免疫检查点抑制剂反应的预测因子PD-L1

DavidR.Spigel,MDChiefScientificOfficerDirector,LungCancerResearchProgramSarahCannonResearchInstituteNashville,TennesseePredictorsofResponsetoImmuneCheckpointInhibitors:PD-L1SupportedbyeducationalgrantsfromBristol-MyersSquibbandFoundationMedicine.AboutTheseSlidesPleasefeelfreetouse,update,andsharesomeoralloftheseslidesinyournoncommercialpresentationstocolleaguesorpatientsWhenusingourslides,pleaseretainthesourceattribution:Theseslidesmaynotbepublished,postedonline,orusedinc[e-mail]:clinicaloptions.comExpertFacultyScottKopetz,MD,PhD,FACPAssociateProfessor,DepartmentofGastrointestinalMedicalOncologyTheUniversityofTexasMDAndersonCancerCenterHouston,TexasJasonN.Rosenbaum,MDAssistantProfessor,DepartmentofPathologyandLaboratoryMedicineUniversityofPennsylvaniaHospitaloftheUniversityofPennsylvaniaPhiladelphia,PennsylvaniaDavidR.Spigel,MDChiefScientificOfficerDirector,LungCancerResearchProgramSarahCannonResearchInstituteNashville,TennesseeFacultyDisclosuresThefacultyreportedthefollowingfinancialrelationshipsorrelationshipstoproductsordevicestheyortheirspouse/lifepartnerhavewithcommercialinterestsrelatedtothecontentofthisCMEactivity:ScottKopetz,MD,PhD,FACP,hasdisclosedthathehasownershipinterestinNavireandhasreceivedconsultingfeesfromAmalTherapeutics,Amgen,BoehringerIngelheim,HolyStone,Lilly,Merck,Navire,Novartis,Roche,andSymphogen.JasonN.Rosenbaum,MD,hasdisclosedthathehasreceivedconsultingfeesfromBayer,Bristol-MyersSquibb,andGenentech.FacultyDisclosuresDavidR.Spigel,MD,hasdisclosedthathehasreceivedconsultingfeespaidtohisinstitutionfromAbbVie,Aeglea,Amgen,ARMO,AstraZeneca,BoehringerIngelheim,Bristol-MyersSquibb,Celgene,Evelo,FoundationMedicine,Genentech/Roche,GlaxoSmithKline,Illumina,Ipsen,Lilly,Merck,Millennium,ModernaTherapeutics,Nektar,Novartis,PharmaMar,Pfizer,PrecisionOncology,andTakedaandfundsforresearchsupportgrantedtohisinstitutionfromAbbVie,Acerta,Astellas,AstraZeneca,BoehringerIngelheim,Bristol-MyersSquibb,Celgene,CellDex,ClovisOncology,DaiichiSankyo,EMDSerono,FoundationMedicine,G1Therapeutics,GlaxoSmithKline,GRAIL,Lilly,Merck,NeonTherapeutics,Nektar,Novartis,Oncogenex,Pfizer,Takeda,Tesaro,andTransgene.PD-L1andtheTumorMicroenvironmentBoussiotis.NEJM.2016;375:1767.Slidecredit:clinicaloptions.comImagenotavailablePD-L1ExpressioninNSCLCSamplesGaron.NEJM.2015;372:2018.Slidecredit:clinicaloptions.comPD-L1ExpressionandBenefitWithPembrolizumabFromBiomarkerAnalysisinPhaseIKEYNOTE-001Garon.NEJM.2015;372:2018.Slidecredit:clinicaloptions.comPatientsatRisk,n119925622543016111958156400765533800001008060402000481216202428OS(%)MosPS1-49%PS1%PS≥50%PSMedianOS,Mos(95%CI)≥50%NR(13.7-NR)1-49%8.8(6.8-12.4)1%8.8(5.5-12.0)KEYNOTE-024:BenefitofImmunotherapyvsChemotherapyinPD-L1+NSCLCReck.NEJM.2016:375;1823.Slidecredit:clinicaloptions.comAnopen-labelphaseIIItrialin305patientswithuntreatedadvancedNSCLCandPD-L1expressionon≥50%oftumorcellsPembro(n=154)CT(n=151)MedianPFS,mos10.36.0HR:0.50(95%CI:0.37-0.68;P.001)1519970189100102030405060708090100036912151810489442231154MosPFS(%)PatientsatRisk,n62%50%48%15%KEYNOTE-024:BenefitofImmunotherapyvsChemotherapyinPD-L1+NSCLCReck.NEJM.2016:375;1823.Slidecredit:clinicaloptions.comPembro(n=154)CT(n=151)MedianOS,mosNRNRHR:0.60(95%CI:0.41-0.89;P=.005)01020304050607080901000369121518211361218239110154151123106643470MosPatientsatRisk,n1280%72%70%54%OS(%)PD-L1ExpressionandORRtoImmunotherapyCallahan.ASCO2014.Slidecredit:clinicaloptions.comNivolumab Solid Tumors (Topalian et al. NEJM 2012)Nivolumab Melanoma (Weber ASCO 2013)Nivolumab Melanoma (Grosso et al. ASCO 2013)MPDL3280a Solid Tumors (Herbst et al ASCO 2013)MPDL3280a Melanoma (Hamid et al ASCO 2013)MPDL3280a NSCLC (Sorial et al ECC 2013)Pembrolizumab Melanoma (Daud et al AACR 2014)Pembrolizumab NSCLC (Gandhi et al AACR 2014)MPDL3280a Bladder (Powels et al ASCO 2014)Pembrolizumab Head & Neck (Selwert et al ASCO 2014)Pembrolizumab Melanoma (Ribas et al ASCO 2014)n= 4244349430531131296555411Response RatesUnselected21%32%29%22%23%23%40%19%26%18%40%PD-L1 +36%67%44%39%27%46%49%37%43%46%49%PD-L1 −0%19%17%13%20%15%*13%11%11%11%13%PrevalenceofPD-L1ExpressioninVariousTumorTypesHerbst.Nature.2014:515;563.Slidecredit:clinicaloptions.comPD-L1prevalencedeterminedusingIHCanddefinedas5%oftumor-infiltratingimmunecells(ICs)ortumorcells(TCs)stainingPD-L1ScoringIHCScoring:%TPSTumorproportionscoreTCvsICTumorcellvsinfiltratingimmunecellCPSPD-L1positivitywasbasedonacombinedpositivescore(CPS)≥1.CPSisdeterminedbythenumberofPD-L1stainingcells(tumorcells,lymphocytes,macrophages)dividedbytotalnumberoftumorcellsevaluated,multipliedby100Herbst.Nature.2014:515;563.Slidecredit:clinicaloptions.comPD-L1ExpressionIsHeterogeneousMcLaughlin.JAMAOnc.2016:2;46.McLaughlin,unpublisheddata.Slidecredit:cl