肺癌靶向治疗-3

肺癌靶向治疗交大医学院附属第三人民医院肿瘤科姜斌EvolutionofknowledgeinNSCLC腺鳞大细胞传统认识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突变特点腺癌女性不吸烟亚洲最常见的药物敏感性突变：Exon19del（LREAdeletion），L858R原发性耐药与KRAS突变和ALK基因重排有关KRAS突变、ALK基因重排与EGFR突变互相排斥继发性耐药：T790M(50%),组织类型转变（向sclc转变）ResistantEGFRmutationsSequistetal,SciTranslMed20193:75ra26T790M(49%)EGFPampUnknowmechemism30%METamp(5%)SCLCtransformation(49%)PIK3CA(5%)非鳞癌EGFR突变检测（1类）纯鳞癌不建议EGFR突变检测，除非患者从来不吸烟或者病理来自少量活检标本因为活检标本很难区分腺鳞癌和鳞癌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

棘皮动物微管相关蛋白样4（EML4）-间变性淋巴瘤激酶（ALK）融合基因，由位于2号染色体的棘皮动物微管相关蛋白样4（EML4）基因断裂、插入位置相对保守的间变淋巴瘤激酶(ALK)的细胞内酪氨酸激酶结构域、导致产生EML4-ALK融合蛋白，活化PI3K-AKT和MAPK-ERK通路。可见于约2%~7%的非小细胞肺癌中，但在年轻、不吸烟或少量吸烟的腺癌（多为印戒细胞亚型）患者中高达20%~30%，且与EGFR和/或K-RAS突变相互排斥、与晚期EGFRTKI治疗抗拒密切相关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-naïvestageIIIB(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靶向治疗NSCLC（Metastaticdisease）

腺癌、大细胞癌、NSCLC-NOSPS0-1，EGFR无突变，ALK(-)一线治疗：贝伐单抗+化疗(2A类)；

爱必妥+长春瑞滨+顺