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ANCO:ASCOHighlights2018Hematologic Malignancies

BrianA.Jonas,M.D.,Ph.D.UC DavisComprehensiveCancerCenter

August25,2018

BrianJonas,MD,PhDANCO:ASCOHighlights2018

Relevantfinancialrelationshipsinthepasttwelvemonthsbypresenterorspouse/partner:

Consulting:AbbVie,Amgen,ToleroGrant/ResearchSupporttoInstitution:AbbVie,Pharmacyclics,Glycomimetics,DaiichiSankyo,Genentech/Roche,Celgene,Forma,Incyte,Esanex,AROG,AcceleratedMedicalDiagnostics,LP

Therapeutics.PatentsPending:AcceleratedMedicalDiagnostics

Thespeakerwilldirectlydisclosuretheuseofproductsforwhicharenotlabeled(e.g.,offlabeluse)oriftheproductisstillinvestigational.

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ASCO2018 AnnualMeetingHeme Abstracts

• Abstract7000:Ivosidenib inmutantIDH1relapsed/refractoryacutemyeloidleukemia:ResultsofaPhase1study.

• Abstract7010:Durableresponsewithvenetoclax incombinationwithdecitabine orazacitidine inelderlypatientswithacutemyeloidleukemia.

• Abstract7502:Phase2CAPTIVATEresultsofibrutinib plusvenetoclax infirst-lineCLL.• Abstract8000:Once-weeklyvstwice-weeklycarfilzomibdosingplusdexamethasonein

patientswithrelapsedandrefractorymultiplemyeloma:Resultsoftherandomizedphase3studyA.R.R.O.W.

• Abstract8007:bb2121anti-BCMACART-celltherapyinpatientswithrelapsed/refractorymultiplemyeloma:UpdatedresultsfromamulticenterphaseIstudy.

Devel Theran=255 Leuk,MDS,Allo n=83 PlasmaCelln=60 LymphomaandCLLn=89

AbstractsCoveredn=5

Ivosidenib (IVO; AG-120) in mutant IDH1 relapsed/refractory acute myeloid leukemia (R/R AML): Results of a phase 1 study

Presented By Daniel Pollyea at 2018 ASCO Annual Meeting

Abstract7000

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Isocitrate Dehydrogenase (IDH) Mutations as a Target in AML

Presented By Daniel Pollyea at 2018 ASCO Annual Meeting

IDH1R132

Study Design and Objectives

Presented By Daniel Pollyea at 2018 ASCO Annual Meeting

DatareportedonR/RAML500mg(n=179)fromescalationandArm1

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AEs of Interest: R/R AML 500 mg (n=179)

Presented By Daniel Pollyea at 2018 ASCO Annual Meeting

OtherG3+TEAEin>1patient– febrileneutropenia(29.1%),anemia(20.1%),diarrhea(2.2%),fatigue(1.7%),dyspnea(3.9%),pyrexia1.1%)

Response in R/R AML 500 mg (n=179)

Presented By Daniel Pollyea at 2018 ASCO Annual Meeting

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Overall Survival by Best Response in R/R AML 500 mg (n=179)

Presented By Daniel Pollyea at 2018 ASCO Annual Meeting

Overalltransfusionindependence:Platelet38.5%,RBC42.3%

Abstract7000 Conclusions

• Ivosidenib isanoralIDH1inhibitorthatiswelltoleratedandinducesdurableresponsesinpatientswithR/RIDH1-mutatedAML– Non-CR/CRh respondersalsohadfavorableOS– 23%ofCR/CRh respondersclearedIDH1mutation

• NeedtobeawareofIDH-DS• Studyimpact:

– ResultspublishedinNEJM2018;378(25):2386-98– Ivosidenib (Tibsovo)FDAapprovedon7/20/18– NewstandardofcareforR/RmIDH1AML

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Durable Response with Venetoclax in Combination with Decitabine or Azacitidine in Elderly Patients with Acute Myeloid Leukemia

Presented By Courtney Dinardo at 2018 ASCO Annual Meeting

Abstract7010

Venetoclax andAML

• AML– medianageatdiagnosis68andptsareoftenineligiblefororrefractorytointensechemotherapy

• BCL-2ishighlyexpressedinAMLandisassociatedwithpooroutcomes

• Ven isanoralBCL-2inhibitorwithactivityinAMLPratz etal,BSH,#BSH18-OR-007.Mihalyova etal,Exp Hematol 2018.

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Study Design and Objectives

Presented By Courtney Dinardo at 2018 ASCO Annual Meeting

*Venetoclax doserampedupfrom100mgto400mgor800mgover3-4days

Treatment Emergent Adverse Events (AE)

Presented By Courtney Dinardo at 2018 ASCO Annual Meeting

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Response Rates by Treatment

Presented By Courtney Dinardo at 2018 ASCO Annual Meeting

CR/CRi andMRDNegative:29%overall45%Aza400

Duration of Response after CR/CRi

Presented By Courtney Dinardo at 2018 ASCO Annual Meeting

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Overall Survival

Presented By Courtney Dinardo at 2018 ASCO Annual Meeting

Abstract7010 Conclusions

• ThecombinationofVen +HMAhassignificantactivityinelderlyandhighriskAML,includinghighCR/CRi rates,MRDnegativity,DoR andOS

• RegimenistolerablebutmanagementisverydifferentfromtypicalHMAmonotherapy

• Studyimpact:– ResultspublishedinLancetOncology2018;19:216-28– FDAbreakthroughdesignationforAML1/2016– Regimenisalreadybeingusedoff-labelbymanygroups– MaybecomethestandardofcareforelderlyAML- P3RDBPCtrialofAza+Ven vsAza+Placebo isongoing

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Phase 2 CAPTIVATE Results of Ibrutinib Plus Venetoclax in <br />First-line Chronic Lymphocytic Leukemia (CLL)

Presented By William Wierda at 2018 ASCO Annual Meeting

Abstract7502

Introduction

Presented By William Wierda at 2018 ASCO Annual Meeting

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Phase 2 CAPTIVATE Study Design (NCT02910583)

Presented By William Wierda at 2018 ASCO Annual Meeting

Most Common Adverse Events* by Time of Onset in <br />All Treated Population (N=164)

Presented By William Wierda at 2018 ASCO Annual Meeting

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Deep Responses Achieved With 12 Cycles I+V With Undetectable MRD in PB and BM

Presented By William Wierda at 2018 ASCO Annual Meeting

UndetectableMRDis<1CLLcellper10,000leukocytes(<10-4)by8-colorflow

Early Undetectable MRD Responses Sustained Over Time

Presented By William Wierda at 2018 ASCO Annual Meeting

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Abstract7502 Conclusions

• ThecombinationofibrutinibandvenetoclaxinduceshighratesofresponseandMRDnegativeresponseinuntreatedCLL,includingdel(17p).

• Tumordebulkingwithibrutiniblead-inphasedecreasedriskofTLSwithvenetoclax

• Studyimpact:– Bothibrutinibandvenetoclax (after1priorRx)areapprovedinCLL

– Promisingcombinationthatmeritsfurtherstudy– P3trialevaluatingI+Vfixeddurationin1stlineCLL

Once-weekly Versus Twice-weekly Carfilzomib Dosing in Patients with Relapsed and Refractory Multiple Myeloma: Results of the Randomized Phase 3 Study A.R.R.O.W.

Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting

Abstract8000

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A.R.R.O.W.StudyBackground

• CarfilzomibapprovedforRRMM– Singleagent:20/27mg/m2days1,2,8,9,15and16ona28dschedule

– Kd:20/56mg/m2days1,2,8,9,15and16ona28dschedulewithDex (ENDEAVOR)

– KRd:20/27mg/m2days1,2,8,9,15and16ona28dschedulewithLenandDex (ASPIRE)

• CHAMPION-1studyinRRMMestablishedMTDforweeklyCarfilzomibat70mg/m2

A.R.R.O.W. Study Design

Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting

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Hematologic and Nonhematologic Adverse Events <br />

Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting

Safetyfindingsconsistentwithknownsafetyprofileofcarfilzomib,includingrisksofneuropathy,renalfailure,cardiacfailure,ischemicheartdiseaseandpulm HTN.

Overall Response Rates

Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting

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Primary Endpoint: PFS<br />

Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting

NosignificantdifferenceinOS(medianNRforbotharms)

Abstract8000 Conclusions

• Once-weeklyKd at70mg/m2improvedPFSandORRcomparedtotwice-weeklyKd at27mg/m2

• Overallsafetyprofilewascomparable• Studyimpact:

– ResultspublishedinLancetOncology2018;19(7):953-64

– AnewconvenienttreatmentoptioninRRMMthatappearstobesafeandeffective

– Overall,however,theoptimalscheduleanddoseofcarfilzomibremainsunclear(e.g.1vs2timesweekly,27mg/m2vs56mg/m2vs70mg/m2)

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ABSTRACT 8007

Presented By Noopur Raje at 2018 ASCO Annual Meeting

Abstract8007

Slide 2

Presented By Noopur Raje at 2018 ASCO Annual Meeting

BCMA(B-cellmaturationantigen)ishighlyexpressedinMMandisnotexpressedinnormalhumantissuesexceptforplasmacells.

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Slide 4

Presented By Noopur Raje at 2018 ASCO Annual Meeting

Slide 7

Presented By Noopur Raje at 2018 ASCO Annual Meeting

CRS– 39%(noG3)at150x106 cellsand82%(noG4,9%G3)at>150x106 cellsMediantimetoonset2d(1-25)

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Slide 10

Presented By Noopur Raje at 2018 ASCO Annual Meeting

MRD-evaluableresponders(n=16)– 100%wereMRD-neg(<1x10-4 byNGS)

Slide 12

Presented By Noopur Raje at 2018 ASCO Annual Meeting

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Abstract8007 Conclusions

• bb2121atactivedoses(≥150x106 CART-cells)inducesdeepanddurableresponsesinheavilypretreatedRRMM

• TolerablesafetyprofilewithmostlyG1/2CRSandinfrequenttocilizumabandsteroiduse

• Studyimpact:– FDAbreakthroughdesignationforRRMM11/2017– Anti-CD19CART-cellsareapprovedforR/RaggressiveB-cellNHLandR/RB-ALL,andthisstudyshowsthataCART-cellplatformforMMisalsofeasibleandeffective

SummaryandTakeHomePoints

• Ivosidenib isanoralmIDH1inhibitorandisanewstandardofcareforR/RIDH1-mutatedAML.IDH-DSisapossibledangeroussideeffect.

• Venetoclax plusHMAhassignificantactivityinelderlyAMLandmayultimatelybecomethestandardofcareforolderunfitAML.ManagementisverydifferentfromstandardHMAmonotherapy.

• Thecombinationofibrutinibplusvenetoclax ishighlyactiveandinducesahighrateofMRDnegativeresponsesin1st lineCLL.TheregimenhaspotentialtobecomeastandardregimenforCLL.

• Convenientonceweeklycarfilzomib70mg/m2dosingplusdexappearssafeandeffectiveinRRMMandrepresentsanewtreatmentoption.Theoptimaldoseandscheduleofcarfilzomibremainsunclear.

• Anti-BCMACART-celltherapyhasatolerablesafetyprofileandiseffectiveinRRMM,andmayultimatelyjointhelistofapprovedCART-celltherapies.

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Questions?bajonas@ucdavis.edu

OtherAbstractsofPotentialInterest

• Abstract7001:EarlyHMAforlowriskMDS

• Abstract7002:Bosutinib vsimatinib firstlineforCML

• Abstract7003:Long-termTFRaftersecond-linenilotinibdiscontinuation

• Abstract7004:moxetumomabpasudotox forR/Rhairycellleukemia

• Abstract8003:ibrutinib/rituximabvsplacebo/rituximabinR/RWM

• Abstracts8015,8017,8022and8032:carfilzomibscheduleanddosing

• Abstract8025:autotransplant inMMfeasibleinages75+

• Abstract7500:lenaidomide plusrituximabvschemoplusrituximabfollowedbyrituximabmaintenanceforuntreatedfollicularlymphoma

• Abstract7501:acalabrutinib foruntreatedandR/RWM

• Abstract7504:anti-CD47plusrituximabforR/RNHL

• Abstract7508:HighratesanddurabilityofMRD- withvenetoclaxplusrituximabinR/RCLL

• Abstract7515:RituximabmaintenanceafterBRinMZL