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.