Update on Novel Therapies in the Myeloma Pipelinedistribute.cmetoronto.ca.s3.amazonaws.com/MED1707/1340-MED1707.pdf · Case 64 yo female diagnosed with MM in 2009. Treated with CYBORD

UpdateonNovelTherapiesintheMyelomaPipeline

SuzanneTrudel,MD,FRCPCAssociateProfessorofMedicine

Consultant,DivisionofHematology/OncologyPrincessMargaretCancerCentre

Disclosures

• GrantSupport:Janssen,GlaxoSmithKline,Astellas

• Consultant:Celgene,Amgen,Novartis• Honouria:Celgene,Amgen,Takeda

Case

64 yo female diagnosed with MM in 2009. Treated with CYBORD induction and ASCT first line. Received CYBORD + salvage transplant + revlimid maintenance for first relapse and carfilzomib + pom + dex (on clinical trial) for second relapse. What treatment would you consider for this patient:

A) DaratumamabB) SelinexorC) VenetoclaxD) Car-T cell therapy E ) All of the above

ProgressionFreeSurvivalandOverallSurvivalinLateStageMyeloma

1. San Miguel J., et al. Lancet Oncol. 2013;14:1055; 2Lonial S et al; Lancet 2016;387:1551

MM-003• Medianofno.ofpriortreatments:5(1-14)

• ORR/CBR(%):31/39• PFS:4.0mos• MedianOS:12.7mos

Pom-dex1

SiriusStudy• Medianpriorlinesoftreatment:5(2-14)

• ORR/CBR(%):31/36• PFS:3.7mos• MedianOS:17.5mos

Daratumumab2

≥3PriorLinesand/ordoublerefractory

What’sNewinMMTherapeutics?

• Oprozomib

Oralproteasomeinhibitors

• Afuresertib (AKTinhibitor)

• Dinaciclib(CDKinhibitor)

• LGH447(PIMkinaseinhibitor)

• Trametinib (MEKinhibitor)

• JNJ-4275693(FGFR3)

Kinaseinhibitors

• Ricolinostat(HDAC6inhibitor)

HDACs

• Venetoclax(Bcl2inhibitor)

• Selinexor(XPO-1inhibitor)

Novelmechanisms

• CAR-T

• BispecificTcellengagers(BiTEs)

• Checkpointinhibitors (PDL-1/PD-L1)

• Antibody-drugconjugates(ADC)

Immuno-therapies

HDAC,histonedeacetylase.

ProfileofSingle-AgentOprozomibinPatientsWithMultipleMyeloma:

UpdatedResultsFromaMulticenter,Open-Label,Dose-EscalationPhase

1b/2Study

RaviVij,1 MichaelSavona,2 DavidSiegel,3 JonathanKaufman,4 AshrafBadros,5 IreneGhobrial,6 AgnePaner,7

SundarJagannath,8 AndrzejJakubowiak,9 JosephMikhael,10 PrashantKapoor,11 LindaNeuman,12 JesusBerdeja13

1WashingtonUniversity,St.Louis,MO;2VanderbiltUniversity,Nashville,TN;3JohnTheurerCancerCenteratHackensackUniversityMedicalCenter,Hackensack,NJ;4WinshipCancerInstitute,EmoryUniversity,Atlanta,GA;5UniversityofMaryland,Baltimore,MD;6Dana-FarberCancerInstitute,Boston,MA;7RushUniversity,Chicago,IL;8Mt.SinaiHospital,NewYork,NY;9UniversityofChicagoMedicalCenter,Chicago,IL;10MayoClinic,Scottsdale,AZ;11MayoClinic,Rochester,MN;12OnyxPharmaceuticals,Inc.,anAmgen

subsidiary,SouthSanFrancisco,CA;13SarahCannonResearchInstitute,Nashville,TN

Phase1b/2StudyofSingle-AgentOprozomibinMM:Safety

VijRetal.Blood.2014;124.Abstract34.

Grade3/4AdverseEvents(AEs),n(%)

2/7Schedule 5/14Schedule2/7Step-UpSchedule

5/14Step-UpSchedule

Phase1b150–330mg/d

(n=21)

Phase1b+2150–270mg/d

(n=47)

Phase2240/300mg/d

(n=10)

Phase2150/180mg/d

(n=9)

Hematologic

Anemia 3(14) 11(23) 0 1(11)

Thrombocytopenia 2(10) 13(28) 0 0

Neutropenia 3(14) 6(13) 1(10) 0

Nonhematologic

Nausea 2(10) 14(30) 1(10) 0

Vomiting 4(19) 12(26) 0 0

Diarrhea 8(38) 16(34) 1(10) 0

Constipation 0 0 0 0

Increasedcreatinine 0 1(2) 0 0

Upperrespiratorytractinfections 1(5) 0 0 0

• Treatment-emergentperipheralneuropathy(PN)andrashoccurredin5(6%)and6(7%) patients,respectively• Dosereductionsanddiscontinuationsweremorecommononthe5/14schedule• DeathsduetoupperGIbleeding(n=2)andprogression(n=1)occurredonthephase2240mg/d5/14schedule

Phase1b/2StudyofSingle-AgentOprozomibinMM:Efficacy

5/14Sched

ule2

2/7Sche

dule

1

Patients,%

CBR50%

CBR32.6%

ORR31.3%

ORR23.3%3

12/7schedule:1patient(6%)wasnotevaluable.25/14schedule:5patients(12%)werenotevaluableand2patients(5%)wereoffstudybeforeresponseassessment.

3ORRin11CFZ-refractorypatients(phase2):18.2%.

Response data not shown for step-up cohorts due to limited treatment exposure


Phase1b/2StudyofSingle-AgentOprozomibinMM


Authors’ ConclusionsThemostcommongrade≥3nonhematologicAEswerediarrhea,nausea,andvomiting;ratesoftreatment-emergentPNandrashwerelow.

Recommendedphase2doseandschedule:240/300mg/dayinthe2/7step-upscheduleand150/180mg/dayinthe5/14step-upschedule.

Preliminarydatasuggestthatstep-updosingisassociatedwithimprovedtolerability.

Single-agentoprozomibhaspromisingantitumoractivity,withresponsesobservedinpatientswhohadcarfilzomib-refractoryMM.

Phase 1/2 study in combination with pom/dex for relapsed and refractory MM to open at PMCC

Selinexor,NovelAnticancerAgent:RestoresTumorSuppressors

• XPO1 is the nuclear exporter for the majority of TSPs, the GR, and eIF4E-bound oncoprotein mRNAs

• Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression

• Demonstrated clinical activity (ORR-21%) in combination with dexamethasone in heavily pre-treated (quad and penta-refractory MM)1

• Multiple postulated mechanisms of synergy with proteosome inhibitors2

1Vogl DT, et al. ASH 2016. Abstract 491; 2Turner2016,Oncotarget 2016;7:78896

SelinexorandbackboneTreatmentsOfmultipleMyelomaPatients:STOMPStudyDesign

§ Primary Objective: Determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D)

§ Patient Populations: § Arm SVd: selinexor + bortezomib + dexamethasone

§ MM patients relapsing after ≥ 1 prior therapy may include prior bortezomib, as long as not refractory to bortezomib in their most recent line of therapy

§ Arm SPd: selinexor + pomalidomide + dexamethasone (ASH 2016 - Poster 3330)

§ Arm SLd: selinexor + lenalidomide + dexamethasone § Dosing Scheme SVd: A standard 3 + 3 design will be used for dose escalations:

Bahlis N et al. ASH 2017; 977a

45% 40%

57%

40%50% 50%

18%

13%

29%

30% 8%

33%9%

7%

14%

10%

8%

17%

5%

7%8%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

AllPa1ents(N=22) PIRefractory(N=15)

PINon-Refractory(N=7)

PriorTherapies1-3(N=10)

PriorTherapies≥4(N=12)

PINon-Refractory&1-3Priors(N=6)

sCR CR VGPR PR

12

ORR 67%

ORR 77%

ORR 100% ORR 100%

ORR 80%ORR 74%


SVd ORR Efficacy: Sub Groups – Phase I



100 mg oral selinexor QW + 1.3 mg/m2 bortezomib SC QW x 4 / 5 +

40 mg dexamethasone QW

§ Good tolerability with clear anti-MM activity with once weekly selinexor in combination with once weekly Velcade

§ Considering prolonged tolerability and efficacy across all cohorts, the RP2D is:

TreatmentRelatedAEsatRP2D



Authors’ Conclusions§ TherecommendedSVdphaseIIdose:weekly POselinexor100mg,scbortezomib1.3mg/m2

andPOdexamethasone40mg.

Selinexor incombinationwithbortezomib andlowdosedexamethasone (SVd)iswelltoleratedwithlowratesofmajoradverseevents.

§ AEs weremanageable(predominantlyG1/2)andincludednausea,fatigue,anorexia,andthrombocytopenia(mostlyG3/G4).

SVdhaspotentactivityinpatientswithORR77%,67%inPI-refractorydisease,and100%inPI-non-refractory.

Convenient,cost-effectiveandhighlypotentanti-MMregimen.

Phase 3 Randomized BOSTON Study of SVd vs Vd to now open at PMCC


Celldeath(apoptosis)

InhibitionofBcl-2CriticalforApoptosis

DeathBH3-only

Bim Bid

Puma

Bak

Bax

MultidomainDeathtriggers Executioners

Caspaseactivation

ActivatedBAX/BAK

Mitochondria

CytC

Bik

Bmf

Bad

NoxaHrk

Bcl-2 Bcl-w

Bcl-xL Mcl-1A-1

Survival

Guardians

Sentinels

Signalsofcellulardamage

TargetsBcl-2

Venetoclax

1. Touzeau C, et al. Leukemia. 2014;28:210-214. 2. Punnouse EA, et al. Mol Cancer Ther.

• Survival of MM cells promoted by proteins BCL-2 and MCL-1[1]

• t(11;14) correlated with higher ratios of BCL2/MCL1 and BCL2/BCL2L1 (BCL-XL) mRNA[1,2]

• In vitro, cells positive for t(11;14) particularly susceptible to venotoclax[1,2]

VenetoclaxMonotherapyforRRMM:ORR

• In subset analysis of pts with t(11;14), similar ORR seen across subgroups with MM refractory to various single agents or multiple agents

Outcome, %Overall

Population(N = 66)

Pts With t(11;14)(n = 30)

Pts Without t(11;14)(n = 36)

Pts With High

BCL2/BCL2L1

(n = 9)

Pts With Low

BCL2/BCL2L1

(n = 15)

ORR 21 40 6 88 20sCR 3 4 3 11 0CR 4 10 0 33 0VGPR 8 13 3 11 13PR 6 13 0 33 7

Kumar S, et al. ASH 2016. Abstract 488

• Patients with RRMM; ECOG PS 0/1 and adequate organ function (N = 66)

• ≥ 70% refractory to bortezomib or lenalidomide; 61% refractory to both

• Dose-limiting toxicity (600 mg): abdominal pain, nausea (n = 2)

• No tumor lysis syndrome documented

VenetoclaxMonotherapyforRRMM:TTP

Kumar S, et al. ASH 2016. Abstract 488

VenetoclaxStudiesinRRMM

Conclusions

Venetoclaxmonotherapyissafeandtolerableandthecombinationwithbortezomibanddexamethasonedoesnotappeartoaddtoxicity.

SingleagentORR=21%;incombinationwithbortezomib+demethasoneORR67%(97%inbortezomibnon-refractory).

Higherresponsesandgreatertimetoprogressionincertainbiomarkergroups:t(11;14);highBCL2/BCL2Lratio;highBCL2 geneexpression.

Phase3trialofvenetoclaxincombinationwithbortezomibanddexamethasoneisongoing.

Kumar S et al. ASH 2016; 488a; Moreau P, et al. ASH 2016. Abstract

FGFR3 is an actionable target for t(4;14) MM

1Chesi M et al. Heamtology AM Soc Hematol Educ Program 2011;2011:344;1Keats JJ et al. Blood 2003;101:1520; 3Santra et al. Blood 2003;101:2374;4Auclair (unpublished data) 4Chang H. et al, Blood 2005;106:353:Trudel et. al, Blood, 2004;103:3521.

• t(4;14) is present in approx 15% of MM patients1

•Activating mutations of FGFR3 were detected in 17 of 57 (30%) FGFR3 expressing newly diagnosed cases, representing an overall incidence of 3% (similar results in MMGI)4 (Data from CoMMpass Study)

• Inhibition of FGFR3 kinase activity inhibits malignant transformation and induced apoptosis of constitutively activated FGFR3 expressing MM cells

JNJ-42756493(FGFRInhibitor)

JNJ42756493+pulsedexx1cycle

\

TrialDesign ScreeningBMRNAseq* and

correlativestudies

FGFR3translocation/FGFR3WT FGFR3mutated

Cycle2/Day1BMforcorrelativestudies

BMforcorrelativestudies

JNJ42756493+pulsedexx1cycle

JNJ42756493+low-dosedexuntilprogression

Documented FGFR3 expression and mutational status must be obtained at screening. Patients in whom FGFR3 expression or mutational status cannot be confirmed will be deemed ineligible 10pts10pts

*MMRF Clinical-grade Sequencing Initiative

Immunotherapeutic Strategies in Development for MM

Neri P et al., Clin Cancer Res 2016; 22:OF1-7

Bispecific T-cell engagers (BiTes)

Antibody Drug Conjugates (ADCs)

Targets for mAbs in MM

Health Canada Approved•Elotuzumab•Daratumumab

IL-6

CD38

CD40

CD56

CXCR4CD74

PD-1

CD138

β2M

MM cell

SLAMF7

Milatuzumab

PembrolizumabNivolumab

Atezolizumab

Indatuximab

Siltuximab

In clinical developmentPreclinical activity

BCMA

CD70

CD317

Lonial S et al, Leukemia 2016;30:526-535

PhaseIbPAVOStudy:SCDaratumumabinRelapsed/RefractoryMultipleMyeloma

§ Open-label,multicenter,dose-finding,proof-of-conceptphaseIbstudy

§ Primaryendpoints: Ctrough ofdaratumumabatcycle3Day1andsafety;secondaryendpoints:ORR,CR,DoR,timetoresponse

Usmani SZ, et al. ASH 2016. Abstract 1149.

Pts with measurable R/R MM, ≥ 2 lines of therapy, no prior anti-

CD38 therapy(N = 53)

*Pre/postinfusion medication includes acetaminophen, diphenhydramine, montelukast, and methylprednisolone.

Daratumumab 1200 mg SC + rHuPH20 30,000 U SC

(n = 8)*

Daratumumab 1800 mg SC + rHuPH20 45,000 U SC

(n = 45)*

4-wk treatment cycles§Every wk for 8 wks§Every 2 wks for 16 wks§Every 4 wks thereafter

Infusion time§1200 mg: 20 min (60 mL)§1800 mg: 30 min (90 mL)

Characteristic 1200 mg (n = 8) 1800 mg (n = 45)Prior lines of therapy, median (range) 5 (2-10) 4 (2-11)Refractory to PI only/IMiD only, % 0/13 4/20Refractory to both PI and IMiD, % 63 58Refractory to last line of therapy, % 88 71

PAVO:Conclusions§ SCadministrationofdaratumumab+rHuPH20safeandeffective

§ BothdosegroupsshowedresponsestoSCdaratumumab

– 1800-mggrouphaddeeperresponsesvs1200-mggroup

– PreliminaryefficacysimilartoIVdaratumumab:38%ORR,including1sCR

§ Adverseevents(AEs)forSCdaratumumab+rHuPH20similartoIVdaratumumabwithnonewsafetysignals

– Lowincidence(24%at1800mgdose)andintensity(1/53grade3,nograde4)ofinfusionrelatedreactions(IRRs)withSCdaratumumab

§ PKofSCdaratumumab1800mgsimilarto16mg/kgIVadministration

Usmani SZ, et al. ASH 2016. Abstract 1149.

Phase 3 Randomized sc vs IV to open at PMCC

BCMA

EffectorCell

MechanismsofAction:1. ADC

mechanism2. ADCC

mechanism3. Immunogenic

celldeath

xBCMA

BCMA

BCMA

GSK2857916

Lysosome

FcReceptor

ADCC

ADC

Cell death

MalignantPlasmaCell

GSK2857916:BMCAAntibodyDrugConjugated(ADC)

• BCMA is restricted to B cells at later stages of differentiation, broadly expressed on malignant PCs

• GSK2857917 is a human IgG1 anti-BCMA Ab conjugated to Monomethyl auristatine-F

– Targetspecific– EnhancedADCC

FcregionoftheAntibody

– StableincirculationLinker

– MMAF(noncellpermeable, highlypotent auristatin

Drug

ADC, antibody-drug conjugate; ADCC, antibody-dependent cell-mediated cytotoxicity; BCMA, B-cell maturation antigen; Fc, Fragment crystallizable; IgG, immunoglobulin G; MMAF, monomethyl auristatin-F

1Tai YT, et al. Blood 2014;123(20):3128-38; 2Cohen et al, ASH 2016; 1148a

*

Patient ongoing

Patient completed 16 cycles

First-in-HumanStudyofGSK2857916:Part1:ClinicalActivityandDurationonStudy

40 60 100 1400 1601208020 340320300280260240220200180 360

PDSD

PDPDSDPD

MissingMissing

SDMR

MissingMissing

SDSD

PDPD

PRSD

SDMR

VGPRSCR

VGPRPR

SDPR

MRVGPR

PRSD

0.03 mg/kg0.06 mg/kg0.12 mg/kg0.24 mg/kg0.48 mg/kg0.96 mg/kg1.92 mg/kg3.40 mg/kg4.60 mg/kg

Study treatment duration (days)

Patie

nts

6 months

≤1.92 mg/kg, n=21ORR=9.5%

≥3.4 mg/kg, n=9ORR= 66.7%

Cycle 8: increased to 0.48

Cycle 13: to 0.96

*

• First in human, dose escalation• n=30 patients at escalating doses; 70% > 5 prior lines• 100% IMiDs exposed, 100% PI exposed, 90% double refractory

Cohen et al, ASH 2016; 1148a

AEs reported in ≥20% patients, n (%)

N=30Any grade ≥Grade 3*

Any event 29 (97) 22 (73)Ocular Toxicity 16 (53) 2 (7)Nausea 15 (50) 0Thrombocytopenia 15 (50) 13 (43)Fatigue 14 (47) 1 (3)Anemia 10 (33) 6 (20)Pyrexia 10 (33) 0Chills 8 (27) 0AST increased 6 (20) 0Hypercalcemia 6 (20) 3 (10)Neutropenia 6 (20) 4 (13)

First-in-HumanStudyofGSK2857916:Part1:AEsRegardlessofRelationship

AE,adverseevent; IRR,infusion-relatedreactions

– MajorityofAEswereGrade1/2andpredicted

– 8/30(27%)patientsexperienced IRR(reportedacrossdoselevels),all Grade1/2; chills was most frequent symptom– Grade3ocularevents:dryeyein1patientimproved; inanother,limbalstemcelldeficiency resolved

– Thrombocytopeniawastransient


FirstinHumanStudywithGSK2857916,inPatientswithRelapsed/RefractoryMultipleMyeloma:

ResultsfromStudyBMA117159Part1DoseEscalation

GSK2857916waswelltoleratedwithnodoselimitedtoxicities(DLTs);Maximumtolerateddose(MTD)wasnotreached

Adverseevents(AEs)weremanageablewithcornealtoxicitiesemergingasthemostfrequentreasonfordosemodification

Thrombocytopeniaemergedmorefrequentlyastreatment-relatedathigherdoses;althougheventsweretransientandmanageable

66.7%ORRincludingastringentCRobservedathigherdosesinthisrefractorypatientpopulation

3.4mg/kgwasselectedasthedosetoinvestigateintheexpansionphase

Authors’ Conclusions


Phase 1/2 study in combination with pom/dex for relapsed and refractory MM underdevelopment and planned to open 2018





AdoptiveCellTherapy– CARTcells

Autologous T cells can be genetically modified to express chimeric antigen receptors (CARs) specific for malignancy-associated antigens

BCMA-Specific CAR in RRMM

Cohen et el ASH 2016; 1147a

Bispecific T cell engagers (BiTEs)

IgG Like• Longer serum half-life • Retain Fc function

Non IgG Like• Better tissue penetrance • Better access to epitopes

BCMA Bispecific Antibodies in Myeloma





Tumor-Mediated Immune Paralysis: PD1 checkpoint pathway

• mAb targeting PD-1/PD-L1 are approved for the treatment of solid tumors• Activities as single agents in myeloma are very modest

• (Single agent Nivolumab 1 CR, N=24; ORR=4%)1

1Lesokhin AM, et al, J Clin Oncol 2016;34:2698-704.

Pembrolizumab inCombinationwithLenalidomide andLow-doseDexamethasone forRRMM(Keynote023)

Mateos M-V, et al. J Clin Oncol 2016;34(suppl):8010a

Phase 1/2 Study: Penbrolizumab + Pom/dex in RRMM

Anti-tumor activity

Badros A, et al. ASH 2016; 490a

Pembrolizumab/Pom/DexaforRRMM

InthissmallstudyofpatientswithRRMM,thecombinationofpembro/pom/dex appearsactive

Adverseevents(AEs)occurredin~50%ofthestudypopulations- Pneumonitis in12%;Discontinuationin10%;mostAEs manageable

HighqualityresponseswereobservedinthosepositiveforPD-L1expressionandwithT-cellinfiltratethatisCD3-/PD-1-

Authors’ Conclusions

Badros A, et al. ASH 2016; 490a

TheresultssuggestthatfuturestudiesarewarrantedtofurtherunderstandtheroleofPD-1/PD-L1inhibitorsinpatientswithMM

Summary• Oralproteasomeinhibitorsareactive;Phase1bstudyofOprozomibincombination

withpom/dextoopensoon

• Selinexorbeingdevelopedincombinations;PhaseIIIofselinexorcombinedwithbortezomibanddex(BOSTONtrial)nowopenatPMCC

• Venetoclaxsingleagentandincombinationforselectpatientpopulationsalsopromising(biomarkerstoidentifytargetpopulationsneedtodevelopinparallel)

• JNJ-42756493(FGFR3inhibitor)willbeevaluatedinpatientswitht(4;14)myelomawithandwithoutFGFR3mutations

• ImmunotherapyforMMhascomeofage– Daratumamabisanewbackbone(future: scadministration-PhaseIIIstudycomparing IV

vssctoopensoon)– BMCAnovelhighly selectivetargetforimmune therapy– GSK2857916highlyactiveassingleagentandwillbeevaluatedincombinations;Phase

1/2incombinationwithpom/dextoopen in2017– BITESandcheckpointinhibitors: toosoon tosay(multiple studiesofanti-PD-1andPD-L1

incombinationsandinvariousmyelomapopulations openandenrolling)– CAR-Tpromising butneedoptimization (BMCACAR-Tplanned toopen2017)

Venetoclax Combined With Bortezomib and Dexamethasone for Patients With RRMM

ORR=PR or better; numbers are based on evaluable patients per subgroups.

Data cutoff of 19Aug2016

• Median prior lines of therapy 3 (1-13)

Moreau P, et al. ASH 2016. Abstract

ORR for all patients was 67% and 90% for bortezomib non-refractory

Venetoclax Combined With Bortezomib and Dexamethasone for Patients With RRMM

ORR: BLC2 high 94%BLC2 love 59%

TTP: bortezomib non-refractory 11.3 monthsbortexomib refractory 1.8 months

Bortezomib refractory

Moreau P, et al. ASH 2016. Abstract

Documents

Update on Novel Therapies in the Myeloma Pipelinedistribute.cmetoronto.ca.s3.amazonaws.com/MED1707/1340-MED1707.pdf · Case 64 yo female diagnosed with MM in 2009. Treated with CYBORD