New drugs development in

lymphomas

Anastasios Stathis, MD

Phase I and Lymphoma Unit Oncology Institute of Southern Switzerland

Bellinzona

Jan 30, 2016

LyFE Forum of Excellence 2016What’s new in lymphoid neoplasias?

Leading new cancer cases and deaths-

2014 estimates USA

2014, American Cancer Society, Inc., Surveillance Research

IOSI LYMPHOID NEOPLASMS DATABASE 1980-2011[N=2035, Median follow-up: 9.8 years]

Traditional Treatment Strategies Are Based on

Histologic Subtypes

WHO classification > 50 distinct lymphoma histologies

Current Regimens in LymphomaRecycling old drugs

Disease Front-Line Regimen Salvage RegimenDLBCL RCHOP R-ICE

R-ESHAPR-DHAP

T-Cell NHL CHOP ICEESHAPDHAP

MCL RCHOPR-HyperCVAD

cHL ABVD ICEESHAPDHAPGND, IGEV

Early 1970s 2002 2010

CHOP RCHOP RCHOPABVD ABVD ABVD

Rappaport Working Formulation REAL WHO

Drugs registered for lymphomas1995-2010

1995 2000 2005 2010

Rituximab

Bortezomib

Vorinostat

Romidepsin

Ofatumumab

Alemtuzumab

Ibritumomab

Tositumomab

Stathis A. and Ghielmini M., Ann Oncol. 2012 Sep;23 Suppl 10:x92-8.

The Lymphomas

Improvement in Survival

Coiffier B, et al. NEJM 2002

OS (N = 399)

Su

rviv

al P

rob

ab

ilit

y

Yrs

0

0.

2

0.

4

0.

6

0.

8

1

0 1 3 5 7 82 4 6

CHOPR-CHOP

P = .0004

Fisher RI, et al. J Clin Oncol. 2005.

DLBCL FL

Explosion of new cancer therapeutics

>800 agents in

clinical trials in

2009

143% increase

from a decade ago

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

Emerging therapeutic options in

relapsed/refractory NHL

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

NativeT cell

Malignant B Cell

PD1

PD-L1PD-L2

MHC I/II

TCRCD3

BiTEEngineered

T Cell

Tumor vaccinesCytokines

Immune checkpointinhibitors

TCR

CAR

Batlevi C, Matsuki E, et al: Nature Rev Clin Oncol 2015

Therapeutic strategies to overcome immune

tolerance to cancer

Breakthrough lymphoma therapies2010-2015 FDA approved

Year Drug Type Target Indication

2011 Brentuximab Vedotin ADC CD30 R/R HL and ALCL

2013 Lenalidomide Small molecule Multiple 3d line, MCL

2013 Obinutuzumab MoAb CD20 1st line CLL with Chl

2013/2014

Ibrutinib Small molecule BTK 2nd line CLL and MCL

2014 Idelalisib Small molecule PI3Kδ R CLL with Rituximab, 3d line FL/SLL

ADC: antibody drug conjugate; MoAb: monoclonal antibody; R/R: relapsed/refarctory; HL: Hodgkin lymphoma. ALCL: anaplastic large cell lymphoma; MCL: mantle cell lymphoma; CLL: chronic lymphocytic leukemia; Chl: chlorambucil; FL: follicular lymphoma; SLL: small lymphocytic lymphoma

� Development of active, non-toxic drugs

� Incorporation of new drugs in standard treatments

� Define long-term toxicities especially in indolent

lymphomas

� Predictive biomarkers of response for rationale

drug development

New drug development for lymphomas:Open questions in 2016

Structure of human CD20 molecule

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

• no dissociation or internalization upon antibody binding

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

Targeting CD20: Old target new drugs

GA101 (Obinutuzumab)

Glycoengineered, Type II Anti-CD20 mAb

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

Type IIanti-CD20 mAb1,2 Glycoengineered

Fc 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.

Decreased complement dependent cytotoxicity

• 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

C1qC1q

mAbmAb

CD20 CD20

B cellMACMAC

MacrophageMacrophage

Anti-CD20 mAbs mechanism of action

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 + ++

Differences between type I and type II anti-CD20 mAbs1-3Differences between type I and type II anti-CD20 mAbs1-3

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

Type IType I

Type IIType II

mAb=monoclonal antibody;CDC=complement-dependent cytotoxicity; ADCC=antibody-dependent cellular cytotoxicity

mAb=monoclonal antibody;CDC=complement-dependent cytotoxicity; ADCC=antibody-dependent cellular cytotoxicity

Anti-CD20 mAbs: two types

Ove

rall

Sur

viva

l in

the

Inte

ntio

n-to

-Tre

at P

opul

ati

on

Obinutuzumab plus Chlorambucil in patients

with CLL and coexisting conditions

G-Clb vs Clb HR 0.41 (95% CI, 0.23-0.74)P=0.002

R-Clb vs Clb HR 0.66 (95% CI, 0.39-1.11)P=0.11

G-Clb vs R-Clb HR 0.66 (95% CI, 0.41-1.06)P=0.08

Goede V et al. N Engl J Med 2014;370:1101-1110.

GADOLIN: Study design (NCT01059630)

G-B

B

Rituximab-refractory CD20+ iNHL

(incl FL, MZL and SLL)

(N=413)

G-maintenanceCR/ PR/ SD

R1:1

Obinutuzumab 1000 mg i.v. Days 1, 8 and 15 Cycle 1; Day 1 Cycle 2–6 (28 day cycles)Bendamustine 90 mg/m2/day i.v. Days 1 and 2 Cycles 1–6 (28 day cycles)

Obinutuzumab 1000 mg i.v. every 2 months for 2 years or until progression

Bendamustine120 mg/m2/day Days 1 and 2 Cycles 1–6 (28 day cycles)

Stratification factors:•NHL subtype (FL vs other) •Prior therapies (≤2 vs >2)•Refractory type (R-mono vs R-chemo)•Geographic region

• International, randomized, open-label study

• Primary endpoint: PFS as assessed by an Independent Radiology Facility (IRF)

• Response monitored by CT scan post-induction, then every 3 months for 2 years, then every 6 months

Cheson et al 13-ICML, Abstract 123

GADOLIN primary outcome: IRF-assessed PFS

Time (months)

Pro

babi

lity

of P

FS

Median F-up: 21 mos

1.0

0.8

0.6

0.4

0.2

0.0

IRF, independent radiology facility; HR, hazard ratio; CI, confidence interval; NR, not reached

0 6 12 18 24 30 36 42 48 54 mos

Cheson et al 13-ICML, Abstract 123

11.718.5

9.09.010.19.5

58.0 50.8

11.2 12.2

0

20

40

60

80

100

G-B

n=188

B

n=189

Pati

en

ts (%

)

GADOLIN: Response to therapy

69.263.0

* Patients ongoing in induction therapy are excluded from analysis. Patients with end of induction response assessment performed >60 days after last induction dose shown as missing.

** Best overall response excludes ongoing patients who have not yet reached the first response assessment. IRF, independent radiology facility

End-of-induction response (IRF)

5.7 7.6

4.7 4.110.9 11.7

62.0 59.4

16.7 17.3

0

20

40

60

80

100

G-B

n=192**

B

n=197**

Pa

tie

nts

(%)

CR

PR

SD

PD

NE/missing78.7 76.7

Best overall response to 12 months (IRF)

• 19 patients still in induction (G-B, n=6; B, n=13)*

Cheson et al 13-ICML, Abstract 123

No difference in PFS in head to head comparison with rituximab in

indolent lymphomas: final results of the GAUSS study

Sehn LH et al, J Clin Oncol. 2015 Oct 20;33(30):3467-74

The GOYA Study

Stratification• Number of planned CHOP cycles (6 or 8)• IPI score• Region of study conduct

IPI, International Prognostic Index.

GA101 + CHOP

Rituximab + CHOP

Previously untreatedDLBCL

1:1

GA101•1000 mg on days 1, 8, and 15 of cycle 1; day 1 of cycles 2–8, every 21 daysRituximab•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

1400 patients

The era of ADCs?

MMAE – microtubule-disrupting agent

Apoptosis

G2/M cell

cycle arrest

ADC binds to CD30

MMAE disrupts

microtubule network

ADC–CD30 complex internalized/ 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.

protease-cleavable linker

anti-CD30 monoclonal antibody

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

Brentuximab vedotin ADC

Brentuximab Vedotin (Adcetris)

Anti-CD30 conjugated to an antitubulin agent

Response rate 75% (34% CR)

Pivotal Phase II study in relapsed or refractory

HL post-ASCT

Younes A et al, J Clin Oncol. 2012

Response rate 86% (57% CR)

Pivotal Phase II study in relapsed or refractory

systemic ALCL (sALCL)

Pro B et al, J Clin Oncol. 2012

� Median observation 3 yrs:-mOS 40.5 mos-mPFS 9.3 mos

� 34 CR pts: -3-yr OS 73%-3-yr PFS 58%

� 16 CR pts progression-free at a median of 53.3 mos (range 29-56.2 mos)

� 12 CR pts progression-free without allogeneic transplant

Durable remissions in a significant proportion

of R/R HL patients

Gopal AK et al. Blood 2014

Brentuximab Vedotin consolidation after ASCT

in HL: the AETHERA trial

Craig H Moskowitz, The Lancet, 2015

HR for PFS 0·57, 95% CI 0·40–0·81 (p=0·0013). Median PFS 42·9 months (95% CI 30·4–42·9) vs 24·1 months (11·5–not estimable)

ADCs in development for B-cell NHL

Drug Target Format Stage of development

Inotuzumab Ozogamicin

(Pfizer)

CD22 Conjugated to calicheamicin

Combination with R-chemo,

Temsirolimus

SAR3419(Sanofi)

CD19 Conjugated to DM4 Combination with Rituximab

DCDT2980S(Roche)

CD22 Conjugated to MMAE

Combination with Rituximab

DCDT2980S(Roche)

CD79b Conjugated to MMAE

Combination with Rituximab

IMGN529 (Immunogen)

CD37 Conjugated to DM1 Phase I ongoing

Tumor cell

Effector cellAntigen

DM1

IMGN529

Fc Receptor

Complement

Apoptosis/growth inhibition by

direct signaling

Antibody-dependentcellular cytotoxicity

(ADCC)

Complement-dependent cytotoxicity

(CDC)

Delivery of cytotoxic agent (DM1)

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

CD37

IMGN529 compound profile and

mechanism of action

A Phase I, Multi-center, Open-label study of

IMGN529 in relapsed or refractory B-cell NHL

Stathis A, et al. ASH 2014, abstr 1760

Tumors exploit pathways that evade immune

destruction including endogenous immune checkpoints

Mellman I, Nature, 2011

MR Green et al,Blood 2010; 116:3268

DJ Andorsky et al, Clin Cancer Res 2011; 17:4232

BJ Chen et al, Clin Cancer Res 2013; 19:3462

RA Wilcox et al, Blood 2009;114:2149

J Liu et al, Blood 2007;110(1):296

Pre-clinical rationale for PD-1/PD-L1 blockade

Ansell SM et al. N Engl J Med. 2014 Dec 6. [Epub] DOI: 10.1056/NEJMoa1411087

RR 87%, CR 17%

PD-1 Blockade with Nivolumab in Relapsed

or Refractory Hodgkin’s Lymphoma

*Patient became PET negative and was therefore declared to be in complete remission.Analysis cut-off date: November 17, 2014.

*

Moskowitz et al, ASH 2014, abstr. 290

Pembrolizumab: RR 66% , CR 21%

Nivolumab Pembrolizumab

Related AE 78% 55%

Grade 3 AE 22% 10%

PancreatitisGI inflammation

ColitisPneumonitis

Axillary painHypoxia

Joint swellingPneumonitis

Safety profile similar to that in solid tumours

Toxicity

Armand et al, ASH 2014, abstr. 289

Moskowitz et al, ASH 2014, abstr. 290

Anti-PD1 in R/R HL studies

Baseline Characteristics

CharacteristicHodgkin

Lymphoma(n=23)

B-cell NHL

(n=31)

T-cellNHL

(n=23)

MultipleMyeloma

(n=27)

Histology, nNS HL: 22MC HL: 1

Follicular: 11DLBCL: 10PMBL: 2Other: 8(MCL, SLL, MZL)

MF: 13PTCL: 5Other: 5

MM: 27

Prior auto transplant, n (%)Prior brentuximab vedotin, n (%)

18 (78)18 (78)

4 (14)3 (10)

2 (9)6 (26)

15 (56)0 (0)

Prior therapies, median (range) 5 (2–15) 3 (1–16) 4 (1–9) 4 (1–12)

Nivolumab updated phase I results

Timmerman J et al, abstr 10; ICML 2018

Tumor Type #pts

ORR CR PR SD

Hodgkin Lymphoma 23 20 (87) 6 (26) 14 (61) 3 (13)

B-Cell Non-Hodgkin Lymphoma 31 8 (26) 3 (10) 5 (16) 16 (52)

Diffuse Large B-Cell 11 4 (36) 2 (18) 2 (18) 3 (27)

Follicular 10 4 (40) 1 (10) 3 (30) 6 (60)

Mantle Cell 4 0 0 0 3 (75)

Primary Mediastinal B-Cell 2 0 0 0 2 (100)

Other B-NHL (SLL n=3, MZL n=1) 4 0 0 0 2 (50)

T-Cell Non-Hodgkin Lymphoma 23 4 (17) 0 4 (17) 10 (43)

CTCL/MF 13 2 (15) 0 2 (15) 9 (69)

Peripheral T-Cell 5 2 (40) 0 2 (40) 0

Other T-NHL 5 0 0 0 1 (20)

Multiple Myeloma 27 1 (4) 1 (4) 0 17 (63)

Best response

Nivolumab updated phase I results

Timmerman J et al, abstr 10; ICML 2018

Targets for the development of small

moleculesKinase inhibitors

B-cell receptor (BCR)

PI3K/AKT/MTOR

JAK/STAT

RAS/RAF/MEK

Cell cycle

Immunomodulators

Microenvironment

Epigenetic modulators

HDAC

BRD

EZH2

Proteasome inhibitors

NFKb

Bcl2 inhibitors

Apoptosis

Ibrutinib

• Ibrutinib was designed to

specifically target and

selectively inhibit BTK

• BTK is a key mediator of at

least three critical B-cell pro-

survival mechanisms

occurring in parallel:

– regulation of apoptosis

– cell adhesion

– cell migration and homing

Phase I study (N=56)

RR DLBCL 28%

FL 38%

MCL 77%

CLL/SLL 79%

Durable responses with median PFS of 13.6 months

Advani et al., J Clin Oncol, 2013

Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

ML, Wang et al NEJM, 2013

Ibrutinib + R-CHOP

A phase Ib study in CD20 positive NHL

Younes A, abstr 69, ICML-12, Lugano 2013

• n=32 CD20 positive treatment naïve pts (23 DLBCL, 5 MCL, 4 FL)

• MTD 560mg + standard RCHOP

• Toxicities: hematologic

420 mgn = 4

ORR 100% (CR 67%, PR 33%)

280 mgn = 6

560 mgn = 5

PR

CR

Num

ber

of P

atie

nts

1

DLBCL

DLBCL

DLBCL

MCL

MCL

MCL

FL

DLBCL

MCL

DLBCL

DLBCL

FL

FL DLBCL

MCL

Assessment performed at end of cycle 3; disease evaluations not complete

Staudt, 12-ICML, Hematol Oncol 2013. 31(suppl 1): 26-28

Responses to BTK-inhibitor ibrutinib are much

higher in ABC- DLBCL than GCB-DLBCL

ABC-DLBCL GCB-DLBCL

OR: 5%OR: 41%

Genetic lesions can partially predict

the response to the BTK-inhibitor ibrutinib

CD79B

MYD88

CARD11

mut.

wt

wt

wt

wt

wt

mut.

mut.

wt

wt

mut.

wt

wt

wt

mut.

Staudt, 12-ICML, Hematol Oncol 2013. 31(suppl 1): 26-28

Idelalisib: a highly selective PI3Kδ inhibitor

Lannutti B J et al. Blood 2011

PI3Kδ Inhibition by Idelalisib in Patientswith Relapsed Indolent Lymphoma

Gopal et al NEJM, 2014

ActivatesT, NK andNKT cells

NK and Tcell-

mediatedtumorkilling

Increasesantigen

presenting properties of tumor

cells

Arrestscell

cycle

Inducestumor

suppressorgenes

Tumorcell

apoptosis

Activatescaspases

Disrupts stromal cell

support

Reduces Tumorburden

Enhances Immunological

synapse formation

Lenalidomide mechanism of action

Rituximab, bendamustine and lenalidomide in

patients with aggressive B-cell lymphoma not eligible

for anthracycline-based therapy or intensive salvage

regimen. A phase II trial

Felicitas Hitz, Emanuele Zucca, Thomas Pabst, Natalie Fischer, Anne Cairoli, Panagiotis Samaras, Clemens Caspar, Nicolas Mach, Fatime Krasniqi, Adrian Schmidt, Christian Rothermundt, Milica Enoiu, Katrin Eckhardt, Simona Berardi Vilei, Stephanie Rondeau, Ulrich Mey

Hitz F et al, ICML 2015

Felicitas Hitz – June 17, 201551

Overall Response Rate

61%n=25

Pro

port

ion

of p

atie

nts

(%)

77%n=10

54%n=15

Felicitas Hitz – June 17, 201552

Overall follow-up time, median (range): 25.9 (0.2-37.9) months

Secondary Endpoints

Overall survivalmedian [95% CI]: 14.4 [4.9-21.6]

months

Time-to-event endpointMedian [95% CI] in

months

Progression-free survival4.8 [2.4-6.7]

Event-free survival 3.7 [1.8-5.2]

Response duration (n=25) 6.8 [3.4-12.3]

Time to progression 6.4 [2.4-8.6]

Overall survival 14.4 [4.9-21.6]

Rituximab-Bendamustine-Lenalidomide

• LBR is a very active regimen in different

lymphoprolipherative diseases

• The combination is very toxic if the drugs are given at full

dose

• A safe schedule seems to be:

Bendamustine 70 mg/m2 d1+2

Rituximab 375 mg/m2 d1

Lenalidomide 10 mg/d d1-14 q28d

• This regimen, although active, needs to be compared to

standard regimens in randomised trials

New drug combinations ICML 2015

Author Abstr Drug Target AEs RR

Mehta-Shah 016 Romidepsin

+Lenalidomide

HDAC+

Immunomodulator

ANC, PLT 53% TCL,

44% BCL

Barr 042 Entospletinib

+Idelalisib

SYK+PI3Kδ Pneumonitis in

20% of pts

29% NHL

Phillips 079 INCB040093

+ INCB039110

PI3Kδ+JAK1 Fatigue,

headache

28/75 (60%

HL)

Nastoupil 106 UBLITUXIMAB,

TGR-1202,

AND IBRUTINIB

CD20, PI3Kδ, BTK Diarrhea 9/13 NHL

Dunleavy 136 TEDDI-R BTK, CD20, CHEMO No DLTs 7/10 PCNSL

after

Ibrutinib

De Vos 147 Venetoclax+RB bcl2 Nausea,

anemia, PLT

66%, 74%

in FL

TGR-1202 (PI3ki) + Ublituximab (anti-CD20) + Ibrutinib (BTKi):

Phase-1 study

BEST PERCENT CHANGE FROM BASELINE IN DISEASE BURDEN

CRPRPRPR

PRPRPR

* * * * * * * * **(4.5) (2.5) (3.5) (7) (9.5) (4.5) (7) (8) (7) (9.5)

CRPRPRPR

PRPRPR

PRPR

* On Study

(X) Months On Study

• ORR, 86% with 76% reduction in nodal disease at first assessment in responders

• Well tolerated (neutropenia grade 3-4 in 6%)

L. Nastoupil , et al. Hematol Oncol. 2015;33: Supp 1. Abs 106

Venetoclax + Rituximab & Bendamustineearly and long-lasting responses with tolerable safety profile

MZLDLBCL FL

DLBCL ,

n=11FL, n=21 MZL, n=3

ORR 5 (45%) 15 (71%) 3 (100%)

CR 1 (9%) 6 (29%) 1 (33%)

Grade 3/4 AEs

(in ≥ 3 pts)

n (%)

Total

N=35

Lymphopenia 13 (34)

Neutropenia 11 (31)

Leukopenia 7 (20)

Thrombopenia 7 (20)

Anemia 6 (17)

Best Percent Change from Baseline in Nodal Size

S. De Vos et al. Hematol Oncol. 2015;33: Supp 1. Abs 147

Pathway Drug Target % Response rate in different histologies

DLBCL FL MCL SLL/CLL T-Cell HL

PI3K/AKT/mTOR

Everolimus mTOR 30% 50% 32% 18% 63% 53%

Temsirolimus mTOR 36% 56% 38% 10% - -

CALI-101 PI3K 0% 55% 67% 30% - -

B Cell Receptor (BCR)

Fostamtinib Syk 22% 10% 11% 55% 0% -

PCI32765 Btk 17% 23% 69% 67% - -

Modern drug development: not histology but

molecular characteristics?

Younes A & Berry D. Nature Rev Clin Oncol 2012

0%0%3%5%10%10%15%17%22%24%28%32%33%35%

0% 20% 40% 60% 80% 100%

Mapatumumab

YM155

SGN40

CMC544

Fostambinib

Lenalidomide

SAR3419

We are moving towards cell-of-origin

as a guide to therapy

Non-GCB type

• NF-kB activated

• BCR signalling

• TLR/IRAK signalling

• Bortezomib

• Ibrutinib

• Fostamatinib

• Lenalidomide

GCB type

• Epigenetic regulators mutant/lost

• EZH2, CREBBP

• ? EPOCH, DHAP

• ? GSK 126

• ? EPZ 6438

� Advances in preclinical research have supported the

development of a high number of new drugs

� Significant clinical activity observed in relapsed/refractory

patients and 5 drugs approved for different lymphomas

� Combination regimens are currently being tested and results

are awaited

� Molecular predictive biomarkers of efficacy are needed to

better select patients

In conclusion