Carcinomamammariotriplonega/vo:Terapiadellamala4ametasta/ca

LauraBiganzoliOncologiaMedica

NuovoOspedalediPratoIs/tutoToscanoTumori

Prato

SABCS2016:TNBC&metasta/cdisease&treatment

•  NOPHASE3STUDIES•  Posters:n=14•  Posterdiscussion:n=0•  Oralpresenta/on:n=1(BCRA1-2

mutatedpts)

Phase 2 study

*Selec&veinhibitorofPARP-1andPARP-2

≤2priorlinesofCTforM+

*

HanHSetal.

TNBCVeliparibarmn=42(42.4%)Placeboarmn=40(41.2%)

S2-05

HanHSetal.

HanHSetal.

HanHSetal.

DierasVetal.

P4-22-02

Sacituzumabgovitecan(IMMU-132)updatedresultsfromtheTNBCcohortofaphaseI-IIstudy

Sacituzumabgovitecan(IMMU-132)isanan/body-drugconjugatethatcontainsSN-38,theac/vemetaboliteofirinotecan.IMMU-132targetsTrop-2,acell-surfacereceptorpresentinmanyepithelialcancers,includingtriple-nega/vebreastcancer(TNBC).

PhaseI:10mg/kgondays1and8q21

OngoingPhaseIIinpa/entswithsolidtumors

TNBCcohort:Pa/entswithTNBCrefractory/relapsedto≥1standardtherapywithmeasurabledisease

Bardiaetal.

P4-22-15

Objec/veresponse,n(%)[CR] 21(30%)[2(3%)]

Medianonsettoresponse,months 1.9

Clinicalbenefit(CR+PR+SD≥6months),n(%)(95%CI) 32(46%)(34%-59%)

Mediandura/onofresponse,months(95%CI) 8.9(6.1-11.3)

MedianPFS,months(95%CI) 6.0(5.0-7.3)

Mediansurvival,months(95%CI) 16.6(11.1-20.6)

Grade≥3AEsincludedneutropenia(39%),anemia(14%),anddiarrhea(13%);7%hadfebrileneutropenia

DatafromtheongoingphaseI/IIstudywillbesubmijedtotheFDAforapoten/alacceleratedapproval.Thissubmissionwouldbecompletedunderabreakthroughtherapydesigna/onreceivedforthemedica/oninTNBCfollowing≥2treatmentsformetasta/cdisease

AphaseIIIrandomized,controlledtrialiscurrentlybeingplannedunderaspecialprotocolagreementwiththeFDA

Most(89%)archivaltumorspecimensweremoderately(2+)orstrongly(3+)posi/vebyIHCforTrop-2

N=69Median#priortherapies5(1-12)taxanes(97%),cyclophosphamide(91%),anthracyclines(84%),andpla/numagents(70%)

Bardiaetal.

PrimaryendpointPhase2:PFS

P5-15-03

YardleyDetal.

CONCLUSIONS

DuetotheevolvinglandscapeincludingphaseIIItrialswithimmunotherapyandothernovelagents,thistrialisnotprogressingtophaseIII

CB-839isaasmallmoleculeinhibitorofglutaminase,akeyenzymeintheu/liza/onofglutaminebycancercells.Glutamineu/liza/oncancontributetoresistancetopaclitaxel.

Phase1studyofCB-839incombina&onwithpaclitaxelinTNBC

P6-11-05

Doseescala/on:3+3design(CB-839:400-800mgBID)+P80mg/m2days1,8,15q28.1DLT,grade3neutropenia!Expansionstudy:800mgBID

CLINICALOUTCOMES ByCB-839dose(mg)

Bypriortaxane(≥600mg)

Byrace(≥600mg)

Pa/ents: Total 400 ≥600 Adv/Met

Neo/Adjonly

None AfricanAmerican

Non-AfricanAmerican

Totenrolled(n) 28 7 21 9 10 2 8 13

Evaluable,n(%) 23 7 16 8 6 2 8 8

PR 5(22) 0 5(31) 3(38) 2(33) 0 4(50) 1(13)

SD 9(39) 3(43) 6(38) 1(13) 3(50) 2……. 1(13) 5(63)

PD 9(39) 4(57) 5(31) 4(50) 1(17) 0 3(38) 2(25)

Notevaluable,n 5 0 5 1 4 0 0 5

(100)

DeMicheleAetal.

CONCLUSIONS

Combina/oncanovercomeresistancetoPinheavilypretreatedpa/entsatdosesofCB-839≥600mg.50%ORRinAfricanAmericanpa/ents(AAP),allofwhomtaxanerefractoryconsistentwithhigherglutamineu/liza/oninAAPtumors.Phase2studyplanned.

N=32(27evaluableforefficacy)78%visceralmetsMedianpriorlinesforM+=3(range1-7)

Updatedresults(medianfollow-up10.7months(range0.4-32.7)

KEYNOTE-012:Longlas&ngresponsesinaphaseIbstudyofpembrolizumabformetasta&cTNBC

P6-10-03

NandaRetal.

n(%)

CR+PR

SD

Clinicalbenefit(CR+PR+SD≥24wk)

1+4(18.5)

6(22.2)

6(22.2)

Primaryendpoint:ORR

NandaRetal.

CONCLUSIONS

Furtherdevelopmentofpembrolizumabfortreatmentofthispopula/onofpreviouslytreatedpa/entswithTNBCisongoing-KEYNOTE-086:asingle-armphaseIIstudyevalua/ngpembrolizumabastreatmentformetasta/cTNBC-KEYNOTE-119:arandomizedphaseIIIstudyofpembrolizumabcomparedwithphysician’schoiceofchemotherapyassecond-orthird-linetreatmentformetasta/cTNBC

Carcinomamammariotriplonega/vo:Terapiadellamala4ametasta/ca

Backup

Efficacyresultsofaphase1/2studyofMIFEincombina&onwitheribulininGR+TNBC

•  N=23TNBCtreatedattherecommendeddoseofMIFEof300mg/day+eribulin1.1mg/m2day1,8q21

•  Median#ofpriorchemotherapyregimens3(range1-9)•  Neutropenia12/23pa/ents(3G4),peripheralneuropathy8/23

pa/ents(2G3).OthermostcommonTEAEs(fa/gue,nausea,alopecia)weremainlyG1orG2,hypokalemia(4G3,1G4)

•  4PR(17%),8SD,11PD•  MedianPFS11.1weeks,medianOSnotreached

P6-12-15

Mifepristone(MIFE),acompe//veglucocor/coidreceptor(GR)antagonist,hasincreasedthecytotoxiceffectsofconcomitantchemoinpreclinicalin-vitroandin-vivomodelsofGRposi/veTNBC(SkorMN,etal.ClinCancerRes.2013).

Part1:solidtumors

Part2:TNBC1-5priorCTregimensforABC

HanHSetal.

CONCLUSIONS

PFSlongerthanthatreportedforlocallyadvancedormetasta/cpa/entswithTNBCtreatedwitheribulinalone.AogiK,etal.AnnOncol.2012;23:1441-8.(PFS=7.2weeks)Basedonthesefindings,addi/onalassessmentofMIFEincombina/onwithstandardchemotherapyiswarrantedinalargerstudypopula/onofpa/entswithTNBC.

COLETstudy:cobime&nibpluspaclitaxelUpdatedclinicalandbiomarkersresults

Brufskyetal

P4-22-22

*

*Biomarkersstudy:characteriza&onintrinsicsubtypesbyPAM50orothersignatures,muta&onandcopynumberchangesingenesassociatedwithTNBCbyDNAsequencing;Levelsoftumorsuppressors,mito&corapopto&cindex,andimmunecellinfiltra&onsbyimmunohistochemistry

Preclinical data suggest that upregulation of the MAPK pathway confers resistance to taxanes. Many TNBC have genetic alterations in the MAPK pathway. Adding a MEK inhibitor to a taxane can increase the sensitivity of BC cells to taxane therapy

matchedpre-andon-treatmentbiopsieswereevaluablefor2pa/ents

Safety:94%experienced≥1TEAE,mostoftheseweregrade1[diarrhea(63%),rash(50%),nausea(44%)].MostfrequentlyreportedG3=stoma//s13%(n=2)

•  Durableresponses:5/6ptswithcPRmaintainingPRat≈20weeksand3pts(19%)maintainingPRat≥40weeks•  Trendforenrichmentofan/tumorresponsesintumorsofthebasalsubtype•  An/tumorresponseswereobservedinpa/entswithoncogenicmuta/onsinparallel

pathways

PRSDPD

Waterfallplotofbesttumorresponsebypa&ent,intrinsicmolecularsubtypeandrelevantgenomicaltera&ons

N=168PR(6confirmed)

Brufskyetal.

TEAE;treatment-emergentadverseevent

•  Responserate30%(21/69)[2CRs+19PRs]•  Medianonsetofresponse1.9months•  Mediandura/onofresponse8.9months(3ongoingat13-21

months);46%ofptshadclinicalbenefit≥6months

•  Currentlyes/matedPFS=6monthsandOS16.6months

•  Grade≥3AEsincludedneutropenia(39%),anemia(14%),anddiarrhea(13%);7%hadfebrileneutropenia

•  ClearancedatasuggestedSN-38remainsboundtotheconjugateandisreleasedataratepredictedfrominvitrostabilitystudies

Bardiaetal.

Combinedtargetedtherapiesforadvancedtriplenega/vebreastcancer

•  N=51evaluablepts17(33%)offstudyduringinduc/onphase•  MedianPFSforthe51ptswas9.1months(95%CI6.9-9.6)

Authorsconclusions:

TheobservedPFSdidnotmeetpre-specifiedcriteriaofinterestLackofiden/fica/onofbiomarkersofresponsetoangiogenictherapieshashamperedprogressoftheseagentsinbreastcancer

AdvancedTNBCFirstline

INDUCTIONPHASENab-paclitaxel100mg/m2day1,8,15+bevacizumab10mg/kgdays1,15q28

MAINTENACEPHASEBevacizumab+

Erlo/nib150mgdaily

FreeofPDat24weeks

Primaryendpoint:PFS

Spechtetal.