NewFron)ersinUrologicOncology:UpdatesonPivotalTrialsin

Metasta)cRenalCellCarcinoma

IbexatEinGedi,Israel;5/2017

NewFron)ersinUrologicOncology:UpdatesonPivotalTrialsin

Metasta)cRenalCellCarcinoma

MayerFishman,M.D.Ph.D.DirectorGUclinicaltrialsSeniorMember,DepartmentofGenitourinaryOncologyMoffiPCancerCenter

Professor,DepartmentofOncologicSciencesDepartmentofInternalMedicineMorsaniCollegeofMedicineUniversityofSouthFlorida

11/4/17

Whatmakesatrialpivotal?

•   OS•   PFS•   ORR•   Non-inferiority

Immune-typetreatmentsCytokinesIVInterleukin-2(Proleukin™)•   Inpa)ent14x2(6daysx2•   Inpa)ent5x4(3daysx4)InterferonEngineeredcytokines

ALKS-4230NKTR-214ALT-801

CHECKPOINTNivolumabIV(Opdivo™)[PD1]PembrolizumabIV[PD-1]AvelumabIV[PD-L1]DurvalumabIV[PD-L1]AtezolizumabIV[PD-L1]IpilumimabIV(Yervoy™)[CTLA4]

VEGF-typetreatments-inib:inhibitor-umab:human-an.bodySuni)nib50mg(Sutent™):14on/7offPazopanib200mg(Votrient™):800/dSorafenib200mg(Nexavar™):400+400/dAxi)nib5or1mg(Inlyta™):5+5(or2+2to10+10)/dBevacizumab(Avas)n™)IVevery2weeksLenva)nib(Lenvima™)witheverolimus

18mg(10+4+4)and5mgCabozan)nib(Cabometyx)60(or40)/d

TargetedtypetherapiesVEGF=vascularendothelialgrowthfactormTOR=mammaliantargetofrapamycin

VEGF&C-MET

mTOR-olimusor“TOR”Everolimus10(Afinitor)mg/dTemsirolimus25IV(Torisel)onceaweek.

Inves)ga)onalforkidneycancertreatment

Spelling&typeorganizer

VEGF&FGFR&mTOR

Marketeddrugs’trials•   Sorafenibvsplacebo,2ndline•   Suni

Recentnega)vetrial–endoglinpathway

•   2ndlineAxi)nib+/-dalantercept•   2ndlineAxi)nib+/-TRC-105

==

Adjuvanttrials–past/nega)ve

Interferonalphavsnone(x4)InterferongammavsnoneHD-IL2vsnoneIL-2/IFNvsnoneRenialevaccinevsnoneThalidomidevsnoneRenalbedirradia)onvsnot*

=

==

x

xP*/os

p/os

(*renalbedPFSdifference,only)

Adjuvanttrials–recent/almost•   PROTECTpazopanibvsplacebo=

Adjuvanttrials–recent/almost•   PROTECTpazopanibvsplacebo=

Star)ngdoseloweredforreasonofaPri)on

Adjuvanttrials–recent/almost•   PROTECTpazopanibvsplacebo=+

ITT-600ITT-800

ITT-ALL

PRIMARY

secondary

secondary

.1649

Adjuvanttrials–recent/almost•   PROTECTpazopanibvsplacebo=

“Acorrela)onwasobservedbetweenhighertroughplasmaconcentra)onandlongerDFS.”“FinalOScut-offwillbe4/15/19"

Adjuvanttrials–recent/almost•   ASSURE:sorafenibvssuni

Adjuvanttrials–recent/almost•   ASSURE:sorafenibvssuni

Adjuvanttrials–recent/almost•   ASSURE:sorafenibvssuni

Adjuvanttrials–recent/almost•   S-TRAC:suni

Adjuvanttrials–recent/almost•   ASSURE:sorafenibvssuni

Adjuvanttrials–current

•   Accrualcompleted,nodatayet–  Everolimusvsplacebo(allhistologies)

•   Accrualopen–  Atezolizumabvsplacebo(mostRCC;openatMCC)–   Ipilumimab/nivolumabvsplacebo(ccRCC)–  Pembrolizumabvsplacebo(ccRCC)

ThebignewsfromMadrid

Checkpointinhibitortrials/done

Also,Ihelpedhim.

NowwewilltalkaboutCheckmate214

Checkpointinhibitortrials/new!

CHECKMATE214attheESMO2017,MadridIni)altherapyofccRCC

ipilumimab(1mg/kg/dose,w-1-4-7-10)nivolumab(3mg/kg/dose,w1-4-7-10) thennivoumab240mg/doseq2…

Vssuni)nib50mg,28on/14off

BernardEscudier

Checkpointinhibitortrials/new!

CHECKMATE214Co-primaryendpoint:ORR(p<0.0001)

Ipi-nivo:41.6%.Mediandura)on:95%CI:(21.82,Notreached)Suni)nib:26.5%.Mediandura)on18.7mo.95%CI:14.82,Notreached)

Co-primaryendpoint:PFS:

HRfavorsIpi-nivo=0.82;95%[CI]=0.64–1.05;2-sidedP=.03*NS*

MedianPFS:(NS)ipi-nivo:11.6months(95%CI=8.7–15.5)Suni)nib:8.4months(95%CI=7.0–10.8)

CR: Ipi-nivo:9.4%Suni)nib:1.2%

Checkpointinhibitortrials/new!CHECKMATE214:Moreanalyses“PDL1>1%subset”:(11-12%ofgoodrisk;26-29%ofintermediatehighrisk)ORR

Ipi-nivo:58%med.dur.22.8(95%CI9.4,NR)suni)nib25%,med.dur5.9(95%CI4.4,7.1)HR0.48(.28-.82),p=0.0003

Favorablerisksubset:***oppositeresult***ORR(p=0.0002)ipi-nivo29%medianPFS15.3(95%CI9.7,20.3)mo.Suni

Checkpointinhibitortrials/new!

CHECKMATE214:Summary: ipilumimab-nivolumab

BePerinintermediate-highrisk MuchbePerinPDL-1%subset

Suni)nib BePeringood-risksubset

“Stoptrea

Checkpointinhibitortrials/accruing

JAVELINsuni)nibvsaxi)nib/avelumab

OpenatMCCTargetcomple)on1stweekofDec.

VEGFà(offstudyotherdrug,suchasnivolumab(PD-1)VEGFandPDL-1

PFIZER

NCT02684006

Checkpointinhibitortrials/accruing

CLEARCompare•   Lenva)nibinCombina)onwithEverolimusor•   Lenva)nibPembrolizumabor•   Suni)nibAloneinFirst-LineAdvancedRenalCellCarcinoma

VEGF/mTORà(offstudyotherdrug,suchasnivolumab(PD-1)VEGFandPDL-1VEGFà(offstudyotherdrug,suchasnivolumab(PD-1)

EISAI

NCT02811861

Checkpointinhibitortrials/accruing

APhase3,Randomized,Open-Label•   Cabozan)nib+NivolumabCombined•   Cabozan)nib+NivolumabandIpilimumab•   Suni)nib

NCT03141177

VEGF-CMET/PD-1VEGF-CMET/PD-1,CTLA-4VEGFà(offstudyotherdrug,suchasnivolumab(PD-1)

BMS/Exelixis

RCCtrialsatMoffiP(p1)

ClearcellRCC,randomized:(closingsoon):JAVELINaxi)nib/avelumabvssuni)nib

(*wemayopenCLEAR).

Adjuvant(notrestrictedtoccRCC)

AtezolizumabvsplaceboFirstline,not-clearcell(pRCC,chromophobe)

Lenva)nibandeverolimus

RCCtrialsatMoffiP(p2)Checkpointbased

HuyaHBS-8000withnivolumabThisisanoralHDACinhibitor.TrialthroughCutaneousProgram

Durvalumab+/-IDOinhibitorAMP-514TrialthroughphaseIProgram,DrGrayCytokinebased,andengineeredcytokines•   PembrolizumabandhighdoseIL-2(Seenextslide)

•   Nektar214(pegylatedIL-2prodrug)withnivolumab

•   ALKS-4230(IL-2/IL-2receptoralpha)

Pembrolizumab/IL-2schema

P P P

P P P

P P P

iiiii

iiiii iiiii iiiii iiiii

P P Piiiii iiiii iiiii iiiii

P=outpa)entPembrolizumabevery3weeks.

=inpa)entIL-2,3-dayadmission,5doses

Thankyouverymuch!

*Theyarebothincollege.