效患者腫瘤緩解深度更深療效突破

阿來替尼緩解率更高，且緩解深度更佳阿來替尼克唑替尼CamidgeDR,etal.2018ASCOAbstract9043.緩解率阿來替尼(n=152)克唑替尼(n=152)ORR，%CR，n(%)PR，n(%)82.9%7(5)119(78)75.5%3(2)111(73)腫瘤緩解深度>50%，n(%)腫瘤緩解深度>75%，n(%)114(90.5)55(43.7)73(64.0)29(25.4)阿來替尼在驅(qū)動(dòng)基因陽性NSCLC的PFS創(chuàng)造了一個(gè)新的高峰~20目前FDA批準(zhǔn)的所有ALK抑制劑臨床研究結(jié)果

*AdaptedandupdatedfromFerreraetal,20187.Forillustrationpurposesonly;notethatcross-trialcomparisonsshouldbeinterpretedwithcautionduetodifferencesinstudydesign,size,patientpopulationanddatamaturity

NR=notreached*BrigatinibnotyetappriovedinEU1.Solomon,etal.NEngJMed2014;2.Shaw,etal.Lancet2017

3.Novello,etal.AnnOncol2018;4.Huber,etal.ASCO2018

5.Soria,etal.LancetOncol2017;6.Camidge,etal.ASCO2018

7.Ferrara,etal.JThorac.Oncol201818PFS:1LALKiPFS:2LALKiCrizotinib

(PROFILE10141)10.95.410.9Alectinib

(ALUR)39.610.9Brigatinib*

(ALTA-2)415.6Ceritinib

(ASCEND-45)16.6Alectinib

(ALEX6)34.8MedianPFS(months)

5.4Ceritinib

(ASCEND-5)2Note:cross-trialcomparisonsshouldbeinterpretedwithcautionduetodifferencesinstudydesign,size,patientpopulationanddatamaturityALEX是第一個(gè)ALK靶向藥物頭對(duì)頭的三期臨床研究ALEX臨床研究很好的證明了ALK+NSCLC一線治療最優(yōu)選方案是阿來替尼指南推薦

阿來替尼是NCCN指南中標(biāo)注“優(yōu)選”的一線治療方案NCCN指南ALK一線優(yōu)先推薦NCCNGuidelines.Non-SmallCellLungCancerv4.2018.NCCN指南中對(duì)于ALK陽性非小細(xì)胞肺癌的指導(dǎo)PD=diseaseprogression;PD-L1=programmeddeathligand1NCCNNSCLCguidelinesV5.201820NCCN指南已經(jīng)明確指出，在對(duì)于ALK+的晚期非小細(xì)胞肺癌患者一線治療，阿來替尼是一線最優(yōu)選方案二線治療方案需要根據(jù)進(jìn)展模式進(jìn)行換藥orConsiderlocaltherapyContinue1LALKiStart2LALKi(onlyaftercrizotinibfailure)or

standardinitialcytotoxictherapyoptionsfor‘NSCLCwithnoactionablebiomarker’Start2LALKi

(onlyaftercrizotinibfailure)ALK+NSCLCPD1LALKiAlectinib(preferred)crizotinibceritinibAsymptomaticSymptomaticbrainmetastasesIsolatedsymptomaticsystemiclesionMultiplesymptomaticsystemiclesions1LALKi2LALKiceritinibalectinibbrigatinibConsiderlocaltherapyContinue1LALKi不同ALK抑制劑在不同線數(shù)使用的有效率的差異BrigatinibnotyetapprovedinEU1.Solomon,etal.NEnglJMed2014;2.Soria,etal.LancetOncol2017;3.Camidge,etal.ASCO2018

4.Shaw,etal.LancetOncol2017;5.Novello,etal.AnnOncol2018

6.Yang,etal.JThoracOncol2017;7.Ahn,etal.WCLC2017;8.Solomon,etal.WCLC20172110.91L2L3LResponserateALKiORRDoRCrizotinib74%111.3months1Certinib72%223.9months2Alectinib83%333.1months3ALKiORRCrizotinib

certinib39%4Crizotinib

alectinib36-51%5,6Crizotinib

brigatinib*55%7LineoftherapyEmergingagenttrialsongoing8在一線治療的時(shí)候ALKTKI藥物的有效率是最高的

克唑替尼、塞瑞替尼、阿來替尼三個(gè)藥物一線治療的基本相同，但是緩解時(shí)間差別非常大如何把最合適的藥物用在最合適的線數(shù)？才能讓患者最大的獲益三代ALKTKI:耐藥后治療是全程管理必須考慮內(nèi)容三代齊發(fā)，如何排兵布陣？三代ALK抑制劑Lorlatinib可能克服所有單一ALK突變耐藥Lorlatinib的臨床可及劑量可抑制幾乎所有單一ALK突變CancerDiscov.2018Jun;8(6):714-729.Lorlatinib耐藥克隆中出現(xiàn)的突變均為復(fù)合突變?nèi)鶤LK抑制劑Lorlatinib治療ALK+NSCLCPhaseII

（多亞組）Solomon,etal.WCLC2017主要臨床終點(diǎn)ORR顱內(nèi)ORRDLTs*PatientsinEXP6wereROS1+Abbreviationsinslidenotes次要臨床終點(diǎn)：DoRORRPFSOSDCRTTPPROsSafetyTTRPKMetastaticNSCLCALK+orROS1+diseaseconfirmedbyIHCorFISH(n=275)EXP1:treatmentna?ve(n=30)EXP2:priorcrizotinibonly(n=27)EXP3A:priorcrizotinib+1–2CT(n=32)EXP3B:priornon-crizotinibTKI±CT(n=28)EXP4:twopriorTKIs±CT(n=65)EXP5:threepriorTKIs±CT(n=46)EXP6*:any(n=47)[ROS1+]Lorlatinib

100mgQD需要III期頭對(duì)頭研究驗(yàn)證一線有效性NCT03052608(versus克唑替尼,1stline)SolomenBJ,etal.WCLC2017Lorlatinib治療ALK+NSCLC：phaseII初治隊(duì)列BestChangeFromBaseline(%)EXP2+3A(n=59)ORR,n/N(%)

(95%CI)41/59(69)(56,81)ICORR,n/N(%)

(95%CI)25/37(68)(50,82)MedianDOR,mo(95%CI)NR(11.1,NR)DOR≥6mo,n?/n(%)20/41(49)MedianPFS,mo

(95%CI)NR(12.5,NR)37patients(63%)hadbrainmetastasesatbaseline.OfftreatmentorPDoccurredCompleteresponsePartialresponseStablediseaseProgressivedisease(PD)706010030205040?10?20?30?40?50?60?70?80?90?100Intracraniala,bCI,confidenceinterval;CT,chemotherapy;DOR,durationofresponse;mo,months;NR,notreached.Lorlatinib治療ALK+NSCLC：

EXP2EXP3AEXP3B706010030205040?10?20?30?40?50?60?70?80?90?100Overalla,bORR69%經(jīng)克唑治療組EXP3B

(n=27)ORR,n/N(%)

(95%CI)9/27(33)(16,54)ICORR,n/N(%)

(95%CI)5/12(42)(15,72)MedianDOR,mo

(95%CI)NR(4.1,NR)DOR≥6mo,n?/n(%)3/9(33)MedianPFS,mo(95%CI)5.5(2.9,9.0)12patients(44%)hadbrainmetastasesatbaseline.ORR33%經(jīng)非克唑的ALK抑制劑治療組Intracraniala,bSolomenBJ,etal.WCLC2017EXP4+5(n=111)ORR,n/N(%)

(95%CI)43/111(39)(30,49)ICORR,n/N(%)

(95%CI)40/83(48)(37,59)MedianDOR,mo(95%CI)NR(5.5,NR)DOR≥6mo,n?/n(%)20/43(47)MedianPFS,mo

(95%CI)6.9(5.4,9.5)83patients(75%)hadbrainmet