肺癌靶向治療-3

肺癌靶向治療交大醫(yī)學院附屬第三人民醫(yī)院腫瘤科姜斌EvolutionofknowledgeinNSCLC腺鱗大細胞傳統(tǒng)認識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突變特點腺癌女性不吸煙亞洲最常見的藥物敏感性突變：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%),組織類型轉變（向sclc轉變）ResistantEGFRmutationsSequistetal,SciTranslMed20193:75ra26T790M(49%)EGFPampUnknowmechemism30%METamp(5%)SCLCtransformation(49%)PIK3CA(5%)非鱗癌EGFR突變檢測（1類）純鱗癌不建議EGFR突變檢測，除非患者從來不吸煙或者病理來自少量活檢標本因為活檢標本很難區(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

棘皮動物微管相關蛋白樣4（EML4）-間變性淋巴瘤激酶（ALK）融合基因，由位于2號染色體的棘皮動物微管相關蛋白樣4（EML4）基因斷裂、插入位置相對保守的間變淋巴瘤激酶(ALK)的細胞內(nèi)酪氨酸激酶結構域、導致產(chǎn)生EML4-ALK融合蛋白，活化PI3K-AKT和MAPK-ERK通路?？梢娪诩s2%~7%的非小細胞肺癌中，但在年輕、不吸煙或少量吸煙的腺癌（多為印戒細胞亞型）患者中高達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、大細胞癌、NSCLC-NOSPS0-1，EGFR無突變，ALK(-)一線治療：貝伐單抗+化療(2A類)；

愛必妥+長春瑞濱+順