Anticorpi Monoclonali: i risultati delle sperimentazioni ... · Innate and Adaptive immunity in cancer Innate cells, including Natural Killer Cells, respond rapidly and are the body’s

Anticorpi Monoclonali: i risultati delle sperimentazioni cliniche nel trattamento del Mieloma Multiplo

Pellegrino Musto

Direzione Scientifica

IRCCS, Centro di Riferimento Oncologico della Basilicata

Rionero in Vulture – Pz

IRCCS

CROB

• 1% of cancer

• 10% of hematological malignancies

• 2-4 cases/year/100.000

• Uncurable disease (?)

Multiple myeloma: a malignant proliferation of bone marrow plasma cells

abnormal production of a monoclonal immunoglobulin (M-protein)

Major clinical issues

• Osteolytic bone lesions

• Hypercalcemia

• Anemia

• Renal failure

• Heterogeneous clinical outcome (MGUS, SMM,

symptomatic myeloma, plasma cell leukemia)

• High molecular/genomic heterogeneity

Survival improvement

Myeloma Trialists’ Collaborative Group J Clin

Oncol. 1998;16:3832-42. Usmani SZ, et al. Leukemia. 2013;27:226–32.

Where we come from…

Median age 61 5-year OS with MP: 24%

OS

Years

0 1 2 3 4 6

0

100

40

60

80

20

5

Allocated cct (% ± SD)

Allocated MP (% ± SD)

24.4%

23.0%19.4%

18.0%

1.4% SD 1.4(log-rank)

2p>0.1; NS)

…where we are now

Median age 59 5-year OS with TT3: 73%

OS CR duration

Years

0 6 7 8 9

0

100

40

60

80

20

3 4 51 2

p<0.0001

TT3

TT2 + Thal

TT2 -Thal

TT1

Years

0 6 7 8 9

0

100

40

60

80

20

3 4 51 2

p<0.0001

TT3

TT2 + Thal

TT2 -Thal

TT1

Melfalane prednisone

Alte dosidi Melfalan

VAD

ABMT

Storia della terapia «real world» del mieloma multiplo

Alte dosi diDesametasone

HDT+ASCT

Talidomide

Bisfosfonati

Bortezomibin recidiva

Len-Dex in recidiva

Bortezomib + antraciclinaliposomiale in recidiva

VMP

MPT

VTD ASCT

Talidomide inmantenimento

1962

1983

1986

1996

1999

2003

2005

2008

2009

2011

2012

2014

1984

2013

BortezomibSCRd FDA

Dara FDA

PomaEMEA

2015

MPR-R

RD cont.MPR-RCarlfizomibKRdDara EMEAIxazomibFDA

Significant Advances in Multiple Myeloma Have Been Made in the Last Decade, but…

N=1038 patients with newly diagnosed MM between January 1, 2001 and

December 31, 2010

Patients were grouped into two time intervals based on year of diagnosis (2001–2005 and 2006 –2010) to compare OS rate

5

MM=multiple myeloma; OS=overall survival.

Kumar SK et al. Leukemia. November 15, 2013. doi:10.1038/leu.2013.313Kumar SK, et al. Leukemia. 2012;26:149-157.

The use of thalidomide, lenalidomide, and bortezomib as part of initial therapy has improved overall survival rates

1-year mortality: 8%, median OS NR

1-year mortality: 19%, median OS 3.8 yrs

Follow-up from diagnosis (years)

6543210

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

po

rtio

n s

urv

ivin

g Received novel agents

No novel agents

Poor survival in patients refractory to IMIDs and PIs

Innate and Adaptive immunity in cancer

Innate cells, including Natural Killer Cells, respond rapidly and are the body’s first line of defense against cancer2

Adaptive cells, including T cells and B cells, take longer to develop a tumor antigen-specific immune response2

NK T cell, Natural Killer T cell.1. Dranoff G. Nat Rev Cancer. 2004;4:11-22. 2. Borghaei H et al. Eur J Pharmacol. 2009;625:41-54.

7

Myeloma cells mediate profound immune dysfunctions in tumormicroenvironment leading, in particular, to NK cell suppression

MDSC

Agrawal et al., Exp Rev Clin Immunol 2008 Myeloid-derivedsuppressor cells

NK precursor

T reg

Killing of DC to preventNK cell priming

Immunosuppressivefactors such as IL-

10,TGFb and IDO Soluble

ligandssuch asMICA/B

Reduced NK differentiation

Myeloid-derivedimmunosuppressive factors(ROS, iNOS, O, IDO, TGFb…)

Anti-tumor immune response

Tumor growth

Tumor immunity: a dynamic interaction

Subclinical pre-diagnosis phase Clinical phase

ELIMINATIONof tumor cells

(partial or complete)

EQUILIBRIUMbetween

immune responseand tumor growth

ESCAPEof tumor cells

from immune control

Imm

un

ose

lect

ion

/ed

itin

g

Jelinek et al. Blood Reviews, 2015

Sondergeld et al. Clini Adv Hematol Oncol, 2015

10

Humanization of antibodies to overcome immunogenicity

‘ximab’

Chimeric mouse or rat Ig variable regions; human

constant regions (Rituximab)

’zumab’

Humanized chimeric mAb with only complementarity

determining regions being mouse origin (Bevacizumab,

Elotuzumab)

’umab’

Fully human(Daratumumab)

’momab’

Fully murine(Tositumomab)

Imai & Takaoka. Nature Reviews Cancer 2006; 6: 714-727

Immunogenicity

+ -

Targets for monoclonal antibody therapy in myeloma

Adapted from: Anderson KC. J Clin Oncol 2012;30:445-452

Cell surface targets

Signaling molecules

IL-6RANKLDKK1VEGFIGF-1SDF-1BAFF, APRIL

Cell Surface Targets

CS1 (SLAMF7) CD38

Vellette et al. Crit Rev Oncol/Hem. 2013 168-77; Malavasi et al., Physiol Rev. 2008;88(3):841-86.

SLAMF7: Signalling lymphocytic activation molecule F7.

Mechanisms of action

Van de Donk et al, Blood 2015 (submitted).

ADCC: antibody dependent cell-mediated cytotoxicity; ADCP: antibody depedent cell-mediated phagocytosis;

CDC; complement dependent cytotoxicity.

Monoclonal antibodies in MM

Target Antibody Mechanism of

action

Activity as

single

agent

Activity/under

evaluation in

combo

CS1

(SLAM

F7)

Elotuzumab

(Humanized IgG1k)

ADCC

Enhance NK

activity

Interference with

cell interaction

- + VD

+ Rd

CD38 Daratumumab

(Fully human IgG1k) ADCC

CDC

ADCP

Direct induction

of apopotosis

Modulation CD38

function

+ + V-based

+ Rd

+ Pd

Isatuximab

(SAR650984; chimeric

IgG1k)

+ + VCD

+ Rd

MOR202

(fully human IgG1l)

+

MM: multiple myeloma; ADCC: antibody depandent cell-mediated cytotoxicity; ADCP: antibody depedent cell-

mediated phagocytosis; CDC; complement dependent cytotoxicity; VD: bortezomib-dexamethasone; Rd:

lenalidomide;dexamethasone; Pd: pomalidomide-dexamethasone; VCD: bortezomib-cyclophosphamide-

dexamethasone; V: bortezomib

Mechanisms of action of Daratumumab

Jelinek et al. Blood Reviews, 2015

Phase 1/2 trial: Daratumumab single agent in

relapsed/refractory MM (GEN501)

Expansion cohort: Extended treatment for close to 2 years

Dose-escalation cohorts

Open label, weekly iv infusion, 8 weeks

Dose-escalation: 3+3 scheme*

0.005→0.05→0.1→0.5→1.0 →2.0→4.0→8.0→16.0 →24.0 mg/kg

Part 2: 72 pts

Open label, single arm, 8 and 16 mg/kg

8 weekly infusions followed by

8 biweekly infusions followed by up to

72 monthly infusions

Different combinations of premedications, predose infusions, infusion

volumes, and infusion rates (3 – 4 hours)

Part 1: 32 pts

* - start with pre-dose at 10% of full dose, max 10 mg

- 3 weeks’ delay after first full dose

- governed by independent data monitoring committee

Lokhorst et al. N Engl J Med 2015; 373:1207-1219

Daratumumab monotherapy (GEN501)

Part 2: Patients characteristics (72 Pts)

8 mg/kg (n=30) 16 mg/kg (n=42)

Median prior lines 4 4

Refractory to

Bortezomib

Lenalidomide

Bortezomib & lenalidomide

70%

87%

63%

71%

74%

64%

Overall, 79% were refractory to last line and 76% had received ASCT


Re

sp

on

se

ra

te (

%)

40

8 mg/kg

(n=30)16 mg/kg

(n=42)

ORR=36%ORR=10%

PR n=3

(10%)

PR n=11

(26%)

VGPR n=2 (5%)

CR n=2 (5%)

30

20

10

0

Response increased to 56% in patients with ≤3 lines

Median time to first & best response: 0.9 & 1.8m


Daratumumab monotherapy (GEN501): Part 2 efficacy

8 mg/kg:

Median 2.4 months

16 mg/kg:

Median 5.6 months

Duration of response: 6.9 m & not reached

OS @ 12 months: 77% in both groups

Response Rate Progression-free survival

Median follow-up:

16.9 months (8 mg/kg), 10.2 months (16 mg/kg)

PR: partial response; VGPR: very good PR; CR complete

response; ORR overall response rate; OS: overall survival

• Most AEs grade 1 or 2

– Most common (≥ 25% of pts): fatigue, allergic rhinitis, pyrexia

– Nasopharyngitis 24%, cough 21%

• Grade 3 or 4 AEs:

– 53% in 8 mg/kg group and 26% in 16 mg/kg group

– In ≥ 2 patients: pneumonia (5 pts), thrombocytopenia (4 pts),

neutropenia, leukopenia, anemia, hyperglycemia (2 each)

• Infusion-related reactions:

– 71% (all grade 1/2, except 1 grade 3)

– Mostly during first infusion (only 8% in more than one infusion)

– No discontinuation


Daratumumab monotherapy (GEN501): Part 2 safety

Infusion-related reactions

• Possible signs and symptoms of acute infusion reactions

– Allergic reactions/hypersensitivity

– Skin reactions

– Systemic reactions

– Respiratory reactions

– Cardiovascular symptoms

• Administer pre-medication to reduce the risk of IRRs (approximately 1 hour prior to every

daratumumab infusion)

– intravenous corticosteroid

(methylprednisolone 100 mg or an equivalent long acting corticosteroid)

– oral antipyretic

(paracetamol at 650-1000 mg)

– oral or intravenous antihistamine

(diphenhydramide 25-50 mg or equivalent)

• Post-medication corticosteroids on 1st and 2nd day

after all infusions

• In case of occurrence of IRRs

– React early to mild signs of symptoms and immediately

stop the infusion

– Manage symptoms appropriately, consider e.g. antihistamines, corticosteroids

– Once symptoms have resolved, treatment may be resumed

at half the infusion rate

– In case of grade 4 IRRs permanently discontinue treatment

• Open-label, international, multicenter study

• Initially, pts randomized 1:1 to receive

DARA

– 8 mg/kg every 4 weeks or

– 16 mg/kg every week for 8 weeks, every

2 weeks for 16 weeks, then every 4 weeks

• 16 mg/kg DARA established as the

recommended dose for further study

• Results are reported for all patients treated

with 16 mg/kg DARA (n=106)

16 mg/kg

(n = 16)

8 mg/kg

(n = 18)

16 mg/kg

(n = 106)

Response

evaluated

Randomization

Additional 90

patients enrolled

at 16 mg/kg

Primary objective

• ORR in pts with ≥3 prior lines of therapy or disease refractory to PI and IMiD

Secondary objectives

• TTP, PFS, OS, DOR, TTR, clinical benefit rate, safety and tolerability

Lonial et al. ASCO 2015 (Abstract LBA8512); oral presentation

Phase 2 trial: Daratumumab in refractory MM

(MMY2002, Sirius trial)

Sirius Trial: Baseline patients characteristics

• Patients (n=106)

– ≥3 prior lines

– 80% prior ASCT

– 97% refractory to last line

– 95% refractory to proteasome inhibitor and IMiD

– 77% refractory to alkylating agents

– 66% refractory to 3 of 4 therapies (Bort, Len, Carf, and Pom)

– 63% refractory to pomalidomide

– 48% refractory to carfilzomib

• Treatment:

– Daratumumab monotherapy (16 mg/kg)


Sirius Trial: overall response rate

• ≥ VGPR 12%, ≥ MR 34%

• Median time to response: 1 month

• Median duration of response: 7.4

months

0

5

10

15

20

25

30

35

16 mg/kg

ORR = 29%

sCR: n=3 (3%)

VGPR: n=10 (9%)

PR: n=18 (17%)


33 33

30

21 20

30 29 28 2826

21

0

5

10

15

20

25

30

35

40

OR

R, %

Refractory to

All patients By patients subgroup

Sirius Trial: survival

Pooled analysis (GEN501/Sirius):

median follow-up:14.8 months, estimated median OS 19.9 months

96106 85 82 64 23 10 2 0Patients at

risk

80

100

60

40

20

00 42 6 8 16141210

Months from start of treatment

Pati

en

ts a

live (

%)

Median NE

(95% CI, 13.7–NE)Median 3.7 months

(95% CI, 2.8–4.6)

63106 38 32 17 5 4 1 0Patients at

risk

80

100

60

40

20

0

0 42 6 8 16141210

Months from start of treatment

Pa

tie

nts

pro

gre

ss

ion

-

fre

e a

nd

ali

ve

(%

)

Usmani et al Abs #29 Orlando, ASH 2015; Lonial et al. ASCO 2015 (Abstract LBA8512)

Progression-free survival Overall survival

Sirius Trial: Safety

• Serious AEs: 30%

• Grade 3/4: 23% (anemia &

thrombocytopenia: more frequently in non-

responders)

• No discontinuations due to DARA-related

AEs

• No febrile neutropenia reported

• Infusion-related reactions (IRR)

– 42.5% (mainly grade 1/2 & during first

infusion (Only 7% at >1 infusion)

– 4.7% grade 3 ( No grade 4)

• The most common IRRs

included nasal congestion

(12%), throat irritation (7%),

cough, dyspnea, chills, and

vomiting (6% each)

• No patients discontinued

treatment due to IRRs


0

5

10

15

20

25

30

35

40

45

Overall 1st infusion 2nd infusion 3rd or laterinfusion

Incid

en

ce

of IR

R, %

Daratumumab plus Len-Dex in Relapsed/Refractory myeloma

Overall Best Response

• Mean duration of follow-up: 12.9 months (Part 1, range: 4.0-22.1) and 5.6 months (Part 2, range: 2.7-7.0)

• Median time to response: 1 month for 16 mg/kg in Part 2

• Median time to CR in Part 2 was 4.9 months

• As has been observed with other mAbs, DARA may interfere with IFE

– Interference assay to be validated

CR 31% CR 6.7%

VGPR 46%

PR 23%

VGPR 43%

PR 37%

CR 6.7%

CR 8.0%CR

11.8%

VGPR 43.3%

VGPR 52%

VGPR 52.9%

100

86.7

50.0

60.064.7

Treatment

Perc

enta

ge (

%)

0

20

40

60

80

100

Part 1 Part 2

Overall best response

Treatment

0

20

40

60

≥2 cycles

(N = 30)

≥4 cycles

(N = 25)

≥6 cycles

(N = 7)

Perc

enta

ge (

%)

VGPR or better response bycycles of treatment (Part 2)

PR VGPR CR

27

Plesner T, et al. Oral presentation: 56th American Society of Hematology (ASH) Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA, USA.

.

Serious Adverse Events

• 15 SAEs reported:

– Part 1: 7 (all assessed as

unrelated to DARA)

– Part 2: 8 (4 DARA-related)

• DARA related SAEs:

– Pneumonia, neutropenia,

diarrhea

(1 patient each [16 mg/kg])

– Laryngeal edema

(1 patient [16 mg/kg])

Plesner et al. ASH 2014 (Abstract 84); oral presentation

Daratumumab plus Len-Dex in RRMM: safety

≤8 mg/kg

Part 1

(n = 10)

16 mg/kg

Part 1

(n = 3)

16 mg/kg

Part 2

Current infusion

program (n = 21)

16 mg/kg

Part 2

Accelerated infusion

program (n = 11)

Perc

ent (%

)

0

20

40

60

Infusion-related reactions

20.020.0

33.3

38.1

4.8

63.6

First infusion Subsequent infusion

Infusion related Reactions

• 19/45 patients reported IRRs

• Majority grade 1 and 2

• Most (86%) during first infusion

• 18/19 patients with IRRs

recovered and continued

subsequent infusion

• Accelerated infusion was

tolerable but associated with

higher incidence of grade 1/2

Aes

•

MMY1001 (NCT01998971): Phase I Study of Daratumumab + Backbone Treatments

• VD: bortezomib (1.3 mg/m2 twice weekly x 4 cycles, then once weekly x 14 cycles)/dexamethasone (20 mg)a

– Newly diagnosed; n = 6

• VMP: bortezomib (1.3 mg/m2 twice weekly x 1 cycle, then once weekly x 8 cycles)/melphalan (9 mg/m2)/prednisone (60 mg/m2)b

– Newly diagnosed transplant ineligible; n = 12

• VTD: bortezomib (1.3 mg/m2 twice weekly x 4 cycles, then once weekly x 14 cycles )/thalidomide (100 mg daily x 21 days)/ dexamethasone (20 mg)a

– Newly diagnosed; n = 12

• PD: pomalidomide (4 mg once daily)/dexamethasone (40 mg)c

– Relapsed/refractory,≥2 lines of therapy including 2 consecutive cycles of lenalidomide and bortezomib; n 100

aDaratumumab once weekly x 2 cycles, then once every 3 weeks x 16 cycles or until transplantation.bDaratumumab once weekly x 1 cycle, then every 3 weeks x 8 cycles.cDaratumumab once weekly x 2 cycles, then once every 2 weeks x 4 cycles, then once every 4 weeks x 7 cycles or until disease progression; dexamethasone 20 mg if age >75 y.

ClinicalTrials.gov Identifier: NCT01998971. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01998971?term=NCT01998971&rank=1. Accessed February 23, 2015.

29

http://www.clinicaltrials.gov/ct2/show/NCT01998971?term=NCT01998971&rank=1

Daratumumab + backbone treatments (MMY1001)

Response rate

MMY1001: Best Response (PR or Better) and Duration of Follow-up

Time from first dosing date (weeks)

VD + DARA VTD + DARA VMP + DARA POM-D + DARA

100003

100001

100004

100011

100005

100008

100014

100015

100017

100016

100019

100021

100022

100026

100024

100027

100028

100012

100023

100029

100018

100018

100018

100013

100009

0 3 6 9 12 16 18 21 24 27 30 33

PR

PR

PR

PR

PR

sCR

PR

PR

VGPR

VGPR

PR

PR

PR

PR

PR

PR

PR

PR

PR

VGPR

VGPR

VGPR

VGPR

PR

PR

PR

PR

PR

X

VGPR

Moreau P, et al. Oral presentation: 56th American Society of Hematology (ASH) Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA, USA.

31

• Most common AEs were hematologic; not likely related

to Dara

• Grade ≥3 AEs occurred in 22 (45%)

– Most common: neutropenia (25%), thrombocytopenia

(10%), anemia (8%), and pneumonia (6%)

• Apart from IRRs, the addition of DARA did not result in

additional toxicity

• IRRs occurred in 24 (49%) patients overall

– Generally grade 1 or 2 (3 grade 3 and no grade 4)

– Most occurred within the first day of the first cycle

Mateos et al. EHA 2015 (Abstract P275); poster presentation

Daratumumab Safety (MMY1001)

Blood compatibility testing for patients

receiving anti-CD38 mAbs

• CD38 is weakly expressed on human red blood cells (RBCs)

• Daratumumab does not interfere with the major antigens of

ABO/RhD typing, but with the minor ones

• Daratumumab binds to CD38 on RBCs false positive results

in the panreactive Indirect Antiglobulin Test (indirect Coombs

test)

Chapuy et al. Transfusion. 2015;55(6 Pt 2):1545-54

Oostendorp et al. Transfusion. 2015;55(6 Pt 2):1555-62

Hannon JL, et al. Transfusion. 2015;55(6 Pt 2):1555-62

Daratumumab binds

to CD38 on RBCs2

CD38

Daratumum

ab

Daratumumab Development In all MM Settings

Ph 1 Ph 2 Ph 3KEY:

Ph 2 Study MMY2002DARA in ≥3

prior lines or double

refractory MM; single agent, 2-part study

Ph 3 Study MMY3007

DARA + VMP vs VMP in noASCT

Ph 3 StudyMMY3006

DARA + Vel/Thal/dex vs Vel/Thal/dex in

ASCT

Ph 1/2 Study 501FIH, single agent, dose escalation,

safety, PK

Ph 1/2 Study 503Rev/dexcombo

Ph 1b Multi-arm MMY1001 combo

Ph 2 Study SMM2001

Randomizedsingle agent

Ph 3 StudyMMY3004

Vel/dex/DARA vsVel/dex in pts1 prior therapy

Smoldering

Myeloma

Newly Diagnosed

Transplant & Nontransplant

Maintenance

Relapsed

1+ Prior Line

Relapsed-Refractory

Double Refractory

3+ Prior Lines

Ph 3 Study MMY3003

DARA + Rev/dexvs Rev/dex

1 prior therapy

Ph 3 StudyMMY3008

DARA + Rd vs R/d NoASCT

34

Elotuzumab: A Monoclonal Antibody Targeting SLAMF7

Elotuzumab Humanized, IgG1 mab specific for human SLAMF7

― No cross-reactivity with non-human homologues or other SLAM family members

Binds to a membrane-proximal motif of SLAMF7― Critical for mediating killing of target cells (in vitro)

SLAMF7 = Signalling Lymphocyte Activation Molecule Family 7;ITSM = Intracellular Tyrosine Switch MotifEAT-2 = Ewing's Sarcoma associated transcript 2

C2

V

Y261

Y281

CO

OH

NH

2

TM

Elotuzumab

mediates “inhibitory” signal

mediates “activating” signal EAT-2/CD45 dependent

mechanism (NK cells)

mediates self-adhesion

ITSM

SLAMF7

Expression highest on Plasma Cells

Varied expression across hematopoietic cells (NK, NK-T, DC, B, TCD8+, PC)

Not express on non-hematopoietic cells

SLAMF7 K/O Phenotype: compromised NK function

Veillette and Guo, Critical Reviews Oncol Hematol, 2013. Cruz-Munoz et al, Nature Immunology, 2009.

Differential SLAMF7 Signalling: Elotuzumab Activates NK Cells but not Myeloma Cells

Guo et al (Mol Cell Bio), 2015: Phosphorylation of SLAMF7 is mediated by Src kinases. Inhibitory mechanism (in EAT2-

/CD45+ cells) is mediated by SHIP-1. MM cells are deficient for EAT-2 and CD45, therefore SLAMF7 does not mediate activating or inhibitory effects in these cells.EAT-2 = Ewing's Sarcoma associated transcript 2; SLAMF7 = Signalling Lymphocyte Activation Molecule Family 7.

Myeloma CellsNK Cells

EAT-2+ EAT-2-

Activation No effect

Mechanisms of action of Elotuzumab

Liu et al. Blood Lymphat Cancer, 2014

The primary mechanism of action of elotuzumab against myeloma cells isNK cell-mediated ADCC. Elotuzumab can also interfere with the adhesionof myeloma cells to BMSC, or can induce NK cell activation directly throughbinding CS1 expressed on NK cells.

Dose-limiting toxicities were assessed during cycle 1

1701 A Phase I Multicenter, Open-Label, Dose Escalation Study of Elotuzumab Monotherapy in Subjects With advanced MM

Zonder JA et al. Blood. 2012;120(3):552-559

1701 Elotuzumab Monotherapy :Tolerability

• MTD was not reached up to the highest dose level of 20 mg/kg

• Key SAEs were first dose infusion reactions (IR)

– Gr 3 allergic reaction, Gr 2 rigors, fever, chest pressure, bradycardia

– No dose correlation seen for infusion reactions

– No serious infusion reactions following IV corticosteroid premedication

• No neutropenia or thrombocytopenia

• Transient reduction in lymphocytes seen within hours following first dose

AEs were generally mild to moderate in severity, and AEs attributed to study medication were primarily infusion-related

Zonder JA et al. Blood. 2012

1701 Elotuzumab Monotherapy : Pharmacodinamics

Saturation of CS1 by elotuzumab on bone marrow target cells increased as the dose of elotuzumab

increased. At dose of 10 mg/kg and 20 mg/kg elotuzumab, CS1 receptors on bone marrow-derived myeloma cells were consistently saturated. Lower dose groups

exhibited more variation in the level of target cell saturation achieved.

1701 Elotuzumab Monotherapy: Efficacy

Zonder JA et al. Blood. 2012

Elotuzumab Synergizes With BortezomibTo Enhance Myeloma Cell Death

42

Van Rhee et al (Molecular Cancer Therapeutics), 2009.

Induces myeloma cell injury and lowers threshold for NK cell-mediated killing of myeloma cells by elotuzumab

Direct NK Cell activation

NK CellMyeloma Cell

Elotuzumab

SLAMF7

ADCC

CD16a +

Enhances expression of activating ligands and reduces inhibitory ligands on MM cells

Elotuzumab Synergizes with Lenalidomideto Enhance Myeloma Cell Death

Balasa et al (Cancer Imm and Immunotherapeutics), 2015.

LenalidomideInduces myeloma cell injury and lowers threshold for NK cell-mediated killing of myeloma cells by elotuzumab

Direct NK Cell activation

NK Cell

Elotuzumab

SLAMF7

ADCC

CD16a +

LenalidomideEnhances adaptive and innate immune system including production of IL2 to increase NK cell activity

Myeloma Cell

Phase 1 and 2 Elotuzumab Trials (Relapsed/refractory)

Trial Phase Treatment Sample Size Efficacy (%)Median

PFS

1701 1 Elotuzumab monotherapy 35 SD=26.5 —

1702 1 Elotuzumab + bortezomib 28 ORR=48 9.46 mo

1703 1Elotuzumab + lenalidomide/

dexamethasone28 ORR=82 33 months

1703 2Elotuzumab + lenalidomide/

dexamethasone73 ORR=84 29 months

009 2Elotuzumab + bortezomib/

dexamethasone152 ORR=65 9.7 months

These results compare favorably with ORR (27-38%/60%–61%) and median TTP (6-7/11.1-11.3 months) observed in four phase II/III clinical studies of bortezomib/dexamethasone or lelenalidomide/dexamethasone, respectively with similar patient populations

1702 Phase 1 trial Elotuzumab in combination with Bortezomib in the treatment of RRMM: Pharmacodinamics

Pharmacodynamic studies of MM cells isolated from patient bone marrow biopsies demonstrated that these threshold concentrations were associated with high saturation (80% and 95%, respectively) of available CS1 binding sites at doses of 10 mg/kg and 20 mg/kg, similar to that seen in murine models and in a clinical study of elotuzumab monotherapy.

Jakubowiak AJ et al. J Clin Oncol. 2012

1703 A Phase Ib/II, Multicenter, Open-Label, Dose-Escalation Study of Elotuzumab in Combination With Lenalidomide and Dexamethasone in Subjects With Relapsed MM: PK and PD

• PK and PD studies demonstrated that elotuzumab doses of 10 and 20 mg/kg achieved serum levels of antibody predicted to achieve optimal antitumor activity based on preclinical xenograftmodels and resulted in similar levels of CS1 receptor saturation on malignant bone marrow plasma cells.

• At these drug levels, 80% of CS1 sites on bone marrow MM cells were fully saturated .

Lonial S et al. J Clin Oncol. 2012

CA204-009: A randomized, open-label, phase 2 study of bortezomib and

dexamethasone with or without elotuzumab in patients with

relapsed/refractory myeloma (RRMM)

EloBd to progression

Bd to progression

E

N

R

O

L

L

M

E

N

T

N = 77

N = 75

PFS: primary endpoint

FOLLOW UP

• Cycles 1-8: 21 day cycles

• Cycle 9 onwards: 28 day cycles

• Cross over not permitted

Sample Size/Power:

N = 152. 80% power to detect a HR of 0.69 with 103 progression events

2-sided 0.30 significance level specified to test for difference in PFS between arms (p≤0.3 was considered significant)

– Investigational arm (EloBd): elotuzumab 10 mg/kg IV + bortezomib 1.3 mg/m2 IV* + (dexamethasone 20 mg po, or 8 mg IV and 8 mg po)

– Control arm (Bd): bortezomib 1.3 mg/m2 IV + dexamethasone 20 mg po

Accrual from Nov 2011

Interim analysis: June 2014

*Bortezomib to be administered SC following regulatory approval Jakubowiak A et al. EHA 2015 abs 103

Key inclusion

criteria

• RRMM

• 1–3 prior

therapies

• ECOG PS ≤2

• Prior

proteasome

inhibitor (PI)

treatment

permitted if not

refractory to PI

CA204-009: Baseline Demographics and Characteristics

Characteristic EBd (n=77) Bd (n=75) Total (N=152)

Age, mean (range) 65.4 (25–82) 65.1 (30–85) 65.3 (25–85)

≥65 years 43 (56) 42 (56) 85 (56)

≥75 years 15 (20) 14 (19) 29 (19)

Male, n (%) 42 (55) 37 (49) 79 (52)

Prior lines of therapy, n (%)

1 55 (71) 51 (68) 106 (70)

2 or 3 22 (29) 24 (32) 46 (30)

Months since diagnosis, median (range) 45 (9–296) 44 (8–285) 45 (8–296)

Prior proteasome inhibitor use, n (%)

Yes 38 (49) 37 (49) 75 (49)

Jakubowiak A et al. EHA 2015 abs 103

Characteristic EBd (n=77) Bd (n=75) Total (N=152)

ISS staging, n (%)

I 26 (34) 19 (25) 45 (30)

II 23 (30) 20 (27) 43 (28)

III 11 (14) 16 (21) 27 (18)

Not reported 17 (22) 20 (27) 37 (24)

Status disease at randomization, n (%)

Refractory 24 (16) 14 (9) 38 (25)

Relapsed 47(31) 57 (38) 104 (69)

Not reported 6 (4) 3 (2) 9 (6)

CA204-009: Overall Response Rate

0

20

40

60

Re

spo

nse

ra

te (

%)

EBd Bd

Overall

response rate

(PR or better)

Complete

response

(sCR + CR)*

VGPR≥ VGPR

(sCR + CR +

VGPR)

*Complete response rates in the EBd group may be underestimated due to interference from

therapeutic antibody in immunofixation and serum protein electrophoresis assay

There was no difference between the 2 treatment arms for stable disease (14 patients each) and

progressive disease (4 patients each)

65

63

4

2327

4

3034


Progression-Free Survival

EBd Bd

HR 0.72 (70% CI 0.49–1.06; 95% CI 0.59–0.88);

stratified log-rank p=0.09

Median PFS

(95% CI)

9.7 mo

(7.4–12.2)

6.9 mo

(5.1–10.2)

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

PFS (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

77 69 58 47 41 32 26 22 14 11 5 3 2 1 0

75 61 50 37 32 25 21 14 11 9 5 3 1 0 0

EBd

Bd

Number of patients at risk

39%

33%

1-year PFS

EBd (events: 52/77)

Bd (events: 59/75)Pro

bab

ility p

ro

gressio

n free

EBd-treated patients had a 28% reduction in the risk of disease progression or death

Overall Survival

Early OS data show an observed improvement in favor of EBd

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

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

16 18 30

OS (months)

85%

74%

1-year OS

HR 0.61 (70% CI 0.43–0.85)

77 76 74 71 69 67 61 61 26 20 7 3 150 38 0

75 67 62 59 57 54 51 48 22 15 6 1 036 30 0

EBd

Bd

Number of patients at riskP

ro

bab

ilit

y o

f su

rviv

al

EBd

(events: 17/77)

Bd

(events: 23/75)

• 40 deaths observed at the time of analysis (17 EBd, 23 Bd), mainly due to

disease progression

Progression-free survival Overall survival



dexamethasone with or without elotuzumab in patients with RRMM

28% reduction in the risk of

disease progression 39% reduction in the risk of death

Events, n (%)EBd (n=75) Bd (n=75)

Any grade Grade 3–4 Any grade Grade 3–4

All adverse events 75 (100) 51 (68) 72 (96) 45 (60)

Infections and infestations 49 (65) 13 (17) 40 (53) 10 (13)

Diarrhea 32 (43) 6 (8) 25 (33) 3 (4)

Constipation 29 (39) 1 (1) 22 (29) 0

Cough 29 (39) 1 (1) 17 (23) 0

Anemia 28 (37) 5 (7) 21 (28) 5 (7)

Peripheral neuropathy 26 (35) 6 (8) 25 (33) 7 (9)

Pyrexia 25 (33) 0 20 (27) 3 (4)

Peripheral edema 22 (29) 3 (4) 18 (24) 0

Insomnia 22 (29) 0 14 (19) 1 (1)

Asthenia 20 (27) 3 (4) 21 (28) 2 (3)

Fatigue 20 (27) 3 (4) 19 (25) 1 (1)

Paresthesia 20 (27) 0 14 (19) 4 (5)

Nausea 19 (25) 1 (1) 16 (21) 1 (1)

Thrombocytopenia 12 (16) 7 (9) 20 (27) 13 (17)


No additional adverse events versus Bd


dexamethasone with or without elotuzumab in patients with RRMM

Safety

Infusion Reactions

• No Grade 3–5 infusion reactions (7% grade 1-2)

• No infusion reactions at maximum planned infusion rate of 5 mL/min

• 27 patients received elotuzumab infusion within 1 hour

• No patient discontinued because of an infusion reaction

• Infusion reactions were low and manageable

Events, n (%)EBd (n=75)

Grade 1–2 Grade 3–5

Infusion reaction 5 (7) 0

Pyrexia 2 (3) 0

Bone pain 1 (1) 0

Chills 1 (1) 0

Flushing 1 (1) 0

Nausea 1 (1) 0

Peripheral sensory neuropathy 1 (1) 0


ELOQUENT-2: Elotuzumab-Rd vs Rd• Open-label, international, randomized, multicenter, phase 3 trial

(168 global sites)

Key inclusion criteria

RRMM

1–3 prior lines of therapy

Prior Len exposure permitted in 10% of study population (patients not refractory to Len)

Elo plus Len/Dex (E-Ld) schedule (n=321)

Elo (10 mg/kg IV): Cycle 1 and 2: weekly; Cycles 3+: every other week

Len (25 mg PO): Days 1–21Dex: weekly equivalent, 40 mg

Len/Dex (Ld) schedule (n=325)

Len (25 mg PO): Days 1–21;

Dex: 40 mg PO Days 1, 8, 15, 22

Repeat every 28 days

Assessment

Tumor response: every 4 weeks until progressive disease

Survival: every 12 weeks after disease progression

Endpoints:

– Co-primary: PFS and ORR

– Other: overall survival (data not yet mature), duration of response,

quality of life, safety

All patients received premedication to mitigate infusion reactions prior to

elotuzumab administration

Elotuzumab IV infusion administered ~ 2–3 hours

Lonial S et al N Engl J Med, 2015

Characteristic E-Ld (n=321) Ld (n=325)

Age (years), median (range) 67 (37–88) 66(38–91)

≥65 years 187 (58) 183 (56)

Region, %

Europe 61 60

North America 21 21

Rest of the world 18 19

International Staging System disease stage, n (%)

I 44 43

II 32 32

III 21 21

Not reported 4 14

Cytogenetics (FISH)del(17p)

Yes 32 32

No 66 67

Not reported 2 1

t(4;14)

Yes 9 10

No 89 89

Not reported 2 1

1q21

Yes 46 50

No 53 49

Not reported 2 1

Baseline Demographics and

Disease Characteristics

FISH = fluorescence in situ hybridization

Baseline Demographics and

Disease Characteristics

Characteristic E-Ld (n=321) Ld (n=325)

Prior regimens, median (range) 2 (1–4) 2 (1–4)

Prior therapies, %

Bortezomib 68 71

Melphalan* 69 61

Thalidomide 48 48

Lenalidomide† 5 7

Response to most recent line of therapy, %‡

Refractory 35 35

Bortezomib refractory 22 21

Thalidomide refractory 9 11

Relapsed 65 65

Prior stem cell transplantation, % 52 57

*Oral or intravenous. †Prior lenalidomide was permitted if best response was ≥partial response and patients were not refractory to prior lenalidomide

treatment; patients could not receive more than 9 cycles of lenalidomide and had at least 9 months between the last dose of lenalidomide and

progression. ‡One patient in the elotuzumab group had an unknown response to the most recent line of therapy

Co-primary Endpoint: Overall Response Rate

*Defined as partial response or better. †Complete response rates in the E-Ld group may be underestimated due to interference from

therapeutic antibody in immunofixation and serum protein electrophoresis assay

0

20

40

60

80

100

Resp

on

se r

ate

(%

)

E-Ld Ld

p=0.0002

79

66

Overall

response

rate*

Complete

response

(sCR + CR)†

Very good

partial

response

Combined

response

(sCR + CR +

VGPR)

Partial

response

47

21

2833

28

38

46

Progression-free survival

Lonial S et al N Engl J Med, 2015: 1-11

ELOQUENT-2: Elotuzumab-Rd vs Rd

Median 19.4 vs 14.9 months

E-Ld−treated patients had a 30% reduction in the risk of disease progression or death;

treatment difference at 1 and 2 years was 11% and 14%, respectively

Progression Free Survival by Tumor Response

• No Grade 4–5 infusion reactions

• 33 patients (10%) infusion reaction , 29/33 grade 1-2

• 2 (1%) discontinued because of an infusion reaction

ELOQUENT-2: Elotuzumab-Rd vs Rd

Safety

Lonial S et al N Engl J Med, 2015: 1-11

Elotuzumab Clinical Development Program

Dex, dexamethasone; liri, lirilumab; ure, urelumab.1. Clinicaltrials.gov. NCT00425347. 2. Clinicaltrials.gov. NCT00726869. 3. Clinicaltrials.gov. NCT01241292. 4. Clinicaltrials.gov. NCT01393964. 5. Clinicaltrials.gov. NCT02252263. 6. Clinicaltrials.gov. NCT00742560. 7. Clinicaltrials.gov. NCT01478048. 8. Clinicaltrials.gov. NCT01632150. 9. Clinicaltrials.gov. NCT01441973. 10. Clinicaltrials.gov. NCT02159365. 11. Clinicaltrials.gov. NCT01239797. 12. Clinicaltrials.gov. NCT01335399.

Phase I Phase IIPhase III

Lenalidomide/dex ±elotuzumab

CA204-004 (N=646)11

Relapsed

CA204-006 (N=750)12

Newly diagnosed

1701 (N=35)1

Relapsedelotuzumab monotherapy

CA204-009 (N=150)7

Relapsedelotuzumab ± bortezomib/dex

1702 (N=28)2

Relapsedelotuzumab + bortezomib

CA204-005 (N=20)3

Relapsedelotuzumab + lenalidomide/dex

CA204-007 (N=26)4

Normal renal function/Renallyimpaired

elotuzumab + lenalidomide/dex

CA204-010 (N=40)8

Relapsedelotuzumab + thalidomide/dex

CA204-011 (N=40)9

Smolderingelotuzumab monotherapy

17036

(N=102)Relapsed

elotuzumab + lenalidomide/dex

CA223-028 (N=136)5

Relapsedelotuzumab + lirielotuzumab + ure

CA204-112 (N=76)10

Newly Diagnosed/Relapsedelotuzumab +

lenalidomide/dex

Analyses of Real World Data on Overall Survival in Multiple Myeloma

Patients with at Least 3 Prior Lines of Therapy Including a PI and an

IMiD, or Double Refractory to a PI and an IMiD

Usmani et al Abs #4498 Orlando, ASH 2015

.

237 days

154 days

Chemotherapy

Immunotherapy

All causes mortality

• Median OS is considered less suitable for survival curves that are skewed to the right since it does not differentiate the proportion of patients alive or dead after 50% of the patients have died

• Median OS provides a measure of when 50% of patients will die, it does not provide a true reflection of the survival time that may be expected from the patients who are alive after the median OS is reached

V

High-dosechemotherapy

ThalidomideBortezomib

Multiple Myeloma - incurable disease?

COMBOMPT VMPVTDRd

Maintenance/Consolidation

New combo with Nextgeneration PI/IMIDsMoAbContinuoustherapy

Future treatment paradigmsstart from nowaday’s evidence

Median survival > 7 yrs

CR: 50-70%

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