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
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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
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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
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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