Treatment approaches to non-Hodgkin’s lymphoma in

elderly patients

Larry W. Kwak, M.D., Ph.D.

Chairman, Department of Lymphoma/MyelomaJustin Distinguished Chair in Leukemia Research

Co-Director, Center for Cancer Immunology Research MD Anderson Cancer Center

Refractory/Relapsed DLBCL: Therapy for “Non-Transplant Candidates”

• Poor disease control and substantial morbidity.

• Goal is generally palliative • Gemcitabine based• Low dose oral chemotherapy• “hyperfractionated cytoxan”• Rituximab• Radiation

• New drugs

Novel Anti-CD20 MoAbs for Relapsed/Refractory Indolent Lymphoma

MoAb Phase Efficacy

OfatumumabI/II Dose (ORR): 300 mg (63%); 500 mg (33%);

700 mg (20%); 1000 mg (50%)

II ORR: 11%, 6-mo PFS in 116 pts withrituximab-refractory FL

Veltuzumab I/II

IV administration: ORR: 44%, CR: 27%DOR in pts with FL: 19.7 mos

Subcutaneous administration: ORR: 53% CR: 20% in pts with indolent NHL

Ocrelizumab I/II ORR: 38%; PFS: 11.4 mos in pts with FL

GA101 I ORR: 69%, CR: 38% in 13 pts with FL

Morschhauser. Ann Oncol. 2010 (Epub ahead of print); Morschhauser. J Clin Oncol. 2009;27: 3346; Negrea. ASH. 2009 (abstr 3757); Hagenbeek. ASH. 2009 (abstr 935); Hagenbeek. Blood. 2008;111:5486; Salles. ASH. 2009 (abstr 1704).

With permission from Chen R et al. Proc ASH 2010; Abstract 283.

Brentuximab Vedotin: Mechanism of Action

Brentuximab vedotin (SGN-35) antibody-drug conjugate (ADC)

monomethyl auristatin E (MMAE), potent antitubulin agentprotease-cleavable linker

anti-CD30 monoclonal antibody

ADC binds to CD30

MMAE disruptsmicrotubule network

ADC-CD30 complex traffics to lysosome

MMAE is released

Apoptosis

G2/M cell cycle arrest

• In terms of response, ALK (+) = ALK (–)• “B” symptom resolution = 82%• Peripheral neuropathy = 38% (median time to resolution 5.4

weeks)

Shustov, ASH 2010 # 961 (Oral)

n=58 Investigator Central ReviewORR 81% 86%CR 59% 53%PD 22% 33%

Median DR 36 weeks NRMedian DR for CR NR NR

Median PFS 41 weeks NRMedian PFS for prior therapy 26 weeks

Brentuximab Vedotin (SGN-35) for Rel/Ref Systemic ALCL

Novel Therapeutics for NHLsCancer Hallmark Therapeutic Target Treatment

Proliferation Syk, Btk, PKCB, MToR, PI3K

FosD, PCI-32765, Enzastaurin, Temsirolimus, Cal-101

Insensitive to Growth Inhibition

HDAC, DNMT Vorinostat, Romidepsin, Belinostat, Panabinostat, Vidaza

Evading apoptosis BCL2/BCLX, MCL-1, Survivin

ABT-263, Obatoclax, YM155

Limitless Replication CDK, PARP AT7519, AZD7762, AT9283

Neoangiogenesis VEGFR, FGFR Sorafenib, Imatinib, Sunitinib

Invasion/Metastasis Src, Fak, TGF Dasatinib, LY2109761, XL228

Immune Evasion NK/T cells Lenalidomide, Pomalidomide

Stress Response Proteasome Bortezomib, Carfilzomib

Stromal Subversion SHh, Wnt, Notch GDC-0449, XL139, XAV939, MK-0752

Cytokine Response CXCR4, IL-21R AMD3100, BKT140, IL-21

Mahadavan and Fisher. JCO 29: 1876, 1884, 2011.

Lenalidomide: Targeting the Tumor Cell and Its Microenvironment

Chng. Cancer Control. 2005;12:91; Drach. Expert Rev Cancer. 2005;5:477.

Tumor Cells

Tumor Stroma

Dendritic Cells

IL-6TNFIL-1

IL-2IFN

CD8+ T Cells

Blood Vessels

ICAM-1

VEGFbFGF

NK Cells

PKCNFAT

PI3K

IL-2

CD28

Lenalidomide/Rituximab for Untreated Stage II-IV iNHL: Response Rates by Subtype

Rituximab Plus Lenalidomide 20 mg daily for 21 days, off 7 days X 6, and if CR, reduce to 10 mg

Lenalidomide + Rituximab for Ref/Rel DLBCL

Group No. of Pt. ORR CRR ReferenceUS 49 (various

histology)35% 12% Wiernik

2008

Italian 23 DLBCL 35% 4% Zinzani 2011

International 217 DLBCL 35% 13% Witzig 2011

Retrospective from 4 sites

40 DLBCLGCB 23

Non-GCB 179%

53%4%24%

Hernandez-Illizaliturri

2011

Lenalidomide for Ref/Rel DLBCL: Response by Molecular Subtype

• 40 patients– GCB 23– Non-GCB 17

• PFS (p=0.004)– Non-GCB 6.2 months– GCB 1.7 months

Hernandez-Ilizaliturri et al. Cancer 2011

13

Lenalidomide vs Investigators Choice for Ref/Rel DLBCL: Study Design

DLBCL Stratify by IHC

GCB

lenalidomiden=25

Inv. Choicen=25

R

Non-GCB

lenalidomiden=25

Inv. Choicen=25

R

Stage 1N = 100

SelectedType(s)

lenalidomiden=74

Inv. Choicen=74

R

Stage 2N = 148 or 296

If lenalidomide is superior to investigator’s choice in either or both subtype(s) then that subtype(s) will be tested in Stage 2.

?

?

Small Molecule Inhibitors: Responses for Various Lymphoma Subtypes

Pathway Drug Target % Response Rate by Histology

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 - -

CAL-101 PI3K 0 55 67 30 - -

B Cell Receptor (BCR)

Fostamtinib Syk 22 10 11 55 0 -

Ibrutinib Btk 17 23 69 67 - -

Results of Activation of the B-Cell Receptor and Targets for Manipulation

bortezomib carfilzomib

?

?

fostamatinib

temsirolimus everolimus deferolimus

CAL-101

enzastaurin

PCI-32765

PCI-32765: A Novel Small Molecule Inhibitor of Btk in the BCR Pathway

• Forms a specific and irreversible bond with cysteine-481 in Btk

• Potent Btk inhibition

• IC50 = 0.5 nM

• Orally available

• Once daily dosing results in 24-hr sustained target inhibition

Phase I PCI-32765 for Recurrent NHL and CLL: Response in 48 Evaluable Patients

*2 CLL pts had nodal response with lymphocytosis

CLL/SLL*

MCL WM MZL/MALT

FL DLBCL 0

20

40

60

80

100

9/13*

7/9

2/3

1/34/13 2/7

CR

PR

Bes

t Res

pons

e R

ate

(%)

CLL/SLL MCL WM MZL/Malt

FL DLBCL

ORR (evaluable) 52%

ORR (ITT) 45%

↓HGB ↓ANC ↓PLT0

20

40

60

80

100 % Grade 4% Grade 3% Grade 2% Grade 1

• No hepatic or renal toxicities

• No evidence of cumulative hematologic toxicity

Phase I PCI-32765 for Recurrent NHL and CLL: Hematologic Tolerability (N=56)

Perc

ent

Interim Results of an International, Multicenter, Phase 2 Study of Bruton’s

Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Relapsed or Refractory Mantle Cell Lymphoma (MCL): Durable Efficacy and

Tolerability With Longer Follow-up Michael Wang, MD1, Simon Rule, MD2, Peter Martin, MD3, Andre

Goy, MD4, Rebecca Auer, MD5, Brad S. Kahl, MD6, Wojciech Jurczak, MD7, Ranjana Advani, MD8,

Jorge Romaguera, MD1, Jesse McGreivy, MD9, Fong Clow, ScD9, Michelle Stevens-Brogan9, Lori Kunkel, MD9,

Kristie A. Blum, MD10 1 Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; 2 Department of

Haematology, Derriford Hospital, Plymouth, United Kingdom; 3 Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY; 4 John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ

5 Department Haemato-oncology, Barts Health NHS Trust, London, United Kingdom ; 6 Department of Medicine-Hematology/Oncology, University of Wisconsin, Madison, WI; 7 Department of Haematology, Jagiellonian University, Krakow, Poland; 8 Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA

9 Pharmacyclics, Inc., Sunnyvale, CA; 10 The Ohio State University, Columbus, OH

Best Response(Efficacy Population n=110, Median Follow-up 9.2 mo)

0

20

40

60

80

100

21 23 22

4449 46

CR PR

Perc

ent o

f pat

ient

s (%

)

Bortezomib-naïve(n=63)

Bortezomib-exposed(n=47)

Total(n=110)

66%72% 68%

Current Active Trials with IbrutinibPhase NCT# Combination DZ State Subtype

I 01704963 Single Agent Rel/Ref B-Cell NHL

I 01479852 Benda/Ritux Rel/Ref NHL

I 01569750 R-CHOP Untreated

LCL, MCL, Indolent

II 01599049 Single Agent Rel/Ref MCL (after Bortez)

II 01583902 Single Agent Rel/Ref SLL/CLL

II 01614821 Single Agent Rel/Ref Waldenstrom’s

III 01578707 vs Ofa Rel/Ref SLL/CLL

III 01611090 BR Rel/Ref SLL/CLL

LYMPH NODEMALIGNANT B-CELL

Class I PI3K Isoform

Cellular Expression Primary Physiological Role

Alpha Broad Insulin signaling and angiogenesisBeta Broad Platelet functionGamma Leukocytes Neutrophil and T-cell function

Delta LymphocytesB-cell signaling, developmentand survival

PI3K Promotes Survival/Growth of Cancer Cells

Best On-Treatment Change in Tumor Size(ITT Analysis)

-100

-75

-25

0

-50*

+25

+50

+75

+100

MCL(N=21)

iNHL(N=30)

CLL(N=54)

Inevaluable (patients without a follow-up tumor assessment)* Criterion for response [Cheson 2007, Hallek 2008]

% C

hang

e in

Lym

ph N

ode

Area

Single-Agent CAL-101 for R/R MCL, iNHL, and CLL: Best Tumor Volume Response

ORR with CAL-101 for R/R iNHL

Slide 24

Bortezomib (N=60)

Fostamatinib (Syk inhibitor) (N=25)

Lenalidomide (N=43)

PCI-32765 (Btk inhibitor) (N=20)

Rituximab (N=166)

Bendamustine (N=123)

CAL-101 (N=30)

12%

Prior Therapies(median)

4

4

3

3

2

2

3

12%

23%

30%

48%

75%

63%

ITT Response Rate [Exact Binomial 95% CI], %

Overall Response Rate Compared to Those with Other Drugs

PFS results are as good or better with CAL-101

• Grade 3-4 events were usually related to underlying disease or prior therapy• Reversible Gr 3-4 ALT/AST elevations were not associated

with increased bilirubin or decreases in liver synthetic function• No obvious pattern of drug-related symptomatic adverse events

CAL-101 for R/R NHL: Cumulative Adverse Events

Fatigu

e

Neutropenia

Diarrhea

Pneumonia

Anorexia

ALT/A

ST0

20

40

60

80

100

10%8%8%

27%

6%10%

Grade 3-4 Adverse Events Occuring in 5%of Patients Regardless of Causality (N=51)

Adverse Event Type

Incid

ence

, %

Department of Lymphoma/Myeloma Disease –specific Working Groups

N. FowlerF. SamaniegoS. NeelapuL. FayadL. Kwak

T cell lymphoma

Multiplemyeloma

D. WeberJ. ShahS. ThomasM. WangR. AlexanianQ. Yi

Michael Wang, M.D.Nathan Fowler, M.D.

Co-DirectorsLymphoma Clinical Research

Robert Orlowski, M.D., Ph.D.Director

Myeloma Clinical Research

BurkittHIV

BrainTesticular

M. Fanale N. Fowler

M. FanaleN. FowlerJ. ShahJ. Westin

Larry W. Kwak, M.D., Ph.D.Chairman, Lymphoma/Myeloma

Low Grade lymphoma

Large Cell lymphoma

Mantle cell lymphoma Hodgkins

L. FayadA. RodriguezF. HagemeisterJ. Westin

M. WangJ. RomagueraM. Fanale

F. Hage- meister

Phase I

Y. OkiM. Fanale