ASCO 2026：关键数据背后的创新趋势与价值判断ICYMI 6 Key Trends at ASCO 2026

ICYMI:6KeyTrends

atASCO2026

Heme:theCAR-Tvs.

bispecificsequencingquestion,plusin-vivoCAR-Tarrives

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Heme:CAR-TvsBispecificSequencingisThe

UnsolvedQuestion

Background:MyelomaandmultipleaggressiveB-celllymphomashavetwoapprovedT-cell-redirectingclasses;BsAbsandCARTs.Thechallengehasshiftedfromselectiontosequencing,asmostpatientsneedboth.Pivotaltrialsgenerallyexcludepriorsame-targetexposure,solimitedhead-to-headorsequencingdataexists,althoughreal-worldregistriesandguidelinesarestartingtofillthegap.

KeyASCO2026data:

•

PrimaryPhaseIIIdatafortheMajesTEC

-

9trial

(7507):Tecvayli(teclistamab;BCMA×CD3bispecific)inr/rMM

oMovesthebispecificearlierthanitsoriginal4L+accelerated-approvalsettingandprovesbenefitthere,butexcludedpriorBCMAexposuresotheorderagainstCAR-Tstaysuntested

•

SubgroupanalysisofthePhaseIIICARTITUDE

-

4

(7536):Carvykti(cilta-cel;BCMACAR-T)inlenalidomide-refractoryMM

oAlready-approvedbasedonthistrial;follow-upcementsCAR-T'searly-lineposition,butexcludedpriorCAR-Tandbispecificslimitssequencingvalue

•

UpdatedPhaseIIIfollow

-

upofthePhaseIIISUNMOtrial

(7007):Lunsumio(mosunetuzumab;CD20×CD3bispecific)plusPolivy(polatuzumabvedotin)intransplant-ineligible2L+r/rlargeB-celllymphoma

oMovesachemo-freebispecificcombinationearlier,andpermitspriorCAR-T,soitbeginstoinformthepost-CAR-Tsequencingquestionratherthanexcludingit

•

Real

-

worldanalysis

(7033)ofbispecificsvsCAR-Tinrelapsed/refractoryDLBCLandfollicularlymphoma

oBispecificsshowedlowerearlyimmune-mediatedtoxicityandlesshealthcareresourceuse,informingwhichmodalityispracticaltogivefirstratherthanwhichorderimprovessurvival

KOLsentimentatASCO2026:Acrossthesessions,KOLskeptreturningtothesameunresolvedquestions:howlongawashoutisneededbetweenabispecificandasubsequentCAR-T,whetherde-escalatedorfixed-durationbispecificdosingcanpreserveT-cellfitness,andhowtochoosewhenapatientneedsrapiddiseasecontrolversusthedeeper,one-timebenefitofCAR-T.TherewasdisagreementonwhetherbispecificsshouldeverprecedeCAR-T,andarecurringacknowledgementthatreal-worldpracticeisbeingdrivenasmuchbyaccess,fitness,andmanufacturinglogisticsasbyefficacy.

BeyondASCO2026:Inrelapsed/refractorymultiplemyeloma,IMWGguidanceandreal-worlddata(USMMImmunotherapyConsortium)favorusingCAR-Tbefore

BCMAbispecifics,sincerecentpriorbispecificexposureisassociatedwithreducedresponseandPFStosubsequentBCMAtherapy,thoughnotrialhasdirectlyproventheoptimalorder.Thelymphomapicturestaysmoremixed,asregistriessuchasDESCAR-TshowpriorbispecificbridgingdoesnotclearlycompromiselaterCAR-T.

3

Nextsteps:Thefieldisnowtestingsequencedirectlythroughpost-CAR-TbispecifictrialsinB-celllymphoma,includingColumviasconsolidationinR/RDLBCLafterCAR-T(PhIIGLORY),OrdsponofollowingCAR-Tinlater-line≥3LB-cellmalignancies(PhIELM-1),andEpkinlyin≥3LR/RLBCLincludingpost-CAR-Tpatients(PhI/IIEPCORENHL-1).AllpositionthebispecificafterCAR-T,reinforcingtheemergingCAR-T-firstorder,thoughtheywillrefinepost-CAR-Tstrategyratherthandelivera

definitivehead-to-headanswer.

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Heme:Next-GenerationCAR-Ts,InVivo

GenerationandEngineeredArchitectures

Background:ConventionalautologousCAR-Tispotentbutfacesset-backs:alogisticalone(apheresis,exvivomanufacturing,lymphodepletingchemotherapy,highcost,

restrictedaccess)andabiologicalone(poorselectivity,persistence,andactivityinsolidtumors).ASCO2026showcasedanapproachtoeach.Invivogenerationtacklesthelogisticalbarrier,makingCAR-Tinsidethepatientfromasingleoff-the-shelfinfusion,removingmanufacturing,apheresisandlymphodepletion.Next-genarchitectures(logic-gating,armoring,cytokineenhancement)tacklethebiologicalbarrier,engineeringthecellfortumorselectivity,durablepersistence,andsolid-tumoractivity.

KeyASCO2026Data:

•

UpdatedPhase

I

inMMyCARtrial

(7509):Kelonia'sKLN-1010(invivoBCMACAR-T)inr/rmultiplemyeloma

o100%ORRandMRD-negativeat1monthinall18patients,longest-followedpatientstillinremissionbeyond10months,nolymphodepletion;firstmulti-patientproofthemodalityworks,thoughnumberssmallandfollow-upearly

•

PhaseIfirst

-

in

-

humanCD8

-

tLNPstudy

(7014):CD8-targetedlipidnanoparticlegeneratingCD19CAR-TinvivoviatransientmRNAinr/rCD19+B-celllymphoma

o7patientsdosed(2PR,1SD,4pending);CARexpressionpeaksat4to6hourswithrapidnear-completeB-celldepletion,nograde≥2CRSandnolymphodepletion;invivoproof-of-conceptinlymphoma,butresponsessofarpartialandexpressiontransient

•

PhaseI/IIEVEREST

-

2

,A2B694arm(8579):A2Bio'slogic-gatedmesothelinTmodCAR-TinadvancedHLA-A02LOHsolidtumors

o13patientsacrossfourdoselevels,includingthefirstreportedCAR-TcompleteresponseinNSCLC;prooflogic-gatingcanproduceasolid-tumorresponsewhilelimitingon-target/off-tumortoxicity

•

PhaseI/IIEVEREST

-

2

,A2B543arm(TPS2673):A2Bio'slogic-gatedTmodCAR-TplusaninducibleIL-12booster,inHLA-A*02LOHsolidtumors

oFirstpatientdosedJanuary2026,dose-escalationongoing,FDAFastTrack;trials-in-progressdesigntestingwhetherembeddedIL-12improvespersistenceandcountersimmunosuppressionwithoutsystemiccytokinetoxicity

•

PhaseILB2102trial

(8012):Legend'sdnTGFβR2-armoredDLL3CAR-Tinr/rSCLCandlarge-cellneuroendocrinecarcinoma

oFirst-in-humandose-escalation,ORR28.6%anddiseasecontrol78.6%athigherdoseswithmanageablesafety;armoredtoresistTGF-βsuppressionintheTME,extendingCAR-Tintoasolid-tumorsettingwhereconventionalCAR-Thasfailed

KOLsentimentatASCO2026:DiscussioncenteredoninMMyCAR,withexcitementdrivenlessbytheresponseratethanbyaccess,sinceanoff-the-shelfproductneedingnoapheresis,manufacturing,orlymphodepletioncouldreachthemajorityofmyelomapatientswhonevergetconventionalCAR-T.KOLstemperedthiswithclearcaveats,asmallcohort,shortfollow-up,andBCMA-naiveenrolmentthatleavesopenhowitperformsintheBCMA-exposed3L+settingitwouldactuallyenter.

CommercialTrend:Invivohasdrivenabig-pharmabuyingspree,AstraZeneca/EsoBiotec(~$1B),AbbVie/Capstan($2.1B),BMS/Orbital($1.5B),Gilead-Kite/Interius($350M),Lilly/Orna(~$2.4B)andLilly/Kelonia(upto~$7B),splittingthefieldintodurablelentiviralversustransientmRNA/LNPcamps.Bycontrast,logic-gatedandarmoredsolid-tumorplayersremainventure-fundednotacquired(A2Bio's$80MSeriesC),sopharmaispayingpremiumsforinvivoaccesswhilewaitingonsolid-tumorproof.

Nextsteps:Forinvivo,thepriorityisdurabilityandbreadth,confirmingearlyresponsesholdinmyelomaintolymphoma.Forengineeredarchitectures,logic-gating,cytokinearming,TGF-βresistance,thetestisconvertingearlysolid-tumorsignalsintodurableresponses.Thesharedquestionbeingwhethernext-genCAR-TcanmatchconventionalCAR-Tondepthandpersistencewhilewinningoncost,speed,access,andsafety.

GLP-1sandCancer:The

impactofanti-obesity

drugsoncancerriskandrecurrence

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GLP-1sandCancer:AnEmergingOnco-

protectiveSignal

Background:GLP-1receptoragonistsarenowamongstthemostwidelyusedmedicinesintheUSforobesityanddiabetesandarenowincreasinglybeingusedamongcancerpatients.Trialsforincretinshadbeguntosuggesttheremaybeaonco-protectiveeffectfromthedrugclass.atASCO2026,largescaledataisbeginningtoshedfurtherlightoncanceroutcomes.

KeyASCO2026data

•Breastcancerprevention(

Abs:10506

):InaPennMedicinebreast-imagingcohort(94k),womenwithaBMIof25whowereexposedtoaGLP-1hada27%lowerriskofbreastcancerincidence(2.2%vs1.6%inthematchedanalysis).

•Leukemiaprevention(

Abs:10507

):InaglobalTriNetXanalysis,across427kindividuals,GLP-1usewaslinkedwithuptoa63%reductionintheonsetofAML(HR0.49)anda50%reductioninAML

•Survivalacrosssolidtumors(

Abs:11017

):IntheUSOncologyNetwork(iKnowMedHER,472kpatientsacross6tumortypes,with1,125GLP-1users),GLP-1usewasagainassociatedwitha42%dropintheriskofdeath.

•Improvedoutcomeswithcheckpointinhibitors(

Abs:11000

):ATriNetXcohortof3,429matchedIOpatientsshowedthat

concurrentGLP-1useledtoimprovementsinsurvival(5-yearmortalityof32%vs45%),andfeweradverseevents,withapyrexiaORof0.73.

•Theevidenceisoccasionallyparadoxical(

Abs:11016

):AseparateTriNetXanalysisshowedthatin9,912matchedGI-cancerpatientsonIO,ahigherBMIactuallyledtoa30%reductioninmortality,withamedianOSgainof12.9months.

Industrysentiment:GLP-1swereoneofthebreakoutstoriesatASCO2026,withtheconsensusfocusingontheemergenceof

“metaboliconcology”,wherebythenarrativeofGLP-1sisshiftingfromonedefinedbysafetytowardsoneaspotentiallyprotective.

KOLSentiment:KOLshavemostlyinterpretedthedatathusfarasprovocativeandhypothesis-generatingratherthanconclusivegivenhealthy-userandotherconfoundingcaveatsbutbroadlyacknowledgethatthebreadthandconsistencyoffindingsacross

independentcohortscallsforprospectivetrialstobeconducted.

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GLP-1sandCancer:WhatItMeansforOncology

Keyfindings:AtASCO2026,GLP-1shavemovedfromearlysignalsinpivotaltrialsandpost-marketingsurveillancetolarge,real-worlddatasetsthatsuggestthedrugclassbothhelpswithcancerpreventionandlowerstheriskofdeathafterdiagnosis.Given

EvaluatePharmaestimatestheobesitymarketcouldhit$110b+insalesby2032,evenamodesteffectoncancerriskwouldcarrypopulation-levelconsequences.

KeytakeawaysfromASCO

•Thereisopportunityacrossthecontinuum:GLP-1shavenowdemonstratedthatthereisaneffectacrossthreepointsinthecancerjourney(Forsomecancers):

1.Primarypreventioninhigh-riskgroups

2.ImprovedsurvivalinconjunctionwithIO

3.Reducedtreatmenttoxicitywhileonanti-cancertreatment

•Promisingsignsbutnochangetoclinicalpractice(yet):Eachdatasetsofarisobservationalnotinterventional,and

confoundingfactorssuchashealthierbehaviorsinGLP-1usersmaybiastheeffectsseen.ThedatadoesnotyetjustifyGLP-1initiationuponcancerdiagnosisbutactsasanotherpredictivemarkerforriskandoutcomes.

•Benchmarksmaybecomehardertoread:IfGLP-1shaveagenuineeffectonefficacy,theirrisingbackgrounduseinthe

broaderpopulationbecomesanewvariablewithinoncology.Contemporarytrialcontrolarmsandreal-worldcohortsincreasinglycontainGLP-1users,whichcouldineffectmaketoday'ssurvivaloutcomeshardertocompareagainstpre-GLP-1-era

benchmarks.

•Evidenceislikelytomaturethroughdataratherthantrials:Giventhatpreventionrandomizedclinicaltrialsareexpensive,slowandhardertojustifyasthereal-worldsignalstrengthens,anymaturationofevidenceshowingonco-protectiveeffectsforGLP-1sislikelytocomethroughreal-worlddataratherthanclassictrials.

•Nextsteps:RandomizedpreventionstudiesandGLP-1×checkpoint-inhibitorinteractiontrialscapturingdose,duration,andlean-masschangemaybethestrongestroutetoconvertthesesignalsintoevidencethatmayaffectpractice.

GynecologicalCancers

Targets,toxicitiesandcombinations

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GynecologicalCancers:NovelTargetsand

ExistingToxicities

Background:Thetreatmentofgynecologicalcancershasbeentransformedbytheidentificationandvalidationofnewtargetsexpressedacrossovarian,endometrialandcervicaltumors.Asapprovalsandclinicaluseexpand(especiallywithADCs),toxicityrecognitionandmanagementarecentraltooptimizingbenefit-risk.

KeyASCO2026data

•

UpdateddatafromthePhaseI/IIaBLUESTARstudy

(5515):NovelADCpuxitatugsamrotecan(Puxi-Sam)targetsB7-H4whichishighly

expressedinendometrialandovariancancers;impressiveORRdataforsingleagentADCinendometrialcohortsupportsadvancementofPhaseIIIBLUESTAR-Endometrial01trial.

•

AnalysisofPhaseIdatafortelisotuzumabadizutecan

(Temab-A)inPROC(5514):Anothernovelbiomarkerinovariancancers(c-Met)identified,with

differentiatingefficacyandsafety

forTemab-AinPROCpatientswithpooroutcomesandrarehistologies.

•

PreliminarydataforNectin

-

4

-

targetingADCCRB

-

701

incervicalcancer(5508):RoleofNectin-4alreadyelucidatedinsolidtumorslikebladdercancer,withCRB-701showingpromisingefficacyinheavilypretreatedcervicalcancerpatientsinaPhaseI/IItrial.

Discussantperspectives:ToxicitieswithADCsremainakeytalkingpointgivenILD/pneumonitiswithEnhertu(trastuzumabderuxtecan)and

oculartoxicitieswithElahere(mirvetuximabsoravtansine).Neweragentswithatopo-Ipayloadappearsaferandwillbemonitoredforrisks,whilemitigationstrategiesforexistingtoxicities(corticosteroiddrops,growthfactorsupport)werediscussedbypanelists.

Futuredirections:Withemergingtargets,targetsequencingbecomesanessentialconsideration.Therearecurrentlynohead-to-headdataonatargetselectionstrategyforthebestoutcomesinefficacyandsafety.Biomarkerexpressioncutoffsalsorequirevalidationforemergingtargets,inthewakeofexistingthresholdsforElahereandEnhertu.

Trialstowatch:

BLUESTAR

-

Endometrial01

(Puxi-Sam),

TroFuse

-

020

(sacituzumabtirumotecan),

ASCENT

-

GYN

-

01

(Trodelvy;sacituzumabgovitecan),

RAINFOL

-

03

(Rina-S;rinatabartsesutecan)

GynecologicalCancers:RationalCombinations

Background:Thegynecologicalcancertreatmentparadigmcontinuestoshifttowardsrationalcombinationspairingimmunecheckpoint

inhibitors,platinumchemotherapyortargetedagentstoaddressresistance,deepenresponsesandexpandbiomarker-selectedpopulations.

KeyASCO2026data

•Datafor

PhaseIIMIROVA

(5506)and

PhaseIIICHIPRO

(LBA5504)trials:WhileElaheremisseditsprimaryendpointinMIROVAin

combinationwithcarboplatin,chiauranibresultsaddedtoexistingdataforadd-ontherapiestoachemobackboneinrecurrentovariancancer.

•

CompetitivesurvivalinPRESERVE

-

004

(5511):Gotistobartfound

success

incombinationwithKeytruda(pembrolizumab)withimprovementinOSinPROC.ICIspreviouslystruggledtofindaroleinovariancancer,butKeytrudacombinationsappearcompetitiveinPROCfollowingon

fromKEYNOTE-B96’ssuccess.

•

ExploratorybiomarkeranalysisofVerzenio

(abemaciclib)inaPhaseIItrial(5516):PromisingactivityforVerzenio+hormonetherapyinlow-gradeserousovariancancerirrespectiveofĸRASmutandinER+endometrialcancerinNSMPpatients.

Discussantperspectives:WiththeemergenceofmultipleADCswithsimilarmechanismsofactionduetosimilarpayloads,severalmechanismsofresistancehavestartedtoemerge,sotheuseofrationalcombinationsiskeytocombattingmechanismsofresistance.Instancesunder

considerationareiforwhentouseTKIcombinations,whentosensitizetoPARPinhibitorsortakeadvantageofimmunecelldeathinducedbyimmunotherapycombinations.

Futuredirections:CombinationsalsoaddtothequestionofsequencingacrosstargetsandwhethercombinationscanincreasesensitivitytosubsequenttherapiessuchasADCs.Toxicitiesarealsoabigconcernespeciallyasadd-ontherapiestochemocontinuetobeexplored.

Combinationsalsoopenthedoortoexploremorebiomarker-drivengyncancersofvaryinghistologies,heraldedinovariancancerbyAvmapki(avutometinib)+Fakzynja(defactinib)inrecurrentLGSOC.

Trialstowatch:

GLORIOSA

(Elahere+bevacizumabinmaintenancePSOC),

TroFuse

-

036

(sacituzumabtirumotecan+Keytrudain1LPD-L1+cervicalcancer)

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ADCsinHER2+Breast

Cancer:EnhertuAnchorsanEvolvingTreatmentParadigm

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ADCsinHER2+BreastCancer:Enhertuis

EntrenchedAcrosstheParadigm

Background:Trastuzumabderuxtecan(T-DXd)hasredefinedHER2+breastcanceroverfiveyears,displacingT-DM1in2L,replacingTHPin1Lthroughthe2025FDAapprovalofT-DXd+pertuzumab(DESTINY-Breast09),andnowenteringcurative-intentcarethroughthe2026FDA

approvalsforneoadjuvant(T-DXdTHP;DB-11)andadjuvantuse(DB-05).ASCO2026addeddepth-of-responseanalyses,thefirst1LADC+IOreadout,early-stagesafetydata,andreal-worldsequencingdatainhigh-riskHER2+subpopulations.

KeyASCO2026ADCdata:

1LT-DXd+pertuzumabdurability

(Abs:1021)

:DB-09T-DXd+pertuzumabarm(n=377):15.4%CR,71.1%PR,13.5%SD/PD.Mediantreatmentduration:28.0mo(CR),22.2mo(PR)vs4.4mo(SD/PD);ILD/pneumonitisratessimilaracrossresponsegroups.

1LT-DXd+durvalumabinHER2+mBC

(Abs:1012)

:DB-07dose-expansion(n=64)ofT-DXd5.4mg/kg+durvalumab1120mgQ3Was1LHER2+mBC:confirmedORR82.8%,medianPFS37.7mo,24-moPFSrate75.5%(medianDOR36.1mo;follow-up30.1mo).Drug-relatedILD/pneumonitis17.5%(mostlyGrade1-2,nofatalevents),supportingADC+checkpointinhibitorcombosin1LHER2+.

DESTINY-Breast05ILD/pneumonitissafetyanalysis

(Abs:516)

:SecondarysafetyanalysisofPhase3DB-05(T-DXdn=806vsT-DM1n=801)inpost-neoadjuvantHER2+EBCwithresidualdisease(~94%adjuvantRT).Drug-relatedILDwashigherwithT-DXdvsT-DM1andelevatedin

Japanesepatients(14.9%vs8.9%forT-DXd;6.7%vs1.2%forT-DM1)andinmoderatevsnormalrenalimpairment(14.3%vs9.7%T-DXd).

Radiationpneumonitiswas~2×higherinJapanesepatientsinbotharms(~47%vs~27%).Mosteventswerelow-gradeandreversible;

geographyandbaselinerenalfunctionareactionableriskfactorsasT-DXdbecomesthepost-neoadjuvantstandardfollowingtheMay2026FDAapproval.

Real-worldbrainmetastasisoutcomes

(Abs:1051)

:RetrospectiveTriNetXcohort(n=540/arm,1:1PS-matched)ofHER2+MBCpatientswithoutbaselinebrainmetspost-1LTHP,comparingT-DXdvstucatinib/trastuzumab/capecitabine(TTC)as2L.T-DXdshowedlowerincidentBM(12.6%vs20.9%;RR0.62,95%CI0.46-0.83;p=0.0015),better1-yrBM-freesurvival(72.7%vs67.9%;HR0.72,p=0.03),lowerCNSmorbidity(seizures4.8%vs13.1%;cerebraledema5.5%vs14.2%;bothp<0.0001),andfewerBM-relatedencounters(mean5.2vs9.6;p=0.03);OSdidnotdiffer

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(HR0.89,p=0.16).Firstreal-worlddatasetinforming2LADCvsCNS-penetrantTKIsequencinginHER2+MBC.

ADCsinHER2+BreastCancer:TheFightfor

theSpaceAfterEnhertu

KOLsentimentatASCO2026:ThegeneralconsensusamongoncologistsattheASCO2026isthatEnhertu’sefficacyisnolongerupfor

debate.Instead,theconversationhasofficiallyshiftedtoreal-worldexecution.Cliniciansarenowfocusingonwhichearly-stagepatientsactuallywarrantT-DXdinsteadofT-DM1,howtosafelymanagelungtoxicityinarapidlyexpandingpatientpool,andwhattheoptimalsequencinglookslikeafterprogression.SincenorivalADChasyetcomeclosetochallengingT-DXd'sdata,theindustry'srealcompetitivefocushasmovedtothepost-Enhertulandscape.

Keytakeaways:

Challengersareconcentratingpost-Enhertu:Zanidatamab(Jazz/BeiGene,aHER2bispecificantibody)andawaveofnewerHER2ADCs,

disitamabvedotin,trastuzumabrezetecan,bispecificssuchasTQB2102,andJ&J'sARX788arelargelypositioninginpatientswhohavealready

progressedonT-DXdratherthanchallengingtheT-DXd–pertuzumabfirst-linestandardhead-on.Theconsensusonrationaleisthatpost-T-DXdisnowawhitespace,withnoprospectivelyestablishedstandardofcareandtolerabilitygapstoexploitgivenT-DXd'sinterstitiallungdiseaserisk.

AstraZenecaandDaiichiSankyoaredefendingonthreefronts:ThepartnersarepushingT-DXdintoearlierlines(neoadjuvantandpost-

neoadjuvant)tocapturepatientssooner,buildingcombinations(includingimmunotherapy)todeepenandprolongresponses,andwideningthesharedDXdplatform(Datrowayandnext-generationADCs)toprotectthefranchisefromrelyingonasingledrug.

Theirownsuccesscreatestheopening:MovingT-DXdearlierislockingpatientsin,butitalsoenlargesthepost-Enhertupopulationrivalsarechasingthefranchiseis,ineffect,defendingagapitsownstrategykeepswidening.

Nextsteps:Themost-watchedreadoutisEmpowHER-303thefirstdedicatedPhase3inthepost-T-DXdsetting(zanidatamabvs.trastuzumabpluschemo)whichshouldshowwhethersequencingafterT-DXdholdsup.Fromhere,anynewagenthastocleartheT-DXd-pertuzumabbarratherthantheoldTHPone,afartougherbenchmark.AsT-DXdmovesintoearlier-stagedisease,theopenquestionsmaybecomepracticalratherthancompetitive,howlongtotreat,andwhethersomepatientscansafelystepdown.

Trialstowatch:EmpowHER-303(zanidatamab;Jazz/BeiGene),thefirstdedicatedPhase3inthepost-Enhertusetting;HORIZON-Breast01(trastuzumabrezetecan;Hengrui)anext-genADCwithstandoutPFS;TQB2102(dual-epitopebispecificHER2ADC)astandoutPhase2

13

neoadjuvantdata;DESTINY-Breast07(AZ/Daiichi)amodularplatformtestingT-DXdcombinations,includingimmunotherapy.

PDx(L)1xVEGFs&ADCs

inNSCLC:KeytrudaUnderCompetitivePressure

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PDx(L)1xVEGFs&ADCsinNSCLC:Keytruda

dominancein1LNSCLCunderthreat

Background:Thefirst-lineNSCLCtreatmentlandscapeisstratifiedbyPD-L1expressionandhaslongbeendominatedbyKeytrudamonotherapyforpatients

withPD-L1-hightumors(TPS≥50%)andKeytruda+platinum-basedchemotherapyforbroaderPD-L1lowandPD-L1negativepopulations.Butthedominance

ofKeytrudainthesesettingsisfacingitsfirstsignificantchallenge.Twoemergingtherapeuticclasses,developedpredominantlythroughChineseclinical

programs,aredrivingthisshift:PD-(L)1xVEGFbispecificantibodiesandTROP2-targetedantibody-drugconjugates(ADCs).BothreportedpivotalPhaseIIIresultsatASCO2026butthesetrialswereconductedinChina,withChinese-specificcomparators,whichlimitsdirectapplicabilitytoWesternclinicalpractice.Thatsaid,theresultssendanencouragingsignalandifreplicatedinglobaltrials,couldpotentiallysetanewbenchmarkinthissetting.

KeyASCO2026data:

PhaseIIIHARMONi-6

(LBA4)

:Ivonescimabpluschemotherapyreducedtheriskofdeathby34%versusTevimbrapluschemotherapy(mOS27.89vs23.69months;HR0.66);thefirstPhaseIIIregimentoshowcaseOSbenefitoverananti-PD-1antibodycombinedwithchemotherapyinfirst-lineNSCLC.

PhaseIIIOptiTROP-Lung05

(Abs:8504)

:Sac-TMTplusKeytrudacuttheriskofprogressionordeathby65%versusKeytrudamonotherapy(mPFSNRvs5.7months,HR0.35,p<0.0001),withafavorableOStrendattheinterim(HR0.55).ThisisthefirstPhaseIIIstudytodemonstratesignificantPFSbenefitofanADCplusKeytrudaasfirst-linetreatmentforPD-L1positiveadvancedNSCLC,validatingtheADCplusIOparadigminthissetting.

ROSETTALung-02

(Abs:8513)

:Pumitamig+chemodelivereda70%uORRand62.5%cORR(25/40)across40evaluable1LNSCLCpatients,with100%confirmeddiseasecontrolacrossallarmsandhistologies;comparessimilarlytoAkeso'sivonescimab,withsquamousORRsof73.7%(pumitamig)vs76%(ivonescimabHARMONi-6)whenbothincludeunconfirmedresponses.

KOLSentiment:KOLsinterpretedthedataascompellingbutnotimmediatelypractice-changinginWesternmarkets.GiventhatKeytrudamonotherapyisthecurrentstandardofcareforthePD-L1-highpatientsintheWesternpopulation,discussantsnotedthattheTevimbracomparatorusedinHARMONi-6limitthereliabilityofcross-trialcomparisons.Similarly,KeytrudapluschemotherapyistheacceptedWesternstandardofcareforPD-L1TPS1-49%patientswhereassac-TMTplusKeytrudawasevaluatedagainstKeytrudaalone,leavingaclinicallyrelevantquestionforWesternregistrationunanswered.However,KOLs

specificallyflaggedpumitamig'sROSETTALung-02dataasasignthatthePD-1×VEGFbispecificclasshasdepthbeyondivonescimabalone,makingthelong-termcommercialrisktoKeytrudahardertodismiss.

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PDx(L)1xVEGFs&ADCsinNSCLC:Western

DatatheRealLitmusTest

Keytakeaways:

CompetitivepressurespansthePD-L1spectrum:Thenewdatademonstratechallengepointsacrossallfirst-lineNSCLCpatientpopulations,withtwoPD-(L)1×VEGFbispecificnowinthepicture:

•PD-L1-positive:TROP2ADCcombinations(sac-TMT+Keytruda)mayaugmentorreplaceKeytrudamonotherapy

•Squamousfirst-line:PD-(L)1×VEGFbispecific(ivonescimab)pluschemotherapyoutperformanti-PD-1combinations(InChinasofar)

•Pumitamig'sROSETTALung-02datasignalsthativonescimabisnottheonlybispecifictowatchandthedrugclasshascompetitivedepth

Promisingsignalsbutnonear-termchangetoWesternclinicalpractice:AllpivotaldatausedChinese-specificcomparators,TevimbrainHARMONi-6andKeytrudamonotherapyinOptiTROP-Lung05ratherthanthewesternstandardofcare.Pumitamig'sROSETTALung-02data,whileencouraging,issimilarlyearly-phase.Therefore,acrossallthreeagents,thedatadoesnotyetjustifyalabelupdateorguidelineshiftinWesternmarkets.

Thebispecificclassmayfragmentitsownopportunity:Currently,ivonescimabistheclearclassleaderasithasdeliveredpositiveChinesePhaseIIIdatain1LNSCLC(HARMONi-6),demonstratedanOSbenefitoverchemotherapyinEGFR-TKIpretreatedpatients(HARMONi-A),andbeatenKeytrudamonotherapyonPFSinPD-L1-positivefirst-linedisease(HARMONi-2).TheglobalHARMONi-3trialcouldreadoutforsqauamousin2026,withthenon-squamousdatain2027.Pumitamig'sdifferentiationargumentisnotefficacyasROSETTALung-02'sresponseratescloselymirrorivonescimab'sbuttrialdesigngivesitanupperhand.Thatisastrategicadvantage,butitonlymattersifpumitamigcangetaPhaseIIIreadoutbeforeivonescimabhasalreadydefinedtheclassinWesternmarkets.Thefragmentationriskispotentiallyasymmetric:

•IfHARMONi-3