肺癌靶向治療-3

肺癌靶向治療交大醫(yī)學(xué)院附屬第三人民醫(yī)院腫瘤科姜斌EvolutionofknowledgeinNSCLC腺鱗大細(xì)胞傳統(tǒng)認(rèn)識(shí)KRASUnknow1987KRASEGFRUnknow2019Unknow2009LungCancerMutationConsortiumIncidenceofSingleDriverMutationsMutationfoundin54%(280/516)oftumorscompletelytested(CI50-59%)Krisetal.ASCO2019ALKfusion(StageIVNSCLC)EGFRMt女，腺癌KRASMt女，腺癌女，腺癌

TargetedTherapiesErlotinibBevacizumabSunitinibSorafenibSorafenibChemotherapyPanitumumabCetuximabTemsirolimusInhibitionofprogrammedcelldeath(apoptosis)TumorcellproliferationTumorcellinvasionmetastasisDevelopmentoftumorvasculature(angiogenesis)

EpidermalGrowthFactorReceptor(EGFR)&HumanCancerEGFRcriticallyregulatestumorcelldivision,proliferation,repairEGFRmayplayacriticalroleinmetastasis,angiogenesis,invasionBindingofspecificligandstoEGFR(eg,EGF,TGF-a)activatesthereceptorandtriggerssignaltransductioncascadesthataffectcellproliferationEGFRisexpressedinasignificantpercentageofhumantumorsandiscorrelatedwithpoorprognosis,decreasedsurvival,and/orincreasedmetastasisInhibitionofEGFRontumorcellsmayinhibitthegrowthorprogressionofEGFR-expressingtumorsTKIntracellularareaTransmembranousareaExtracellularareaEGFRstructureActivatingEGFRmutationsEGFR

mutationsareobservedin4exonsoftheEGFRgen;exon18tot21TyrosineKinaseDomeinExon18-24Exon18EGFRGeneExon19Exon20Exon21G719CG719SG719A5%DelE746-A750DelE746_S752>VDelE746_T751>ADelE746_T751DelL747_A750>PDelL747_E749DelL747_P753>QDelL747_P753>SDelL747_S752DelL747_T751>PDelL747_T751DelS752_I759&additionaldeletions~45%T790MD770_N771(insNPG)D770_N771(insSVQ)D770_N771(insG)S768I~5%L858RL861Q~45%Lynchetal.,2019Paezetal.,2019Sharmaetal.,2019HirschandBunn,2009RandomizedstudiesconfirmingtheroleofEGFRTKIasfirstlinetherapy

AuthorStudyN(EGFRmut+)RR(TKIvsChemo)PFS(HR,95%CI)MoketalIPASS26171.2%vs47.3%0.48(0.36,0.64)LeeetalFirst-SIGNAL4284.6%vs37.5%0.61(0.31,1.22)MitsudomietalWJTOG340519862.1%vs32.2%0.49(0.34,0.71)KobayashietalNEJGSG00217774.5%vs29%0.36(0.25,0.51)ZhouetalOPTIMAL15483%vs36%0.16(0.10,0.26)RosellEURTAC17458%vs15%0.37(0.25,0,54)MoketalNEJM2009,LeeetalWCLC2009,MitsudomietalESMO2009,KobayahsietalASCO2009,Zhouetal.Lancet201904812162024TimeFromRandomization(Months)0.00.20.40.60.81.0ProbabilityofPFSGefitinibEGFRM+(N=132)

GefitinibEGFRM–(N=91)

Carboplatin/paclitaxelEGFRM+(N=129)Carboplatin/paclitaxelEGFRM–(N=85)HR<1impliesalowerriskofprogressionintheM+groupcomparedwiththeM–group.IPASS:PFSbyEGFRMutationStatusWithinTreatmentArmsGefitinib,HR=0.19;P<0.0001

Carboplatin/paclitaxel,HR=0.78;P=0.1103

AdaptedwithpermissionfromMok.NEnglJMed.2009;361:947;Mok.ESMO.2019(abstrLBA2).M=mutation.EGFRKinaseInhibitorsClinicalactivityinEGFRmutantNSCLC1,21stlineresponserate:60%-80%1stlineprogressionfreesurvival10–14monthsGefitinibanderlotinibsuperiorto1stlinechemotherapy1,3HigherRRandlongerPFS;noOSimprovementBettertoxicityprofileHowever–resistancedevelopsinmostifnotallpatients1Moketal.NEJM2009;2Roselletal.NEJM2009;3Zhouetal.LancetOncol2019EGFR突變特點(diǎn)腺癌女性不吸煙亞洲最常見(jiàn)的藥物敏感性突變：Exon19del（LREAdeletion），L858R原發(fā)性耐藥與KRAS突變和ALK基因重排有關(guān)KRAS突變、ALK基因重排與EGFR突變互相排斥繼發(fā)性耐藥：T790M(50%),組織類(lèi)型轉(zhuǎn)變（向sclc轉(zhuǎn)變）ResistantEGFRmutationsSequistetal,SciTranslMed20193:75ra26T790M(49%)EGFPampUnknowmechemism30%METamp(5%)SCLCtransformation(49%)PIK3CA(5%)非鱗癌EGFR突變檢測(cè)（1類(lèi)）純鱗癌不建議EGFR突變檢測(cè)，除非患者從來(lái)不吸煙或者病理來(lái)自少量活檢標(biāo)本因?yàn)榛顧z標(biāo)本很難區(qū)分腺鱗癌和鱗癌EML4-ALKTranslocationsinNSCLC

EML4-ALKtranslocationEML4-ALKfusionsresultfromsmallinversionswithintheshortarmofchromosome2.Ninevariantsaredescribes.EML4-ALKtranslocation2–7%inunselectedNSCLC，30%inselectedNSCLCFequencyincreasesinAdenocarcinomasYoungadultsNever-smokers(<100cigarettesinlifetime)Light-smokers(<15pack-years)TumoursharboringwildtypeEGFRandKRASCrizotinibleadstoRR＞60%，improvesurvivalALK-fusionpositivelungtumorsresistanttogefitinibanderlotinibKoivunenetal.CCR14(13):2019;Shawetal.ASCO2019Abstract7507;Krisetal.onbehalfofLCMCinvestigators,ASCOJune2019Abstract#CRA7506

棘皮動(dòng)物微管相關(guān)蛋白樣4（EML4）-間變性淋巴瘤激酶（ALK）融合基因，由位于2號(hào)染色體的棘皮動(dòng)物微管相關(guān)蛋白樣4（EML4）基因斷裂、插入位置相對(duì)保守的間變淋巴瘤激酶(ALK)的細(xì)胞內(nèi)酪氨酸激酶結(jié)構(gòu)域、導(dǎo)致產(chǎn)生EML4-ALK融合蛋白，活化PI3K-AKT和MAPK-ERK通路。可見(jiàn)于約2%~7%的非小細(xì)胞肺癌中，但在年輕、不吸煙或少量吸煙的腺癌（多為印戒細(xì)胞亞型）患者中高達(dá)20%~30%，且與EGFR和/或K-RAS突變相互排斥、與晚期EGFRTKI治療抗拒密切相關(guān)Crinoetal.ASCO2019Abstract7514PhaseIIcrizotinibinALK-positiveNSCLCCrinoetal.ASCO2019Abstract7514BestresponseORR 51.1%SD 34%DCR week6 85% week12 74%PD 7.5%TumorresponseCrizotinibwasFDAapprovedforuseinpre-treatedEML4ALKpatients.AdaptedfromPoonRT,etal.JClinOncol2019;19:1207–25Angiogenesisisinvolvedthroughouttumourformation,growthandmetastasisStagesatwhichangiogenesisplaysaroleintumourprogressionPremalignantstageMalignanttumourTumour

growthVascular

invasionDormant

micrometastasisOvert

metastasis(Avasculartumour)(Angiogenic

switch)(Vascularised

tumour)(Tumourcell

intravasation)(Seedingin

distantorgans)(Secondaryangiogenesis)Summary:mechanism

ofactionofanti-VEGFtherapyInhibitionofVEGFmayactagainsttumoursinthreewaysregressionofexistingmicrovasculaturenormalisationofmaturevasculatureinhibitionofproductionofnewvasculatureEARLYBENEFITCONTINUEDBENEFITRegressionofexistingmicrovasculatureNormalisationofsurvivingmicrovasculatureInhibitionofvesselregrowthandneovascularisationBevacizumab

VEGFR-2VEGFR-1PPPPPPPPEndothelVEGFAnti-VEGFantibody(Bevacizumab)Prestaetal.CancerRes.2019;57:4593.PhaseIIItrialofbevacizumabinNSCLC

(ECOG4599):studydesignPrimaryobjective:toassessoverallsurvivalinpatientswithadvancednon-squamousNSCLCtreatedwithCP(carboplatin/paclitaxel)versusCP+bevacizumabSecondaryobjective:toassessresponserates,timetoprogressionandtoxicityPreviouslyuntreatedstageIIIB/IVnon-squamousNSCLC(n=878)CP

6(n=444)Bevacizumab(15mg/kg)every3weeks+CP

6(n=434)PD*PD*NocrossoverwillbepermittedBevacizumabevery

3weeksuntilprogressionSandlerA,etal.JClinOncol2019;23(Suppl16PtI):2s(Abs.4)PhaseIIItrialofbevacizumabinNSCLC

(ECOG4599):keyeligibilitycriteriaChemotherapy-na?vestageIIIB(pleuralorpericardialeffusiononly)orstageIVnon-squamousNSCLCMeasurableornon-measurablediseaseECOGPS0–1INR<1.5andaPTTnogreaterthanupperlimitsofnormalwithin1weekpriortorandomisationNohistoryofthromboticorhaemorrhagicdisordersNogrosshaemoptysis(definedasbrightredbloodofa1/2teaspoonormore)BrainmetastaseswerenotallowedSandlerA,etal.JClinOncol2019;23(Suppl.16PtI):2s(Abs.LBA4)PhaseIIItrialofbevacizumabinNSCLC

(ECOG4599):patientpopulation9091Caucasian5058Male4038ECOGPS04344Age

65years2828Priorweightloss

5%9191Measurabledisease1314StageIIIBCP+bevacizumabn=424(%)

CP

n=431(%)SandlerA,etal.JClinOncol2019;23(Suppl.16PtI):2s(Abs.LBA4)PhaseIIItrialofbevacizumab

inNSCLC(E4599):efficacyCPCP+bevacizumabpvalue(HR)Completeresponse,n(%)0(0)5(1.4)Partialresponse,n(%)35(10)92(25.8)Overallresponserate,n(%)35(10)97(27.2)<0.0001MedianOS(months)10.212.50.007(0.77)MedianPFS(months)4.56.4<0.0001(0.62)SandlerA,etal.JClinOncol2019;23(Suppl.16PtI):2s(Abs.4)ECOG4599-SurvivalSandleretal.ASCO2019;23:LBA4.0.00.20.40.60.81.0363024181260%16.9%43.7%22.1%51.924ay12ayAyProbabilityMedyan:10.2,12.5PCBPCHR:0.77(0.65,0.93)P=0.007ECOG4599-PFS3630241812600.00.20.40.60.81.0MtsProbability%6.4%32.6%14.6%55.012mts6mtsMedian:4.5,6.4PCBPCHR:0.62(0.53,0.72)Sandleretal.ASCO2019;23:LBA4.P<0.0001PhaseIIItrialofbevacizumabinNSCLC

(ECOG4599):haematologicaltoxicity*IncludesonedeathoneacharmduetoneutropenicfeverCP

(n=427)

Grade4CP+bevacizumab

(n=420)

Grade4

pvalueNeutropenia(%) 16.4240.006Thrombocytopenia(%)01.4

0.01Anaemia(%) 0.70NSFebrileneutropenia(%) 1.9*3.3*NSSandlerA,etal.JClinOncol2019;23(Suppl.16PtI):2s(Abs.LBA4)PhaseIIItrialofbevacizumabinNSCLC

(ECOG4599):non-haematologicaltoxicity

CP

n(%)

>Grade3

CP+bevacizumab

n(%)

>Grade3

pvalue

Haemorrhage

Haemoptysis

CNS

GI

Other

3(0.7)1(0.2)02(0.5)1(0.2)19(4.5)8(1.9)4(1.0)5(1.2)4(1.0)<0.0010.040.03

NS

NSHypertension

3(0.7)25(6.0)<0.001Venousthrombosis

13(3.0)16(3.8)

NSArterialthrombosis

4(1.0)8(1.9)

NSSandlerA,etal.JClinOncol2019;23(Suppl.16PtI):2s(Abs.LBA4)PhaseIIItrialofbevacizumabinNSCLC

(ECOG4599):treatment-relateddeathsCP

(n=427)

CP+bevacizumab

(n=420)

Haemorrhage

Haemoptysis

GIbleed

01

52Neutropenicfever

11Total

28SandlerA,etal.JClinOncol2019;23(Suppl.16PtI):2s(Abs.LBA4)PhaseIIItrialofbevacizumabinNSCLC

(ECOG4599):conclusionsTheadditionofbevacizumab(15mg/kgevery3weeks)toCPimprovesOS,RRandPFSinpatientswithNSCLCIncertainpatients,bevacizumabplusCPisassociatedwithlife-threateningandfatalhaemorrhageeventisassociatedwithsquamouscellhistologypatientswithsquamouscellNSCLCexcludedfromongoingtrialsBevacizumabinfirst-lineadvancedNSCLCBevacizumabisthefirstnovelagentcombinedwithstandardchemotherapytosignificantlyimproveoverallsurvivalinunselectedpatientswithadvancedNSCLCinthefirst-linesettingBevacizumabplusCPisnowtheECOGreferencestandardforthefirst-linetreatmentofadvancednon-squamousNSCLCNCCN：NSCLC靶向治療NSCLC（Metastaticdisease）

腺癌、大細(xì)胞癌、NSCLC-NOSPS0-1，EGFR無(wú)突變，ALK(-)一線治療：貝伐單抗+化療(2A類(lèi))；

愛(ài)必妥+長(zhǎng)春瑞濱+順