TIVO-3:APhase3StudytoCompareTivozanibtoSorafenibinSubjectswithRefractoryAdvancedRenal

CellCarcinoma(RCC)OverallSurvival2-YearUpdate

Sumanta K. Pal1, Brian I. Rini2, Bernard J. Escudier3, Michael B. Atkins4, Thomas E. Hutson5, Camillo Porta6, Elena Verzoni7, Michael N. Needle8, David F. McDermott9

Kidney Cancer Program, City of Hope National Medical Center, Duarte, CA, USA1; Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA2; Department of Oncology Medicine, Gustave Roussy Cancer Campus, Villejuif, France3; Department of Medical Oncology, Georgetown Lombardi University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC4; Urologic Oncology, Baylor Sammons Cancer Center-Texas Oncology, Dallas, TX, USA5; Department of Internal Medicine, University of Pavia Chief, Division of Translational Oncology, IRCCS Istituti Clinici Scientifici Maugeri, Pavia, Italy6; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy7; AVEO Oncology, Cambridge, MA, USA8; Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA9

•  Tivozanibisapotent,selectiveinhibitorofVEGFR1,2&3withalonghalf-lifedesignedtooptimizeVEGFRblockadeandminimizeoff-targettoxicities1,2

•  TIVO-1:1stlinePhaseIIIRCCstudyoftivozanibvs.sorafenib3•  Received1stlineEMAapproval(Aug2017)basedonsuperiorPFS•  FDArequestedadditionalPh3(PFSPrimaryandnoadverseeffectonOS)

•  RefractoryRCCLandscape•  NoRCCtreatmentshaveshownsuperiorbenefitoveranotheractivetherapyinthe3rd/4thlinesetting

•  ImmunotherapyhasemergedastandardofcareforearlylinesoftreatmentforRCCpatients,limitedprospectivedataexisttoinformsequencingafterIOfailure

2 1.NakamuraKetal.CancerRes2006;66:9134–9142.2.EskensFAetal.ClinCancerRes2011;17:7156–71633.MotzerRetal.JournalofClinicalOncology2013;Volume31,Number30

Tivozanib:Properties&ClinicalExperienceinRCC

TIVO-3:StudyDesign

IMDC,InternationalMetastaticRCCDatabaseConsortium;QD,onceperday;BID,twiceperday;PO,oraladministration

KeyEligibilityCriteria:

• AdvancedclearcellRCC• Failed2or3priorregimensincluding≥1VEGFRTKI• ECOGPS0or1

Tivozanib1.5mgPO,QD

(3weekson,1weekoffpercycle)

Sorafenib400mgPO,BID(Continuouslyin4weekcycles)

Treatmentuntilprogressionorunacceptable

toxicity

Stratification:

• PriorRegimen(TKI-PD1;TKI-TKI;TKI-Other)• IMDCPrognosticScore(Fav;Int;Poor)

1:1n=350

RANDO

MIZE

•  PrimaryEndpoint•  PFSperIndependentReviewCommittee(IRC;datacutoffOct.4,2018)

•  SecondaryEndpoints•  ORR,OS,InvPFS,DOR,Safety

3

Characteristic Tivozanib(N=175)

Sorafenib(N=175)

Medianage,years 62 64

Male,% 72 73

IMDCprognosticrisk,

Favorable 19% 21%

Intermediate 62% 60%

Poor 18% 19%

ECOGperformancestatus,%(0/1) (49/50) (47/48)

Region,%(NA/EU) (18/82) (15/85)

PriorLinesofTherapy,%(2/3) (62/38) (59/41)

PriorTreatmentRegimen,

TKI-PD1 27% 25%

TKI-TKI 45% 46%

TKI-Other 28% 29%

4

TIVO-3:PatientDemographicsatEntry(ITT)

LancetOncology,InPress

MedianPFS,mo(95%CI)

Tivozanib 5.6(5.3,7.3)

Sorafenib 3.9(3.7,5.6)

HR,0.73(95%CI:0.56,0.94)

P=0.0165

2yrPFS18%

5%

28%1yrPFS

11%

5

TIVO-3:PrimaryEndpointProgression-FreeSurvivalperIRC(ITT)SurvivalProbability

RED = Patients Progression Free* and Still on Therapy (Tivozanib n=20 / Sorafenib n=2)

Patie

nts

N=52

*InvestigatorassessedPFS

Overall Response Rate: 18% tivozanib vs 8% sorafenib, p=0.02

6

TIVO-3:SwimmersPlotofPatientsProgressionFree>1Year

*Finalanalysis,asofOct4,2018

Tivozanib Sorafenib

Tivozanib Sorafenib

Porta et al. ASCO 2019

PriorCheckpointInhibitor+VEGFRTKITivozanib(n=47)

Sorafenib(n=44)

MedianPFS,months(95%CI)

7.3(4.8,11.1) 5.1(3.2,7.4)

HR(95%CI) 0.55(0.32,0.94)

PValue 0.028

ORR 24.4% 6.8%

TwoPriorVEGFRTKIsTivozanib(n=79)

Sorafenib(n=80)

MedianPFS,months(95%CI)

5.5(3.6,7.4) 3.7(3.6,3.9)

HR(95%CI) 0.57(0.39,0.83)

PValue 0.003

ORR 15.2% 7.5%

7

TIVO-3:PFS&ORRinKeySubgroups*

•  44additionaleventssinceOct.4,2018datacut•  16tivozanibeventsand28sorafenibevents•  OSevents114tivozaniband113sorafenib

• Medianfollowupdurationof33months,24monthsfromlastpatientenrolled

8

TIVO-3:OverallSurvivalUpdate

Oct4,2018 Aug15,2019OSHR 1.12 0.9995%CI;pvalue 0.84-1.51;p=0.44 0.76-1.29;p=0.95OSEvents 183(52%) 227(65%)

MedianOS,mo(95%CI)

Tivozanib 16.4(13.4-21.9)

Sorafenib 19.6(14.9-24.2)

HR=0.99,(0.76-1.29)

P=0.95,stratifiedlogranktest

9

TIVO-3:OverallSurvival–ITT(August15,2019)SurvivalProbability

Group(n) %ofEvents OSHR %ofEvents OSHR

ITT(350)

52% 1.12 65% 0.99

VEGF/IO(91)

43% 1.14 58% 0.88

VEGF/VEGF(159)

58% 1.05 66% 0.98

VEGF/Other(100)

54% 1.42 69% 1.10

Oct4,2018 Aug15,2019

10

TIVO-3:OSDatabySubgroup

*PFSassessmentbyinvestigator

Tivozanib(N=173) Sorafenib(N=170)PreferredTerm AllGrades% Grade3/4% AllGrades% Grade3/4%

TreatmentRelatedAEs 84 44 94 55

Hypertension 36 20 25 14

Diarrhea 33 2 50 9

Fatigue 29 4 19 5

DecreasedAppetite 26 4 21 2

Dysphonia 24 1 8 0

Asthenia 21 5 17 4

PPE* 16 1 38 10

Rash 4 0 24 8

>5%differencebetweenarms

11

TIVO-3:Treatment-RelatedAdverseEvents

Feweradverseeventsobservedfortivozanib

Tivozanib(N=173) Sorafenib(N=170)MeanNumberofCyclesInitiated 11.9 6.7

AEsLeadingtoDoseReductions(%) 24 38AEsLeadingtoDoseInterruption(%) 48 63

TreatmentRelatedSAEs(%) 12 11TreatmentRelatedDeaths(%) 0 0

P=0.005

P=0.007

12

TIVO-3:PatientDispositionandDrugExposure(ITT)

•  TivozanibsignificantlyimprovesPFSandORRcomparedtosorafenibinrefractoryadvancedRCC

•  TivozanibwassuperiorinpatientspreviouslytreatedwithcheckpointinhibitorsaswellastwoVEGFR-TKIs

•  Responseswithtivozanibweremoredurablethansorafenib

•  UpdatedOverallSurvivalHR0.99

•  Tivozanibwaswelltoleratedwithloweroverallratesofadverseevents•  Fewerdoseinterruptionsandreductionsrequiredontivozanib

TIVO-3:Conclusions

Acknowledgements

•  Patientsandtheirfamilies•  Ourinvestigatorsandtheirpersonnel:Belgium:GThierry;SRottey;DLuyten;Canada:CKollmannsberger;GBjarnason;SGhedira;CzechRepublic:JKatolicka;JPrausova;BMelichar;APoprach;JKopecky;Denmark:FDonskov;PGeertsen;NJensen;France:FRolland;NPenel;BEscudier;CLinassier;JMTourani;Germany:MBoegemann;MWirth;MRink;MOGrimm;PIvanyi;MStöckle;Hungary:BPikó;KMahr;LMangel;BJuhász;ZPápai;MDank;PNyirády;LGeczi;ÁRuzsa;ZKahan;Italy:PPedrazzoli;ABearz;RSabbatini;FCalabro;CCaserta;FBoccardo;GFacchini;GFerretti;GTonini;BPerrucci;AHamzaj;EVerzoni;FMorelli;UDeGiorgi;FNolè;CNatoli;MAglietta;Poland:JWojcik-Tomaszewska;RZdrojowy;BItrych;PKoralewski;AWronski;DSawka;Spain:APintoMarin;EGallardoDiaz;TAlonsoGordoa;JVirizuelaEchaburu;JMarotoRey;CSuarezRodríguez;GRubioRomero;BMellado;MJMéndezVidal;NLainezMilagro;JGarcía-DonásJiménez;ARodríguez-Vida;MGarcía;CSantanderLobera;ÁMontesaPino;FVázquezMazón;EMartínezOrtega;JMuñozLanga;DCastellano;JArranzArija;CMaximiano;NSala;FXGarciadelMuroSolans;SHernandoPolo;MLaraÁlvarez;MClimentDurán;UnitedKingdom:MSarwar;FThistlethwaite;MWheater;STurajlic;JWagstaff;DFarrugia;PNathan;SAGrumett;OParikh;PPatel;UnitedStates:BRini;UVaishampayan;AMolina;RAlter;DSahasrabudhe;EGelmann;JClark;STejwani;LNordquist;SPal;LAppleman;JWang;RHauke;THutson;NVogelzang;JYorio;AFlaherty;DShaffer;MMims;SAgarwala;SRichey

•  AVEOOncology

Backup Slides

TIVO-3:OverallSurvivalbyQuartile

OSQuartiles(95%CI) Tivozanib Sorafenib

25% 7.4(6.0,10.2) 7.3(6.4,10.9)

50% 16.4(13.4,21.9) 19.6(14.9,24.2)

75% NR(32.8,NR) NR(32.4,NR)