Anti-CD38, SLAMF-7 and BiTE immunotherapy: Are immune therapeutics ready for the frontline?

AlexanderM.Lesokhin,M.D.AssistantMember,MyelomaServiceMemorialSloanKetteringCancerCenter,NewYork

Disclosures

• ConsultingforBristolMyersSquibb,Janssen,Aduro,andJuno

• ResearchFunding:BristolMyersSquibb,Genentech,CelgeneandJanssen

• Royalties:Serametrix,inc.

Overview

• MonoclonalAntibodiesHaveTransformedRelapsedMMTherapy

–  Anti-CD38singleagentandcombinationdata–  Anti-SLAMF7combinationdata

• EmergingdataformAbsearlierinMMnaturalhistory

• mAbbasedproductsonthehorizon

Anti-CD38

•  Human CD38 IgG1κ monoclonal antibody

•  Direct and indirect anti-myeloma activity1-5

•  Depletes CD38+ immunosuppressive regulatory cells5

•  Promotes T-cell expansion and activation5

Daratumumab Mechanisms

1.  Lammerts van Bueren J, et al. Blood. 2014;124:Abstract 3474. 2.  Jansen JMH, et al. Blood. 2012;120:Abstract 2974. 3.  de Weers M, et al. J Immunol. 2011;186:1840-8. 4.  Overdijk MB, et al. MAbs. 2015;7:311-21. 5.  Krejcik J, et al. Blood. 2016. Epub ahead of print.

Daratumumab Single Agent: GEN501 Ph I/II and SIRIUS Ph II Pooled

•  Daratumumab as a single agent1,2 –  Approved by FDA and by EMA in

relapsed/refractory multiple myeloma

•  Patients received a median of 5 prior lines of therapy

–  86.5% of patients were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD)3

•  Combined overall response rate (ORR):31%3

•  Median overall survival (OS) of 20.1 months3

–  2-year OS was ~75% in responders –  Median OS was 18.5 months in MR/SD

patients

1.  Lokhorst HM, et al. N Engl J Med. 2015;373:1207-19. 2.  Lonial S, et al. Lancet. 2016;387:1551-60. 3.  Usmani SZ, et al. Blood. 2016. 128 (1);:37-44

MR, minimal response; SD, stable disease; PD, progressive disease; OS, overall survival; CI, confidence interval; NE, not evaluable.

6

RespondersMR/SDPD/NE

RespondersMR/SDPD/NE

MedianOS=NE(95%CI,NE-NE)

MedianOS=18.5months(95%CI,15.1-22.4)

MedianOS=3.7months(95%CI,1.7-7.6)

PaAe

ntsA

live(%

)

100

75

50

25

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28Months

No.atrisk

467725

467416

466712

456311

44577

43537

43485

41454

40384

39344

28203

1282

1241

210

000*FDAapproved11/2015forrefractorymyelomaaRer3therapies

POLLUX study: design and endpoints

DimopoulosetalNEJM2016

CASTOR study: design and endpoints

PalumboetalNEJM2016

Daratumumab Combination with Lenalidomide or Bortezomib Improves Outcome in Early Relapse

DimopoulosMA,etal.NEnglJMed.2016(updatedASH2017);PalumboA,etal.NEnglJMed.2016(updatedASH2017)

POLLUX(ITT)MedianFollowup:32.9months

CASTOR(ITT)MedianFollowup:19.4months

Addition of Dara in Early Relapse Resulted in Deeper Responses

Dimopoulosetal,ASH2017;Avet-LoiseauH,etal.ASH2016

PolluxTrial

Daratumumab Associated Toxicities

• InfusionReactions– 48%(5%G3/4)inPOLLUXtrial– 45%(8.6%G3/4)inCASTORtrialHemeToxicities*(%) DRd Rd DVd VdNeutropenia 51.9 37.0 12.8 4.2Thrombocytopenia 12.4 13.5 45.3 32.9Lymphopenia 5.3 3.6 9.5 2.5

*Grade3and4

Non-HemeToxicities*(%) DRd Rd DVd VdNeuropathy NR NR 47.3 37.6Diarrhea 42.8 24.6 31.7 22.4Fatigue 35.3 27.8 21.4 24.5Infection(G3orG4) 28.3 22.8 21.4 19.0Upperrespiratoryinfxn 31.8 20.6 24.7 18.1Pneumonia 14.1 13.2 11.9 11.8

*Allgrade,unlessotherwisestated

DimopoulosMA,etal.NEnglJMed.2016;PalumboA,etal.NEnglJMed.2016

HemeToxicities*(%) DRd Rd DVd VdNeutropenia 51.9 37.0 12.8 4.2Thrombocytopenia 12.4 13.5 45.3 32.9Lymphopenia 5.3 3.6 9.5 2.5

*Grade3and4

Non-HemeToxicities*(%) DRd Rd DVd VdNeuropathy NR NR 47.3 37.6Diarrhea 42.8 24.6 31.7 22.4Fatigue 35.3 27.8 21.4 24.5Infection(G3orG4) 28.3 22.8 21.4 19.0Upperrespiratoryinfxn 31.8 20.6 24.7 18.1Pneumonia 14.1 13.2 11.9 11.8

*Allgrade,unlessotherwisestated

Daratumumab Associated Toxicities

• InfusionReactions– 48%(5%G3/4)inPOLLUXtrial– 45%(8.6%G3/4)inCASTORtrial

DimopoulosMA,etal.NEnglJMed.2016;PalumboA,etal.NEnglJMed.2016

HemeToxicities*(%) DRd Rd DVd VdNeutropenia 51.9 37.0 12.8 4.2Thrombocytopenia 12.4 13.5 45.3 32.9Lymphopenia 5.3 3.6 9.5 2.5

*Grade3and4

Non-HemeToxicities*(%) DRd Rd DVd VdNeuropathy NR NR 47.3 37.6Diarrhea 42.8 24.6 31.7 22.4Fatigue 35.3 27.8 21.4 24.5Infection(G3orG4) 28.3 22.8 21.4 19.0Upperrespiratoryinfxn 31.8 20.6 24.7 18.1Pneumonia 14.1 13.2 11.9 11.8

*Allgrade,unlessotherwisestated

Daratumumab Associated Toxicities

• InfusionReactions– 48%(5%G3/4)inPOLLUXtrial– 45%(8.6%G3/4)inCASTORtrial

DimopoulosMA,etal.NEnglJMed.2016;PalumboA,etal.NEnglJMed.2016

HemeToxicities*(%) DRd Rd DVd VdNeutropenia 51.9 37.0 12.8 4.2Thrombocytopenia 12.4 13.5 45.3 32.9Lymphopenia 5.3 3.6 9.5 2.5

*Grade3and4

Non-HemeToxicities*(%) DRd Rd DVd VdNeuropathy NR NR 47.3 37.6Diarrhea 42.8 24.6 31.7 22.4Fatigue 35.3 27.8 21.4 24.5Infection(G3orG4) 28.3 22.8 21.4 19.0Upperrespiratoryinfxn 31.8 20.6 24.7 18.1Pneumonia 14.1 13.2 11.9 11.8

*Allgrade,unlessotherwisestated

Daratumumab Associated Toxicities

• InfusionReactions– 48%(5%G3/4)inPOLLUXtrial– 45%(8.6%G3/4)inCASTORtrial

DimopoulosMA,etal.NEnglJMed.2016;PalumboA,etal.NEnglJMed.2016

Daratumumab plus Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

ChariA,etal.Blood.2017.

MedianPFS8.8months

PaAe

nt

Timefromfirstdosingdate(months)

Side Effect Profile

• IRRin50%ofpatients;most1stdose• Neutropenia77%G3/4

– Febrileneutropenia8%– G-CSFrequiredin57%

• Infection32%G3/4– Pneumonia9%;Sepsis5%

• Upperrespiratorytractinfections29%

ChariA,etal.Blood.2017.

Daratumumab - Infusion time

•  Acceleratedinfusionstartingwith3rddose–  90minuteinfusionstartingwith3rddose(Barretal,Leukemia2018)

•  Dara-rHuPH20(PAVOtrial)PhI/II(Charietal,ASCO2018)–  Recombinanthyaluronidaseformulationpermitssubqinjection–  25patientstreatedat1800mg/15mlsubq

•  12%Infusionrelatedreactions;8%neutropenia

•  44%ORR;28%VGPR–  PhaseIIIcomparingIVandscformulationaccruing(NCT03277105)

Anti-SLAMF7

Elotuzumab: Immunostimulatory Mechanisms of Action

TheimmunomodulatorydrugsmaysynergizewithelotuzumabthroughmultiplemechanismstoincreasethekillingofMMcells

ADCC, antibody-dependent cell cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; FcγR, Fc gamma receptor; NK, natural killer; SLAMF7, signaling lymphocytic activation molecule F7 1. Hsi ED et al, Clin Cancer Res 2008 and Tai YT et al, Blood 2008. 2. Balasa B et al, Cancer Immunol Ther 2015. 3. Collins SM et al, Cancer Immunol Ther 2013 and Pazina T et al, Oncoimmunology 2017. 4. Pazina T et al, EHA 2018 [PS1277]. 5. Kurdi AT et al, Mol Cancer Ther 2018. 6. Chen J et al, Nature 2017

NK

MM

Macrophage-mediated ADCP of MM cells NK-cell activation

through SLAMF7

MM cells tagged for recognition; mediation of

cell death via ADCC

NK-cell activation through CD16 (FcγR)

2

3 4

Macrophage

5

6

1

SLAMF7 Elotuzumab FcγR

Immune enhancement MM cell killing

Blood2012,120(3):552-559

•  Maximumtesteddoseof20mg/kgwithoutDLT•  Stabledisease(26.7%)

LancetHematology2015,2:e516-27

•  73paAentstreatedwithcombinaAonelotuzumab,lenalidomide,dexamethasone•  10mg/kgand20mg/kgcohorts•  84%responserate(92%in10mg/kgcohort)•  PFSimprovedrelaAvetohistoricallenalidomide/dexamethasonedata

Elotuzumab

ELOQUENT-2—Len/Dex ± Elotuzumab: Design

•  Elotuzumab*10mg•  Cycles1-3d1,8,15,22•  Cycle4+d1,15

•  Lenalidomide25mgd1-21•  Dexamethasone40mgweek

w/o•  Elotuzumab8mgIV+28mg

POw/Elo

•  Lenalidomide25mgd1-21•  Dexamethasoned1,8,15,22

PrimaryEnd-Points:PFS,ORR

SecondaryEnd-Points:

Timetotumorresponse,duraAonofresponse,HRQoL,safety

Cyclesrepeatedun?ldiseaseprogression,unacceptabletoxicity,orwithdrawal

LonialetalNEJM2015

3-yearPFS 5-yearPFSElotuzumabgroup:26% 18%Controlgroup: 18% 12%

ELOQUENT-2—Len/Dex ± Elotuzumab: PFS

LonialetalNEJM2015

34% 29%

ORR79%*ORR66%

*P<.001 •  Commongrade3or4AEswerelymphocytopenia,neutropenia,faAgue,andpneumonia

•  InfusionreacAonsoccurredin33paAents(10%)intheelotuzumabgroup

1 ElotuzumabGroup(n=321)

Controlgroup(n=325)

MedianTimeToResponse(IR)–mo 2.8 2.8

MedianDuraAonofResponse(≥PR)-mo

20.73 16.25

0

20

40

60

80

100

Elo-Rd Rd

Res

pons

e R

ate,

%ELOQUENT-2—Len/Dex ± Elotuzumab: response and safety

LonialetalNEJM2015

PR:45%

VGPR:29%

CR:5%

PR:37%

VGPR:20%

CR:9%

ELOQUENT-3 Study Design

a20 mg in patients aged >75 years bDexamethasone was split between oral (28 or 8 mg in patients aged ≤75 or >75 years) and IV (8 mg) doses on days with elotuzumab cFollow-up continued until disease progression; follow-up for survival occurred at least every 12 weeks HR, hazard ratio

An international, open-label, randomized, phase 2 trial (NCT02654132), with a 2-sidedα=0.2 and 85% power to detect a true HR of 0.57

Database lock: Feb 21, 2018 Minimum follow-up: 9.1

months

Endpoints

Primary •  PFS by investigator

Secondary •  Overall response rate (ORR)

•  Overall survival (OS)

Exploratory •  Safety

•  Duration of response (DOR)

Elotuzumab 10 mg/kg IV

Weekly

Elotuzumab 20 mg/kg IV

Every 4 weeks

Pomalidomide 4 mg orally; Days 1–21

Cycles 1–2 Cycles 3+

EPd

Pd

Dexamethasone 40 mga equivalentb; weekly

Dexamethasone 40 mga orally; weekly

Cycles are 28 days

Pomalidomide 4 mg orally; Days 1–21

Patients with MM

•  ≥2 prior lines of therapy

•  Refractory to last therapy

•  Refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor

•  Prior pomalidomide not permitted

Follow-up every 4 weeksc

Dimopolousetal.EHA2018

Progression-Free Survival (ITT Definition)

ITT, intent-to-treat; NE, not estimable

60 54 48 46 43 41 37 33 32 27 25 15 7 4 1 1 1 1 1 1 1 1 0

57 51 42 33 31 24 22 20 16 14 10 8 6 3 2 1 1 0 0 0 0 0 0

EPd

Pd

Patients at risk

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Pd

EPd

Prob

abili

ty o

f PFS

EPd n=60

Pd n=57

HR=0.54 (95% CI 0.34, 0.86); p=0.0078

Median PFS

95% CI

10.3 mo 5.6, NE

4.7 mo 2.8, 7.2

•  46% reduction in the risk of progression or death with EPd •  Median PFS was more than twice as long with EPd vs Pd

Dimopolousetal.EHA2018

All-Cause Hematologic and Special Interest Adverse Events

EPd (n=60) Pd (n=55) Exposure adjustment No PY=47.7 No PY=34.3 AEs, n (%)a Any grade Grade 3–4 Events/100 PY Any grade Grade 3–4 Events/100 PY

Hematologic AEsb 31 (52) 23 (38) 178 30 (55) 23 (42) 224 Anemia 15 (25) 6 (10) 46 20 (36) 11 (20) 85 Neutropenia 14 (23) 8 (13) 52 17 (31) 15 (27) 73 Thrombocytopenia 9 (15) 5 (8) 23 10 (18) 3 (5) 35 Lymphopenia 6 (10) 5 (8) 21 1 (2) 1 (2) 3

Special interest AEs Infections 39 (65) 8 (13) 182 36 (65) 12 (22) 230 Vascular disorders 8 (13) 2 (3) NR 5 (9) 0 NR Cardiac disorders 7 (12) 4 (7) 17 6 (11) 2 (4) 17 Neoplasmsc 1 (2) 1 (2) 2 12 (22) 6 (11) 38

Second primary malignancy 0 0 NR 1 (2) 1 (2) NR

aIncludes AEs reported between first dose and 60 days after last dose of study therapy; bIncludes hematologic AEs in ≥10% of patients; cIncludes malignant, benign, and unspecified neoplasms NR, not reported

•  Neutropenia was less common with EPd vs Pd, despite similar pomalidomide dose intensity •  Exposure-adjusted hematologic AEs and infections were lower with EPd vs Pd

Addition of Monoclonal Abs Improves Treatment of Relapsed MM

• DaratumumabadditionimprovesuponLen/DexorBort/DexresponseandPFS

–  Activeasasingleagent–  Encouragingefficacyinothercombos(PhIIIpending):

•  Carfilzomib/dex(84%ORR,CharietalASCO2018)•  Pom/DexinRRMM(60%ORR,Charietal,Blood2017)

• ElotuzumabimprovesuponLen/DexorPom/DexresponseandPFS

• BothmAbswelltolerated

Newer myeloma drugs provide better clinical response

Mailankodyetal.NatureReviewsClinOncology2015

DoesmAbbasedtherapyimproveoutcomes?

RVd +/- upfronttransplant2

Transpl armCR:59%CR/VGPR:88%

RVd armCR:48%CR/VGPR:77%

Transpl armMRD10-4:79%

RVd armMRD10-4:65%

KRd withouttransplant3

SinglearmCR:43%CR/VGPR:91%

SinglearmMRD10-5:77%MRD10-6:42%

Modified from Landgren O, et al. Semin Hematolol 2018

CR/VGPRrates

Attaletal,NEJM2017 Korde etal,JAMAOncol 2015,

MRDstatus

Daratumumab in Newly Diagnosed MM

Mateosetal.ASH2017

D-VMP with D Maintenance Improves PFS in Comparison to VMP x 9 cycles

Mateosetal.ASH2017

Charietal.ASH2017

Results •  n=22,mediancycles13(range1-13)

Side Effect Profile

•  Grade1/2IRRin27%ofpatients–mostly1stdose•  1transientgrade3cardiacfailure

Charietal.ASH2017

Elotuzumab in Newly Diagnosed MM • PhaseIIa:Elo-RVd

–  100%ORR,71%VGPRorbetter(24%CR)Laubachetal.ASCO2017

–  Lowrateofgrade3toxicity,however2deathsontrial

• RandomizedStudiesAwaitingReadout:–  RVd+/-Elo

•  PhIIIinGermany(NCT02495922)•  SWOG/NCIPhIIinHRNDMM(NCT01668719)

–  Rd+/-Elo•  Eloquent1(NCT01335399)

Monoclonal Abs as Drugs ADCC/CDC

–  CD38–  SLAMF7

FcRegion DrugDelivery

TumorCell

Bi-specifics–  BCMA-CD3–  CD38-CD3

Abdrugconjugates(ADC)–  BCMA

•  GSK2857916:60%ORR(n=35)

TargetAn]gen

Engineered Antibodies Targeting BCMA

Taietal.Front.Immunol.,10August2018

Myeloma drug pipeline for clinical practice in the U.S.

Melphalan/prednisone

Highdosemelphalan

Developedin1950sto1980s

Isatuximab

BCMA-ADC

BCMA-CD3

Melflufens.c.Dara

CD38-CD3

Selinexor

CAR-TCells

Ongoingdevelopment

Bortezomib

Thalidomide

Lenalidomide

“Noveldrugs”

2003

2006

Pomalidomide

Carfilzomib

Panobinostat

2012

2013

2015Elotuzumab

Daratumumab

Ixazomib

MyelomaServiceHaniHassoun,MDAlexLesokhin,MDNikolettaLendvai,MDNehaKorde,MDEricSmith,MD,PhDSeanDevlin,PhDShamMailankody,MDOlaLandgren,MD,PhDandteamBMTransplantServiceSergioGiralt,MDHeatherLandau,MDGunjanShah,MDDavidChung,MD,PhDandteam

Myeloma Program at MSKCC MolecularPathologyElliPapaemmanuillab,PhDHematoPathologyAhmetDoganlab,MD,PhDCellularTherapyReneirBrentjenslab,MD,PhDMolecularImagingStevenLarsonlab,MDWolfgangWeberlab,MD,PhDImmunotherapyJeddWolchoklab,MDPhD

Thankyouforyourattention!

AlexanderM.LesokhinAssistantMember

MyelomaServiceandImmunotherapeu]csClinicalCoreMemorialSloanKeaeringCancerCenter

212-639-3069