results of a phase ii trial of selinexor, in paents …...title: opening session and award lectures...

PresentedatESMOCongress2016byIgnaceVergote

Last update: 10-08-2016 01:46:24pm esmo.org

07-10-201610:15 - 11:45 Type: Educational session

Title: Cancer Immunotherapy (CIT): What every oncologist should knowVienna

Chair(s): S. van der Burg, NL; I. Melero, ES

10:15 - 10:30 Back to the basics

, Leiden, NLS. van der Burg

10:30 - 10:55 Cancer vaccines: Can we make them work?

, Leiden, NLC.(. Melief

10:55 - 11:20 T cell therapy: For whom and when?

, Herlev, DKI.-M. Svane

11:20 - 11:45 Immune checkpoints: Do we really know how they work?

, Pamplona, ESI. Melero

12:00 - 13:20 Type: Opening sessionTitle: Opening Session and Award lectures - Followed by welcome refreshments

Copenhagen

ResultsofaPhaseIITrialofSelinexor,inPa5entswith

GynaecologicalCancersIgnaceVergote1,BenteLund2,HanneHavsteen3,ZazaUjmajuridze4,ElsVanNieuwenhuysen1,CharloLeHaslund2,TrineJuhler-NøLrup4,PatrickNeven1,MortenMau-Sørensen4,PatrickBerteloot1,AnneKranich6,TamiRashal5,JulieMeade5,YosefLandesman5,GregWright5,MarshaCrochiere5,Jean-RichardSaint-Mar[n5,SharonShacham5,MichaelKauffman5,MansoorRazaMirza5

(1)KatholiekeUniversiteitLeuven,Leuven,Belgium,EuropeanUnion(2)AalborgUniversityHospital,Aalborg,Denmark(3)HerlevUniversityHospital,Herlev,Denmark(4)Rigshospitalet,UniversityofCopenhagen,Copenhagen,Denmark(5)KaryopharmTherapeu[csNewton,MA,USA(6)GSOHamburg;Germany















Copenhagen

•  EmploymentorLeadershipPosi5on:No

•  Consultant/AdvisoryRole:No

•  StockOwnership:No

•  Honoraria:No

•  ResearchFunding:No

•  ExpertTes5mony:No

•  OtherRemunera5on:No

PresenterDisclosures

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Acknowledgments

•  Wewouldliketothank:

–  Pa[entsandtheirfamilies

–  Inves[gators,co-inves[gatorsandthestudyteamsateachpar[cipa[ng

center:

•  KatholiekeUniversiteitLeuven,Leuven,Belgium,EuropeanUnion

•  AalborgUniversityHospital,Aalborg,Denmark

•  HerlevUniversityHospital,Herlev,Denmark

•  Rigshospitalet,UniversityofCopenhagen,Copenhagen,Denmark

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ThisstudywassponsoredbyKaryopharmTherapeu[cs















Copenhagen

Selinexor–MechanismofAc5on

•  Expor[n1(XPO1)istheonlynuclearexporterforthemajortumorsuppressorproteins(TSPs)includingp53,p73,BRCA1andpRB

•  Selinexor,afirst-in-classinhibitorofXPO1,inducesnuclearreten[on,accumula[onandac[va[onofTSPs

•  Reac[va[onofTSPsleadstotumorapoptosis•  Selinexorhasshownpreclinicalac[vityin-vivo

aswellasclinicalac[vityinaPhaseIstudyinovarianpa[ents(Razaket.al,JCO2016)

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SelinexorInGynecologicalNeoplasms(SIGN)–PhaseIIStudyDesign

•  PrimaryEndpoint:

•  Diseasecontrolrate(DCR)completeorpar9alresponse,orstablediseaseforatleast12weeks(SD≥12)

o  Lookingfor≥8pa[entsinthefirst21pa[entsenrolledpercohorttoreachDCR,whichwillwarrantPhaseIIIexplora[on

•  MainInclusionCriteria:

o  Pa[ents≥18yearsold,ECOGperformancestatus0-1,Lifeexpectancy≥12weeks

o  Ovarianpa[ents–Pla[numrefractory/resistantpa[ents,≥1priorchemotherapyline

o  Endometrial/Cervicalpa[ents–≥1lineofchemotherapyforrelapsedoradvanceddisease

•  TreatmentScheme:TwiceWeekly(BIW)orOnceWeeklyDosing(QW)/28daycycle

• 50mg/m2(BIW)• 35mg/m2(BIW)• 50mg/m2(QW)

OvarianCohort

• 50mg/m2(BIW)

EndometCohort

• 50mg/m2(BIW)

CervicalCohort

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SIGN–Pa5entCharacteris5cs

Characteris5c Ovarian(N=66) Endometrial(N=23) Cervical(N=25)

Pa5entsEnrolled 66 23 25

MedianAge(Range) 62years(31–80) 67years(53–75) 53years(32–75)

MedianPriorTreatmentRegimens(Range) 6(1–11) 2(1–5) 3(1–8)

PriorTreatmentsN(%)Pla5numsTaxanesAnthracyclines

66(100%)66(100%)55(83%)

22(96%)23(100%)19(83%)

25(100%)23(92%)2(8%)

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Gastrointestinal Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4

Nausea 25 (34%) 9 (12%) -- 8 (38%) -- -- 10 (50%) 1 (5%) --

Vomiting 16 (22%) 6 (8%) -- 3 (14%) 1 (5%) -- 6 (30%) 1 (5%) --

Anorexia 19 (26%) 4 (6%) -- 6 (29%) 1 (5%) -- 6 (30%) -- --

Dysgeusia 8 (11%) -- -- -- -- -- 1 (5%) -- --

Diarrhea 7 (10%) 1 (1%) -- 2 (10%) -- -- 2 (10%) -- --

Dehydration -- 2 (3%) -- 3 (14%) -- -- -- -- --

Constitutional

Fatigue 31 (43%) 11 (15%) -- 7 (33%) 5 (24%) -- 6 (30%) 1 (5%) --

Weight Loss 15 (21%) -- -- 5 (24%) 1 (5%) -- -- 1 (5%) --

Blood

Thrombocytopenia 13 (18%) 17 (23%) 1 (1%) 2 (10%) 1 (5%) -- 1 (5%) -- --

Anemia 21 (29%) 8 (11%) -- 6 (29%) 2 (10%) -- 3 (15%) 1 (5%) --

Other

Hyponatremia -- 6 (8%) 1 (1%) -- 1 (5%) -- -- 2 (10%) --

AE Term

Ovarian/Endometrial/Cervical 50 mg/m2 Twice Weekly

Ovarian – 35 mg/m2 Twice Weekly

Ovarian – 50 mg/m2 Once Weekly

N=73 N=21 N=20















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SIGN–TreatmentRelatedAdverseEvents≥10%

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•  Grade3-4toxici[eswerereducedintheonceweeklydosing(50mg/m2)regimenascomparedtotwiceweeklydosing















Copenhagen

PrimaryEndpoint–DiseaseControlRate(CR+PR+SD≥12Weeks)

CancerType Dose N DCR(%) PR(%)

Ovarian

35mg/m2(BIW) 18 11(61%) 2(11%)

50mg/m2(BIW) 22 10(45%) 3(14%)

50mg/m2(QW) 19 8(42%) 3(16%)

AllDoses 59 29(49%) 8(14%)

Endometrial 50mg/m2(BIW) 20 9(45%) 3(15%)

Cervical 50mg/m2(BIW) 23 6(26%) 1(4%)

ResponseswereadjudicatedaccordingtotheResponseEvalua9onCriteriainSolidTumors(RECISTv1.1)basedoninterimunauditeddata–DCR=DiseaseControlRate(CR+PR+SD≥12)

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-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

100%

120%

Percen

tCha

nge

PecentChangeinTargetLesions















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SIGN–TumorResponse

Ovarian(N=50)

Endometrial(N=19)

Cervical(N=18)

ProgressiveDisease

Par5alResponse

CancerType Dose N PR(%) SD≥12Weeks(%)

SD<12Weeks(%) PD(%)

Ovarian AllDoses 59 8(14%) 21(36%) 4(7%) 26(44%)

Endometrial 50mg/m2(BIW) 20 3(15%) 6(30%) 3(15%) 8(40%)

Cervical 50mg/m2(BIW) 23 1(4%) 5(22%) 2(9%) 15(65%)

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PresentedatESMOCongress2016byIgnaceVergote.














Copenhagen

DCRPa5entsResponse&TimeonStudy

DiseaseControlRatePa5ents–TimeonStudy•  Forpa[entswhomet

DCR(N=44),themedian[meonstudywas20weeks

•  Fourpa[entscon[nue

ontreatment>40weeks

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PR=par[alresponse,SD≥12Weeks=stabledisease≥12weeks,PD=progressivedisease,WC=withdrewconsent0 5 10 15 20 30 55 80 105

OEOOCOOEOOCOOOEOOCCOEEOOOOOCOOOEEOOOOECOOOEO

Weeks Following Initiation of Selinexor Treatment

Canc

er T

ype

Progressive Disease

On Study

Withdrew Consent

PR PatientsSD ≥12 Weeks















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SIGN–ProgressionFreeSurvival(PFS),OverallSurvival(OS)

MedianProgressionFreeSurvivalandMedianOverallSurvival

•  MedianPFSoverallfortheovarianpa[entswas3months,endometrial3months,andcervical1month

•  MedianOSoverallfortheovarianpa[entswas7months,endometrial8months,andcervical5months

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0 12 240

50

100

Months Elapsed

Perc

ent s

urvi

val

Progression Free Survival: Ovarian, Endometrial, Cervical

Ovarian (N=59)Endometrial (N=20)Cervical (N=23)

0 12 240

50

100

Months Elapsed

Perc

ent s

urviv

al

Overall Survival: Ovarian, Endometrial, Cervical

Ovarian (N=59)Endometrial (N=20)Cervical (N=23)















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SIGN–Conclusions

•  Singleagentselinexorhasinteres[ngan[-tumorac[vityinheavily-pretreatedovarianandendometrialcancerpa[ents,withdiseasecontrolformorethan12weeksof49%and45%intheOCandECcohort,respec[vely

•  Themaintoxici[esofSelinexorarenausea,anorexia,fa[gue,andvomi[ng.Theseside

effectsaremanageablewithsuppor[vecare,especiallyinonceweeklydosing(50mg/m2)•  Majororgantoxici[esarerarelyobserved•  Clinicallysignificantcumula[vetoxici[esareuncommon

•  Fiseenpa[ents(13%)remainedonsingleagentselinexor>6months,including4pa[ents

>12months•  Combina[onstudiesareongoing&PhaseIIItrialsinOC&ECarebeingplanned

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results of a phase ii trial of selinexor, in paents …...title: opening session and award lectures...

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