Immunotherapy for lymphoma andresearch strategy in the local network

Anastasios Stathis, MD

SAMO Interdisciplinary workshop on immunotherapy

Anastasios Stathis, MD

Phase I and Lymphoma UnitOncology Institute of Southern Switzerland

Lucerne Apr 5, 2014

Explosion of new cancer therapeutics

>800 agents inclinical trials in2009

LoRusso PM et al. Clin Cancer Res 2010:16:1710-1718

143% increasefrom a decade ago

Targeted therapy for lymphoma

Modified from: A. Younes, Nat. Rev. Clin. Oncol. 8, 85–96 (2011)

Emerging therapeutic options inrelapsed/refractory NHL

Adapted from M.P. Chao. Cancer Manag Res. 2013; 5: 251–269

Structure of human CD20 molecule

• B cell-specific tetra-transmembrane protein localized to microvilli andconstitutively associated with membrane rafts

• no dissociation or internalization upon antibody binding

• role in B cell function not fully clear (regulator or component of acalcium channel), it forms homo-oligomers that physically associatewith the BCR

C1qC1q

mAbmAb

CD20CD20

MacrophageMacrophage

Mechanisms of actions of anti-CD20 antibodies

• CDC1-3

• ADCC1-3

• Apoptosis1-3

1Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program; 2007: 233–242; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837;3Jazirehi AR, Bonavida B. Oncogene 2005; 24(13): 2121–2143

1Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program; 2007: 233–242; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837;3Jazirehi AR, Bonavida B. Oncogene 2005; 24(13): 2121–2143

ADCC=antibody-dependent cellular cytotoxicity;CDC=complement-dependent cytotoxicity;MAC=membrane attack complex

ADCC=antibody-dependent cellular cytotoxicity;CDC=complement-dependent cytotoxicity;MAC=membrane attack complex

CD20CD20

B cellMACMAC

Vaccinal effect of monoclonal antibodies

• Priming antigen-specific T-cells through cross-presentation oftumor antigens released by dying cells

TypeI

TypeII

CD20 clusteringin B-cellmembrane

++ -

Type IType I

Two types of anti-CD20 mAbs

Cragg MS, et al. Curr Dir Autoimmun 2005 Glennie MJ, et al. Mol Immunol 2007Teeling JL, et al. Blood 2004

Induction of CDC ++ +

Induction ofADCC ++ ++

Induction ofapoptosis + ++

– = no activity; + = some activity; ++ = significant activity– = no activity; + = some activity; ++ = significant activity

Type IIType II

Event-Free Survival

5-year EFS (95%CI):Chlorambucil , 52% (42%-60%)R-Chlorambucil, 70% (61%-77%)Rituximab, 51% (40%-61%)

Zucca, E. et al, ICML; 2013

The IELSG-38 study

A phase II study of Chlorambucil in combination

with subcutaneous Rituximab followed by

maintenance therapy with subcutaneous

Rituximab in patients with extranodal marginal

zone B-cell lymphoma of mucosa associatedzone B-cell lymphoma of mucosa associated

lymphoid tissue (MALT lymphoma)

IELSG Annual Meeting 2014

• Low CD20 density

– Rituximab requires high CD20density for CDC

– Relatively low CD20 density in CLL

• Complement inhibition

Potential mechanisms for rituximab limitations

100

80

60

40

%C

DC

• Complement inhibition

– B-cell overexpression ofcomplement inhibitory proteinsmay reduce rituximab-mediatedCDC

• Carriers of the FcgRIIIa lowaffinity receptor polymorphism

Lower rituximab-induced CDCcorrelates with lower CD20 densityAntibodies bound per cell = number of CD20molecules per cell

Lower rituximab-induced CDCcorrelates with lower CD20 densityAntibodies bound per cell = number of CD20molecules per cell

20

0

0

CLL Lymphoma

CD20-ABC*CD20-ABC*

How to boost antibodies effectiveness

Adapted from M.P. Chao. Cancer Manag Res. 2013; 5: 251–269

How to boost naked monoclonal antibodies

• increase CDC

• increase ADCC

• enhance affinity for all variants of FcγRIIIa receptors

• reduce immunogenicity• reduce immunogenicity

– humanized and fully human mAbs

• overcome immune resistance

– e.g., by blockade of programmed death 1 (PD-1), aninhibitory receptor expressed by T cells

How to boost antibodies effectiveness

• Radio-immunotherapy

• Antibody-drug conjugates

• Bispecific antibodies

VeltuzumabOcrelizumab

Ofatumumab AME-133vGA-101PRO-31921

MurineMurine ChimericChimeric HumanizedHumanized Fully humanFully human EngineeredEngineered

Antibody technology has moved forwardsince the rituximab introduction

19871987 19941994 19971997 20062006 20092009

1f5 “serotherapy” in 4pts with refractory B-cell carcinoma

1f5 “serotherapy” in 4pts with refractory B-cell carcinoma

CD2B: phase I study in pts withrecurrent B-cell lymphomaCD2B: phase I study in pts withrecurrent B-cell lymphoma

Rituximab: FDA approval forrelapsed or refractory, lowgrade, CD20+, B-cell NHL

Rituximab: FDA approval forrelapsed or refractory, lowgrade, CD20+, B-cell NHL

Rituximab: approved for first-line use in B-cell lymphomasRituximab: approved for first-line use in B-cell lymphomas

Ofatumumab: approved in USfor CLL refractory to fludarabineand alemtuzumab

Rituximab: approved in Europefor untreated andrelapse/refractory CLL

Ofatumumab: approved in USfor CLL refractory to fludarabineand alemtuzumab

Rituximab: approved in Europefor untreated andrelapse/refractory CLL

mAb=monoclonal antibody; pts=patients; FDA=Food and Drug Administration (US); NHL=non-Hodgkin’s lymphomamAb=monoclonal antibody; pts=patients; FDA=Food and Drug Administration (US); NHL=non-Hodgkin’s lymphoma

Second generation of anti-CD20 monoclonal antibodies

S. Cang et al. J Hematol Oncol. 2012

Ofatumumab binding to a unique CD20 epitopelinked to more efficient CDC

Modified from B.D. Cheson J Clin Oncol. 2010

Ofatumumab• 42% ORR in CLL refractory to fludarabine and

alemtuzumab

• median duration of response of 6.5 months

• most common adverse reactions :– neutropenia and anemia– neutropenia and anemia

– pneumonia, bronchitis and upper respiratory tract infections

– diarrhea

– Fatigue, dyspnea, rash.

Wierda W G et al. JCO 2010;28:1749-1755

Third generation of anti-CD20 monoclonal antibodies

Adapted from S. Cang et al. J Hematol Oncol. 2012

GA101 (Obinutuzumab)Glycoengineered, Type II Anti-CD20 mAb

FDA approved (Nov 2013) 1st line CLL with Chlorambucil

Type IIanti-CD20 mAb1,2

GlycoengineeredFc region1

Increaseddirect cell death1

Increased ADCC1

1Mossner E et al. Blood. 2010;115(22):4393-402; 2Niederfellner G et al. Blood. 2011;118:358–67.mAb, monoclonal antibody.

Decreasedcomplementdependentcytotoxicity

• The presence of certain fucose residues on theFc region of an antibody may interfere with itsability to bind to immune effector cells1,2

GA101 Glycoengineering

1Ferrara C et al. J Biol Chem. 2006;281:5032–6;2Ferrara C et al. Proc Natl Acad Sci U S A. 2011;108:12669–74;3Mossner E et al. Blood. 2010;115(22):4393-402.

• Removal of fucose via glycoengineering mayincrease binding affinity to–and activation of–immune effector cells3

R

A

N

D

O

1

:

2GA101 + chlorambucilx 6 cycles

Chlorambucil x 6 cyclesPreviouslyuntreated CLLwith comorbidities

Total CIRS* score > 6

Stage I, n = 590Additional 190 patients

to complete stage II

Stage IaG-Clb vs Clb

Stage IbR-Clb vs Clb

GA101+Clb or R-Clb vs Clb in CLL pts withcomorbidities. The CLL11 trial

• GA101: 1,000 mg days 1, 8, and 15 cycle 1; day 1 cycles 2–6, every 28 days• Rituximab: 375 mg/m2 day 1 cycle 1, 500 mg/m2 day 1 cycles 2–6, every 28 days• Clb: 0.5 mg/kg day 1 and day 15 cycle 1–6, every 28 days• Patients with progressive disease in the Clb arm were allowed to cross over to G-Clb

O

M

I

Z

E

2

:

2

Rituximab + chlorambucilx 6 cycles

x 6 cyclesTotal CIRS* score > 6and/or creatinineclearance < 70 ml/min

Age ≥ 18 years

N = 780 (planned)

Stage IIG-Clb vs R-Clb

R-Clb vs Clb

*Cumulative Illness Rating Scale

26Hallek M, Abstr. 056, 12-ICML

Final results of the stage IIand update of stage I analysis

Stage II (total N=663)

G-Clb(n = 333)

R-Clb(n = 330)

HR 0.41, CI 0.23-0.74,p=0.002.

Goede V. (ASH 2013), Blood 2013 122:6

(n = 333) (n = 330)

ORR 78 65

CRb 21 7

Median PFS, months 26.7 15.2

HR, CI, p 0.39, 0.31-0.49, <0.0001

Median OS, months NR NR

HR, CI, p 0.66, 0.41-1.06, 0.09

Grade 3-5 AEs 66 47

IRR 20 4

Neutropenia 33 27

Infections 7 7

RClb over Clb: HR 0.66, CI0.39-1.11, p=0.113.

The GOYA Study

GA101 + CHOP

Rituximab + CHOP

Previously untreated

DLBCL1:1

1400 patients

Stratification

• Number of planned CHOP cycles (6 or 8)

• IPI score

• Region of study conduct

IPI, International Prognostic Index.

GA101

•1000 mg on days 1, 8, and 15 of cycle 1;day 1 of cycles 2–8, every 21 days

Rituximab

•375 mg/m2 on day 1 of cycles 1–8,every 21 days

• Phase III, open-label, multicenter, randomized

• Sites choose between use of 6 or 8 cycles of CHOP-21

New study proposalA phase I study of GA101 in combination with ABT199 inA phase I study of GA101 in combination with ABT199 inpatients with relapsed/refractory follicular lymphoma

Dr. A. Stathis

PD. Dr. E. Zucca

Phase I study of GA101 with ABT-199in R/R Follicular lymphoma: rationale

-Need to identify “no-chemotherapy” active regimens in FL

-Both GA101 and ABT-199 have single agent activity withacceptable toxicity profile in iNHLacceptable toxicity profile in iNHL

-GA101 with ABT-199 results in enhanced cell death androbust anti-tumor efficacy in xenograft NHL models (SampathD et al, ASH 2013)

Cell-Surface Antigens on the B Cell

B.D. Cheson & J.P. Leonard. N Engl J Med 2008

Targeting other antigens with new mAbs

Target Single agent RR

Epratuzumab CD22 45% FL, 15% DLBCL

Medi-551 CD1925% CLL, 24% DLBCL,

41% FLMedi-551 CD19

41% FL

Mogamulizumab CCR450% ATL, 34% PTCL, 39%

CTCL

Pidilizumab PD1 66% FL (w Rituximab)B-specific T-cell engager(BiTEs)

BlinatumomabCD19 57% DLBCL (B-ALL)

Blinatumomab Is a BispecificT-Cell Engaging (BiTE) Antibody

-CD3Antibody

VH

VL

CD3 T Cell

Blinatumomab

Bargou R, et al. Science. 2008;321(5891):974-977.

-CD19Antibody

VH

VL

Target AntigenCD19

RedirectedLysis

TumorCell

BlinatumomabBiTE®

Phase II study of Mogamulizumab (KW-0761) incutaneous and peripheral TCL

• A first-in-class defucosylated anti-chemokine receptor-4(anti-CCR4 humanized moAb)

• Approved in Japan in 2012 for R/R ATL

• Phase II study in 37 (PTCL-NOS:16, AITL:12, ALCL ALK-:1;• Phase II study in 37 (PTCL-NOS:16, AITL:12, ALCL ALK-:1;MF:7, C-ALCL:1)

• CCR4 assessed by IHC before study entry• KW-0761 dose: 1mg/Kgr/day iv weekly x8

• AEs: skin rash,infusion reactions, leuco- and lymphopenia• ORR 35% (34% in PTCL and 385 in CTCL), PFS 3 months,

OS not reached

Ueda R, abstr 151, ICML-12, Lugano 2013

Targeting the micorenvironment: Pidilizumabwith Rituximab in R/R FL. A phase II study

• The inhibitory programmed death (PD)-1 receptor isoverexpressed in intratumoral T cells in FL

• Pidilizumab is a humanized anti-PD1 moAb whichenhances function of antitumor NK and T cells

• Phase II study in gr1-2 FL

Westin JR, abstr 159, ICML-12, Lugano 2013

• Phase II study in gr1-2 FL• n=30 pts (all previous R and 69% previous chemo)• Pidilizumab 3mg/kgr iv q4 w x4 with R 375mg/m2 qw x4

with 8x maintenance Pidilizumab

• No gr3 or gr4 toxicities

• ORR: 66%, CR 52%

The era of ADCs?

Brenduximab Vedotin (Adcetris)Anti-CD30 conjugated to an antitubulin agent

MMAE – microtubule-disrupting agentprotease-cleavable linker

anti-CD30 monoclonal antibody

Brentuximab vedotin ADC

Apoptosis

G2/M cellcycle arrest

ADC binds to CD30

MMAE disruptsmicrotubule network

ADC–CD30 complexinternalized/ traffics to

lysosome

MMAE is released

Adapted from Ansell SM. Expert Opin Investig Drugs 2011;20:99–105 and Younes A, et al. N Engl J Med 2010;363:1812–21.

ADC, antibody–drug conjugate; MMAE, monomethyl auristatin E.

Pivotal Phase II study in relapsed orrefractory HL post-ASCT

102 patients with relapsed or refractory HL post-ASCT

• Relapsed or refractoryCD30+ HL

Follow-upTreatment (n=102)Eligibility

• Brentuximab vedotin1.8 mg/kg IV every

Younes A et al: J Clin Oncol, 2012, 30:2183-2189

CD30+ HL

• Age ≥12 years

• Measurable disease≥1.5 cm

• ECOG 0–1

• Prior ASCT

21 days

• Administered outpatientover 30 min

• Max 16 cycles for SD orbetter

• Restage at cycles 2, 4, 7,10, 13, 16

• Every12 weeks

94% of patients achieved tumour reduction

Response rate 75%(34% CR)

PFS notably longer in pts with CR

PFS 5.6 mo;PFS 5.6 mo;21.7 mo in CR

Side effects

Pivotal Phase II study in relapsed orrefractory systemic ALCL (sALCL)

Phase II study of brentuximab vedotin in 58 patients withrelapsed or refractory sALCL

• Relapsed or refractorysALCL

Follow-upTreatment (n=58)Eligibility

• Brentuximab vedotin 1.8mg/kg IV every 21 days

sALCL

• Age ≥12 years

• Measurable disease ≥1.5cm FDG-avid

• ECOG performancestatus of 0–1

mg/kg IV every 21 days

• Administered tooutpatients, >30 min

• Maximum 16 cycles forSD or better

• Restage† at cycles2, 4, 7, 10, 13, 16

• Every12 weeks

Pro B et al: J Clin Oncol, 2012, 30:2190-2196

97% of patients achieved tumour reduction

Response rate 86%(57% CR)

PFS independent of ALK status

11(4)Positiven at risk (events)

35 (7)Negative

11(4)

26 (16)

10 (5)

22 (19)

9 (6)

20 (20)

7 (8)

13 (21)

2 (9)

7(22)

0 (9)

3 (23)

0 (9)

0 (23)

16 (0)

42 (0)

Advani, R. et al. Presented at American Society of Hematology annual meeting, San Diego, CA, USA; 9–13 Dec 2011. Oral presentation: Abstract #443.

Adcetris - future directions

• Incorporation into standard first line regimens

– Phase III study of ABVD vs A+AVD in cHL (NCT01712490)

– Phase II with modified eBEACOPP in cHL (NCT01569204)

– Phase I study of CH(O)P+ A in CD30+ TCL (NCT01309789)– Phase I study of CH(O)P+ A in CD30+ TCL (NCT01309789)

• Salvage regimen before or consolidation after ASCTin HL

– Phase II study in R/R HL (NCT01393717)

– AETHERA Phase III maintenance post ASCT (NCT01100502)

• Development in other lymphoma subtypes

Adcetris in PTCL-NOS and AITL

• n=29 (11 AITL and 18 PTCL-NOS) R/R• 2 prior lines• primary refractoy 55%

Maximum Tumor Volume Reduction AITLPTCL ORR 36%, 50% inORR 36%, 50% in

AITL (4/11 CR)

Responses also inlow/undetectableCD30 by IHC

Oki Y, abstr 152, ICML-12, Lugano 2013

Comparison of CD30 expression by IHC and CD30mRNA levels in a large series of PTCL

• n=324 PTCLs diagnosed between 1999 and 2012• CD 30 expression by IHC and mRNA expression GEP• Correlation between IHC and mRNA data

100

IHC correlates wellwith mRNA

Bossard C, abstr 151, ICML-12, Lugano 2013

0

20

40

60

80

ALCL EATL ENKTL PTCLNOS

ATLLHTLV1+

AITL

score 4 (> 75%)

score 3 (50 - 75%)

score 2 (25 - 49%)

score 1 (5 - 24%)

score 0 (<5%)

Only 21% of PTCL(non ALCL) stronglyexpress CD30(6% in AITL)

58% of PTCL (nonALCL) expresssome level of CD30

Adcetris in DLBCL?

CD30 expressed in 20-25% of DLBCL

Higher level of expression in:- Younger patients- Younger patients- Non-GCB phenotype?- EBV+ non-GCB cases

Phase II study in CD30+ NHL:ORR, 40% in highly refractoryDLBCL

CD30

Barlett NL, et al. ASH 2013

CD30 expression defines a novel DLBCLsubgroup with favorable prognosis anddistinct gene expression signature

The favorable outcome of CD30 expression was mantained in both GBC and non GBC subtypes

S. Hu, et al. Blood 2013

Immunoconiugates for NHL treatmentusing MoAbs to deliver toxins to cells that have aspecific target receptor

Target FDA approvedindication

SGN-CD19A (anti-CD19 + toxin) CD19 -

SAR3419 (anti-CD19 + maytansinoid) CD19 -

DT2219ARL (anti-CD19 & anti-CD22 + immunotoxin) CD19 CD22 -

Inotuzumab Ozogamicin (anti-CD22 + calicheamicin) CD22 -

DCDT2980S (anti-CD22 + MMAE) CD22 -

DCDS4501A (anti-CD79b + MMAE) CD79b

LMB-2 (anti-CD25 antibody + immunotoxin) CD25 -

IMGN529 (anti-CD37 antibody + maytansinoid ) CD37

Brentuximab Vedotin, formerly SGN-35 (Adcetris®)(anti-CD30 + MMAE)

CD30 HL / ALCL

R/R CD22+ NHLs progressed after at least 1 priortherapy

At least one site of measurable disease

Phase I Study of Inotuzumab Ozogamicin +Temsirolimus in Patients With Relapsed or Refractory

CD22+ B-cell NHL (NCT01535989)

No signs of VOD or VOD-like symptoms in earlier lineof treatment

No chronic obstructive or chronic restrictivepulmonary disease

2014 AACR Meeting, April 9 2014

A phase I study of inotuzumab ozogamicin in combinationwith temsirolimus in patients with relapsed or refractory

CD22-positive B-cell non-Hodgkin lymphomas (NHL).

A. Stathis1, F. Hitz2, U. Novak3, F. Bertoni4, T. Terrot1, L. Moser1, I. Xenidou1 , L.Mazzucchelli5, M. Ghielmini1, C. Sessa1, E. Zucca1, F. Cavalli1.

1 Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 2 Department ofOncology and Hematology, Cantonal Hospital St.Gallen, Switzerland; 3 Institute of

Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland; 4

IOR-Institute of Oncology Research, Bellinzona, Switzerland, 5Institute of Pathology,Locarno, Switzerland

IMGN529 compound profile andmechanism of action

Antibody-dependentcellular cytotoxicity

(ADCC)

Delivery of cytotoxicagent (DM1)

IMGN529 is an anti-CD37 immunotoxin. Multiple mechanisms of action: apoptosis,CDC, ADCC, and cytotoxicity by maytansinoid delivery

CD37

Tumor cell

Effector cellAntigen

DM1

IMGN529

Fc Receptor

Complement

Apoptosis/growthinhibition by

direct signaling

Complement-dependentcytotoxicity

(CDC)

Potent activity in vitro and in vivo studies

CD37 staining similar to CD20

J. Deckert, et al. Blood, 2013

R/R FL, DLBCL, MZL, MCL failing at least one line oftreatment (must have included a rituximab-basedregimen)

A Phase I, Multi-center, Open-label study ofIMGN529 in adult patients with relapsed or

refractory NHL (NCT01534715)

regimen)

At least one site of measurable disease

No limitation on number of previous treatments

CD37 analysis only for the expansion cohort

2014 ASCO annual Meeting, May 30 2014

Preliminary findings from a phase I, multicenter, open-labelstudy of the anti-CD37 antibody-drug conjugate (ADC),

IMGN529, in adult patients with relapsed or refractory non-Hodgkin lymphoma (NHL).

Stathis, A.1, Maddocks, K.2 Flinn, I.3, Weitman, S.4, Palomba, M. 5; Ponte, J. 6;Deckert, J6; Murphy, M.6; Zildjian, S.6, Ruiz-Soto, R.6, Freedman, A.7

Oncology Institute of Southern Switzerland, Bellinzona, Switzerland1; Ohio StateUniversity, Columbus OH2; Sara Cannon Research Institute, Nashville, TN3; Cancer

Treatment Research Center, San Antonio, TX4; Memorial Sloan Kettering CancerCenter, New York, NY5; ImmunoGen, Inc., Waltham, MA6; Dana Farber Cancer Institute,

Boston, MA7

ADCs: toxicities

Drug

Brentuximab Vedotin

Inotuzumab Ozogamicin

Toxicity

Neuropathy

Thrombocyopenia, Hepatic

SAR3419

DCDT2980S

DCDT2980S

Ocular toxicity, neutropenia

Neutropenia

Neutropenia

it has taken some time

1900 P. Ehrlich envisioned therapies using specific magic bullets

1975 G. Köhler and C. Milstein (Cambridge, UK) published a paperon the production of moAbs of predefined specificity

1980 Preliminary evidence of the clinical activity and feasibility of1980 Preliminary evidence of the clinical activity and feasibility ofmoAbs against either a human lymphoma-associated antigenor the idiotype (Lee Nadler, Boston; Ron Levy, Stanford)

1984 Nobel prize to Köhler and Milstein

1997 First FDA approval of a moAb to treat cancers: rituximab forrelapsed or refractory low-grade or follicular lymphoma

Breakthrough lymphoma therapies

• Aug 2011: Adcetris for HL after autoSCT or after two linesand ALCL after at least 1 line

• June 2013: Revlimid for MCL after at least two lines oftreatmenttreatment

• Nov 2013: Obinutuzumab with Clb for untreated CLL

• Nov 2013: Imbruvica for MCL after failure of at least oneline

Thank you for the attention and see you in Lugano