New agents for the

treatment of lymphoma

Michele Ghielmini

Anastasios Stathis

Oncology Institute of Southern Switzerland

Bellinzona

Target

DNA

Microenvironment

Surface antigens

Intracellular

pathways

...

...

Structure

Antibodies

Large molecules

Small molecules

...

...

...

...

Mech. of action

Pro-apoptotic

Tubulin inhibition

Complement

activation

Immunostimulants

...

...

Classification

New drugs

registered for lymphomas

1995 2000 2005 2010

Rituximab

Bortezomib

Vorinostat

Romidepsin

Ofatumumab

Alemtuzumab

Ibritumomab

Tositumomab

SGN35

Promising new drugs

Immuno modulators

Monoclonal - anti-CD20

antibodies - anti-others

- immuno-toxins

Small - against signaling pathways

molecules (BCR, others)

- Histone deacetylase inhibitors

(HDACi)

Promising new drugs

Immuno modulators

Monoclonal - anti-CD20

antibodies - anti-others

- immuno-toxins

Small - against signaling pathways

molecules (BCR, others)

- Histone deacetylase inhibitors

(HDACi)

Lenalidomide + Rituximab

Rituximab d1

Lenalidomide d1-21 qd 4 wks

75 pts with indolent NHL (FL, MZL, CLL)

Previously untreated

RR 90% CR 66% (87% in FL)

52 pts with relapsed/resistant MCL

RR 58% CR 33% Fowler et al., Abstr. 137, ICML-11

Wang et al., Abstr. 109, ICML-11

Histone deacetylase inhibitors

(HDACi)

• Vorinostat and Romidepsin approved for CTCL

(RR 30% in relapsed patients)

• > 80 clinical trials testing different HDACi

• Limited single agent activity in DLBCL

• Significant single agent activity in R/R Hodgkin

(Panobinostat 20% RR)

1Cragg MS, et al. Curr Dir Autoimmun 2005; 8: 140–174; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837;

3Teeling JL, et al. Blood 2004; 104(6): 1793–1800

Type I Type II

CD20 clustering in B-

cell membrane ++ -

Induction of CDC ++ +

Induction of ADCC ++ ++

Induction of

apoptosis + ++

Type I

Type II

mAb=monoclonal antibody; CDC=complement-dependent

cytotoxicity; ADCC=antibody-dependent cellular cytotoxicity

Anti-CD20 mAbs: two types

Old target, new drugs:

anti-CD20 MoAbs

Antibody Typ

e

Format Stage of development

and disease target

Ofatumumab

I Human

high CDC

Approved for CLL,

phase II for iNHL,

DLBCL

Obinotuzumab

(GA-101)

II Humanized

increased ADCC and apoptosis,

reduced CDC

Phase III DLBCL, iNHL

Veltuzumab

(Ah20)

I Humanized,

i.v. and s.c. formulation

Phase I/II: aggressive

and iNHL

AME-133v I Humanized

greater potency in FcRIIIa158-F carriers

Phase I/II: FL

PRO-131921

I Humanized

increased ADCC and apoptosis

Phase I/II: CLL, iNHL

Use of antibodies in oncology

«Naked» - immune mediators (Rituximab)

- block surface receptors (Cetuximab)

- block receptor ligands (Bevacizumab)

«Hot» Brings radiotherapy to the target

(Zevalin®, Bexxar®)

«Immunotoxins» Brings toxin to the target

Brentuximab Vedotin (SGN35) Anti-CD30 conjugated to an antitubulin agent

MMAE – microtubule-disrupting agent

ADC binds to CD30

MMAE disrupts

microtubule network

Internalized in lysosome

MMAE is released

anti-CD30 monoclonal antibody

Brentuximab vedotin (SGN-35) FDA approved

on August 2011 for R/R HL and ALCL

58 relapsed or refractory ALCL

ORR 86%

CR 53%

median duration of response 13 ms

102 post-auto transplant HL

ORR 75%

CR 34%

Response duration 7 ms

Shustov et al., Abstr. 125, ICML-11

Younes et al., Abstr. 160, ICML-11

Inotuzumab ozogamicin

Calicheamicin-conjugated anti-CD22 antibody

J F de Vries, et al. Leukemia 2011

• CD22 expressed

in > 90% B-NHL

Inotuzumab Ozogamicin

in refractory indolent B-cell NHL

Goy A et al. 11-ICML (Lugano 2011)

57%

n = 35

26%

n = 16

67%

n = 35

31%

n = 16

0

20

40

60

80

100

All (N = 61) Follicular (n = 52)

% r

esp

on

ders

ORR CR

15

SAR3419

Anti-tubulin targeting CD19

ANTIBODY

CYTOTOXIN Binds tubulin on Vinca site

S

SS

S

DM4

DM4

DM4

DM4MeO

ClN

O

O

ON

O

NH

O

OMeO HO

O

HS Targets CD19

Expressed on nearly all B-cell

malignancies

SAR3419

Response by histology R

ela

tive

ch

an

ge

fro

m b

as

elin

e

400

160

140

120

100

80

60

40

20

0

-20

-40

-60

-80

-100

Histology type

SLL Other DLBCL MCL FL

Blinatumomab Is a Bispecific

T-Cell Engaging (BiTE) Antibody

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

-CD19 Antibody

-CD3 Antibody

VH

VL

VH

VL

Target Antigen CD19

CD3

Redirected Lysis

T Cell

Tumor Cell

Blinatumomab BiTE®

Response Rate to Blinatumomab

Treated with to 60 g/m2/d N = 28

Histologic subtype

CR + CRu

n (%)

ORR

n (%)

All patients 10/28 (36) 20/28 (71)

FL 4/12 (33) 10/12 (83)

DLBCL 3/7 (43) 4/7 (57)

MCL 3/7 (38) 5/7 (71)

Other (MZL, LPL) 0/2 (0) 1/2 (50)

Continuous infusion over 4 weeks

Ig Igb

B-cell Receptor

P

Syk P

Antigen

BTK

PI3K

mTOR

B-cell receptor signaling

(BCR) cascade

Courtesy of J. Friedberg, Pan Pacific Conference 2011

Ig Igb

B-cell Receptor

P

Syk P

Antigen

BTK

PI3K

mTOR

PCI32765

CAL101

Temsirolimus

Fostamatinib

Novel inhibitors of BCR signaling

Courtesy of J. Friedberg, Pan Pacific Conference 2011

Fostamatinib

Oral Syk-inhibitor

Dose: 200 mg 2 x day

Side effects: hematologic

hypertension

Fostamatinib: efficacy

In heavily pre-treated patients

RR DLBCL 22%

FL 10%

CLL/SLL 55%

Friedberg et al, ASH 2008

Oral ibrutinib (PCI 32765) (N=48)

CLL/SLL

MCL

DLBCL

FL

Other Indolent NHL

% C

han

ge o

f Tu

mo

r B

urd

en

41/48 (85%)

Advani et al., Abstr. 153, ICML-11

Ibrutinib (PCI 32765)

O’Brien et al., Abstr. 122, ICML-11

Advani et al., Abstr. 153, ICML-11

Oral, given continuously

39 CLL (1/3 treatment naive)

89% RR, lasting for months

56 NHL (relapsed / refractory)

60% RR

PI3k inhibitor CAL-101

Oral, BID 50mg to 350mg

n=30 iNHL, n=21 MCL, 4 previous lines,

Kahl B et al, 11-ICML, #350

iNHL MCL

CR 63% 48%

PFS >12m 4m

JP Leonard et al. 11-ICML (Lugano 2011)

CAL-101 in combination with rituximab and/or Bendamustine in previously treated B-NHL

Progression-Free Survival

0 2 4 6 8 10 12 0

10

20

30

40

50

60

70

80

90

100

iNHL: CAL-101 + B (N=15)

iNHL: CAL-101 + R (N=12)

CLL: CAL-101 + B (N= 9)

CLL: CAL-101 + R (N=13)

Cycle (28 days)

% P

rog

res

sio

n F

ree

N=49

Temsirolimus experience in NHL

Author Lymphoma type phase n pts previous

lines

RR

Witzig 2005 MCL II 35 3 38%

Ansell 2008 MCL II 29 4 41%

Smith 2008 non MCL NHL II 72 2 35%

Hess 2009 MCL III 54 2 22%

Everolimus activity in different

lymphoma types

RR

50% in FL

30% in DLBCL

18% in SLL

53% in HL

63% in PTCL

Promising drugs in T-cell lymphoma

Phase I-II data (caution!) RR in relapse

Romidepsin / Belinostat /

Panobinostat / Vorinostat 25%

Alisertib 30%

Everolimus 60%

Denileukin diftitox 50%

Brentuximab vedotin (ALCL) 85%

Immunotoxins

Brentuximab Vedotin neuropathy, fatigue, lung, BM

Inotuxumab Ozogamicin BM, liver

SAR3419 ocular, BM

BCR signalling inhibitors

Fostamatinib GI, fatigue, BM, hypertension

PCI-32765 (Ibrutinib) GI, fatigue, headache, rash

CAL-101 liver, lung

Everolimus/Temsirolimus stomatitis, GI, headache, fatigue,

Side effects

Conclusions

Hundreds of new agents in clinical development.

Significant clinical activity from different new classes of drugs.

Immunotoxins are a new hope: we must learn to use them in combinations

Inhibiting lymphoma specific intracellular pathways is a promising strategy