Therapy of Relapsed or Refractory Aggressive Lymphomas

Report
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
I/II
Dose (ORR): 300 mg (63%); 500 mg (33%);
700 mg (20%); 1000 mg (50%)
II
ORR: 11%, 6-mo PFS in 116 pts with
rituximab-refractory FL
Ofatumumab
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
GA101
I/II
ORR: 38%; PFS: 11.4 mos in pts with FL
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).
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
ADC-CD30 complex
traffics to lysosome
MMAE is released
G2/M cell cycle arrest
MMAE disrupts
microtubule network
Apoptosis
With permission from Chen R et al. Proc ASH 2010; Abstract 283.
Brentuximab Vedotin (SGN-35) for
Rel/Ref Systemic ALCL
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
• 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)
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
Tumor Cells
IL-6
TNF
IL-1
Tumor
Stroma
ICAM-1
Blood Vessels
NFAT
PKC
IL-2
IL-2
IFN 
VEGF
bFGF
PI3K
Dendritic
Cells
CD28
CD8+
T Cells
Chng. Cancer Control. 2005;12:91; Drach. Expert Rev Cancer. 2005;5:477.
NK Cells
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 DLBCL
GCB 23
Non-GCB 17
9%
53%
Hernandez
4% -Illizaliturri
24%
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
Lenalidomide vs Investigators Choice
for Ref/Rel DLBCL: Study Design
Stage 1
lenalidomide
Stage 2
N = 100
n=25
N = 148 or 296
Non-GCB
R
Inv. Choice
DLBCL
n=25
Stratify
by IHC
GCB
?
Selected
Type(s)
lenalidomide
R
n=25
Inv. Choice
lenalidomide
n=74
R
Inv. Choice
n=74
?
n=25
If lenalidomide is superior to investigator’s choice in either
or both subtype(s) then that subtype(s) will be tested in Stage 2.
13
Small Molecule Inhibitors: Responses
for Various Lymphoma Subtypes
Pathway
Drug
% Response Rate by Histology
DLBCL
FL
MCL
SLL/
CLL
T-Cell
HL
mToR
30
50
32
18
63
53
mToR
36
56
38
10
-
-
CAL-101
PI3K
0
55
67
30
-
-
Fostamtinib
Syk
22
10
11
55
0
-
Ibrutinib
Btk
17
23
69
67
-
-
PI3K/AKT Everolimus
/mTOR
Temsirolimus
B Cell
Receptor
(BCR)
Target
Results of Activation of the B-Cell
Receptor and Targets for Manipulation
CAL-101
fostamatinib
PCI-32765
?
enzastaurin
?
bortezomib
carfilzomib
temsirolimus
everolimus
deferolimus
PCI-32765: A Novel Small Molecule
Inhibitor of Btk in the BCR Pathway
•
Forms a specific and
irreversible bond with cysteine481 in Btk
•
Potent Btk inhibition
O
NH
2
N
• IC50 = 0.5 nM
N
N
N
N
O
•
Orally available
•
Once daily dosing results in 24hr sustained target inhibition
Phase I PCI-32765 for Recurrent NHL and
CLL: Response in 48 Evaluable Patients
Best Response Rate (%)
100
80
7/9
9/13*
ORR (evaluable) 52%
2/3
ORR (ITT) 45%
60
CR
PR
40
1/3
4/13
2/7
20
0
CLL/SLL
MCL
WM
*2 CLL pts had nodal response with lymphocytosis
MZL/Malt
FL
DLBCL
Phase I PCI-32765 for Recurrent NHL and CLL:
Hematologic Tolerability (N=56)
• No hepatic or renal toxicities
• No evidence of cumulative hematologic toxicity
Percent
100
% Grade 4
% Grade 3
% Grade 2
% Grade 1
80
60
40
20
0
↓HGB
↓ANC
↓PLT
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 MedicineHematology/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)
CR
PR
Percent of patients (%)
100
72%
80
68%
66%
60
40
44
49
46
23
22
Bortezomibexposed
(n=47)
Total
(n=110)
20
21
0
Bortezomibnaïve
(n=63)
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
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
R-CHOP
PI3K Promotes Survival/Growth of
Cancer Cells
Class I PI3K Cellular
Isoform
Expression
Primary Physiological Role
Alpha
Broad
Insulin signaling and angiogenesis
Beta
Broad
Platelet function
Gamma
Leukocytes
Neutrophil and T-cell function
Delta
Lymphocytes
B-cell signaling, development
and survival
LYMPH NODE
MALIGNANT B-CELL
Single-Agent CAL-101 for R/R MCL, iNHL,
and CLL: Best Tumor Volume Response
Best On-Treatment Change in Tumor Size
(ITT Analysis)
+100
% Change in Lymph Node Area
+75
+50
+25
MCL
iNHL
CLL
(N=21)
(N=30)
(N=54)
0
-25
-50*
-75
-100
Inevaluable (patients without a follow-up tumor assessment)
* Criterion for response [Cheson 2007, Hallek 2008]
ORR with CAL-101 for R/R iNHL
Overall Response Rate Compared to Those with Other Drugs
Prior Therapies
(median)
63%
CAL-101 (N=30)
4
75%
Bendamustine (N=123)
48%
Rituximab (N=166)
30%
PCI-32765 (Btk inhibitor) (N=20)
3
3
2
23%
Lenalidomide (N=43)
2
Fostamatinib (Syk inhibitor) (N=25)
12%
4
Bortezomib (N=60)
12%
3
ITT Response Rate [Exact Binomial 95% CI], %
Slide 24
PFS results are as good or better with CAL-101
CAL-101 for R/R NHL:
Cumulative Adverse Events
Grade 3-4 Adverse Events Occuring in 5%
of Patients Regardless of Causality (N=51)
100
Incidence, %
80
60
40
27%
20
8%
6%
10%
8%
10%
T
AS
AL
T/
xia
or
e
An
Pn
eu
m
on
ia
ea
ar
rh
Di
ni
a
tro
pe
Ne
u
Fa
tig
ue
0
Adverse Event Type
• 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
Department of Lymphoma/Myeloma Disease –
specific Working Groups
Larry W. Kwak, M.D., Ph.D.
Chairman, Lymphoma/Myeloma
Michael Wang, M.D.
Nathan Fowler, M.D.
Co-Directors
Lymphoma Clinical Research
Low Grade
lymphoma
N. Fowler
F. Samaniego
S. Neelapu
L. Fayad
L. Kwak
T cell
lymphoma
Y. Oki
M. Fanale
Large Cell
lymphoma
Robert Orlowski, M.D., Ph.D.
Director
Myeloma Clinical Research
Mantle cell
lymphoma
L. Fayad
A. Rodriguez
F. Hagemeister
J. Westin
Hodgkins
M. Wang
J. Romaguera
Burkitt
HIV
M. Fanale
M. Fanale
F. Hagemeister
Brain
Testicular
N. Fowler
Phase
I
M. Fanale
N. Fowler
J. Shah
J. Westin
Multiple
myeloma
D. Weber
J. Shah
S. Thomas
M. Wang
R. Alexanian
Q. Yi

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