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Treatment approaches to non-Hodgkin’s l ymphoma in elderly patients. Larry W. Kwak, M.D., Ph.D. Chairman, Department of Lymphoma/Myeloma Justin Distinguished Chair in Leukemia Research Co-Director, Center for Cancer Immunology Research MD Anderson Cancer Center. - PowerPoint PPT Presentation
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Treatment approaches to non-Hodgkin’s lymphoma in
elderly patients
Larry W. Kwak, M.D., Ph.D.
Chairman, Department of Lymphoma/Myeloma
Justin 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
Ofatumumab
I/IIDose (ORR): 300 mg (63%); 500 mg (33%);
700 mg (20%); 1000 mg (50%)
IIORR: 11%, 6-mo PFS in 116 pts with
rituximab-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 agent
protease-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 Review
ORR 81% 86%
CR 59% 53%
PD 22% 33%
Median DR 36 weeks NR
Median DR for CR NR NR
Median PFS 41 weeks NR
Median PFS for prior therapy 26 weeks
Brentuximab Vedotin (SGN-35) for Rel/Ref Systemic ALCL
Novel Therapeutics for NHLs
Cancer 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-2
IFN
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 Reference
US 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
DLBCLStratify by IHC
GCB
lenalidomide
n=25
Inv. Choice
n=25
R
Non-GCB
lenalidomide
n=25
Inv. Choice
n=25
R
Stage 1
N = 100
Selected
Type(s)
lenalidomide
n=74
Inv. Choice
n=74
R
Stage 2
N = 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
Be
st
Re
sp
on
se
Ra
te (
%)
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)
Per
cen
t
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
Per
cen
t o
f p
atie
nts
(%
)
Bortezomib-naïve(n=63)
Bortezomib-exposed(n=47)
Total(n=110)
66%72% 68%
Current Active Trials with Ibrutinib
Phase 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 angiogenesis
Beta Broad Platelet function
Gamma Leukocytes Neutrophil and T-cell function
Delta LymphocytesB-cell signaling, development
and 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
Are
a
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
Inci
denc
e, %
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
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