A Look Forward:
New and Emerging Therapies
Brad S. Kahl, MD
Skoronski Chair of Lymphoma Research
University of Wisconsin School of Medicine and Public Health
Associate Director for Clinical Research
UW Carbone Cancer Center
Changing Landscape
• FDA approvals last 12 months
– Obinutuzumab for CLL
– Lenalidomide for MCL
– Ibrutinib for MCL and CLL
• Horizon
– Idelalisib for indolent NHL
– ABT-199 for CLL, NHL
– CART therapy
Examples of How We Treat
• Hodgkin lymphoma
– ABVD + IFRT
• Diffuse Large B-cell Lymphoma
– R-CHOP + IFRT
• Follicular Lymphoma
– R-bendamustine or R-CHOP + maintenance rituximab
• CLL/SLL
– FCR or R-bendamustine
“Everything works
better with R”
• Rituximab added to CHOP increased cure rate
in DLBCL by 15% (absolute difference)
• Rituximab added to chemotherapy increased 5yr PFS by 20% and OS by 5% in FL.
• Major effort into development of new moAbs.
– Target different Ags
– New “improved” anti-CD20s
Proposed Mechanisms of Action of Rituximab
Macrophage, ADCC
monocyte, or
natural killer cell
Rituximab
CD20
FcgRI, FcgRII, FcgRIII
Cell lysis
CDC
B cell
Complement activation (C1qC1rC1s)
MAC
CD20
Cell lysis
Apoptosis
Anderson et al. Biochem Soc Trans. 1997;25:705; Golay et al. Blood. 2000;95:3900; Reff et al. Blood. 1994;83:435; Clynes
et al. Nat Med. 2000;6:443; Shan et al. Cancer Immunol Immunother. 2000;48:673; Silverman et al. Arthritis Rheum.
2003;48:1484.
MoAb’s for Lymphoma
•
•
•
•
•
•
•
FDA approved
Rituximab (CD20)
Alemtuzumab (CD52)
Ofatumomab (CD20)
Obinutuzimab (CD20)
Zevalin (CD20) -Y90
Bexxar (CD20) -I131
Brentuximab vedotin
(CD30) -MMAE
Dropped
•
•
•
•
•
•
Lumiliximab (CD23)
Galiximab (CD80)
Epratuzumab (CD22)
Hu1D10 (HLA DR)
SGN-30 (CD30)
SGN-40 (CD40)
Under Study
• Biosimilars (CD20)
Type I (rituximab) vs Type II (obinutuzimab)
ANTIBODY TYPE
LIPID RAFTS
CDC
ADCC
DIRECT CYTOTOXICITY
BINDING SITES
HOMOTYPIC
AGGREGATION
I
YES
HIGH
+
WEAK
2
WEAK
II
NO
LOW
+
STRONG
1
STRONG
TYPE I
TYPE II
FREE END
Adapted from Cragg MS Blood 2011
CLL11: Phase III Study of Chlorambucil (Chl) Alone vs
Chl + Obinutuzumab vs Chl + Rituximab in Previously
Untreated CLL Patients With Comorbidities
Primary endpoint:
PFS
(investigator assessed)
R
GA101 + chlorambucil
× 6 cycles
1:2:2
Rituximab + chlorambucil × 6
cycles
Secondary endpoints:
ORR
DOR
DFS
OS
MRD
Chlorambucil = 0.5 mg/kg d1, d15 q28d (based on GermanCLLSG CLL5 study)
GA101=100 mg d1, 900 mg d2, 1000 mg d8, 15 cycle 1; 1000 mg d1 cycles 2-6
Rituximab=375 mg/m2 d1 cycle 1; 500 mg/m2 d1 cycles 2-6 q28d (GCLLSG CLL8)
DATA (from PI)
Stage I analysis, ASCO 2013 and FDA data, of G-Chl vs Chl
Progression-Free
Survival
11mos
23mos
Stage 2 analysis of G-Chl vs R-Chl, ASH PLENARY
Obinutuzumab
• FDA approval Nov 1st
– For use in combination with chlorambucil
– First line CLL treatment
• Unknown if “FCO” or “BO” will be superior
to FCR or BR
CLL: CART Therapy
T Cell
CLL
CART
CD19
Targeted agents
• Principle
– Find the driver of growth for a particular
cancer (in the lab)
– Identify this driver in your patients (predictive
biomarker)
– Attack the pathway with the correct kinase
inhibitor or other small molecule “disruptor”
I wish it were this simple
Figure 1A: B cell receptor pathway. Taken from http://www.cellsignal.com/reference/pathway/B_Cell_Antigen.html
Challenges
• Reality
– Numerous agents with 20-30% response
rates and median durations of 6 months
• Identifying biomarkers is hard
– Assay challenges, sample challenges,
specificity challenges,
• Running biomarker driven clinical trials is
difficult
– Regulatory overload
Targeting Intracellular Pathways
Potential Targets
• Proteasome
• RAS-RAF-MEK
• Angiogenesis
• Histones
• mTOR
• JAK-STAT
• PI3 kinase
• BTK
• BCL-2
Agent (disease)
Bortezomib (MCL)
Sorafenib (bust)
Bevacizumab (bust)
SAHA, romidepsin (CTCL)
Temsirolimus (MCL)
SB1518 (TBD)
Idelalisib (TBD)
Ibrutinib (MCL, CLL)
ABT-199 (TBD)
Targeting the B Cell Receptor
• Pathway utilized by normal cells
– Differentiation, proliferation
• Appears some B cell malignancies have
“tonic” signaling through pathway
– Unclear what is source of signaling
• Currently most promising area of research
in B cell malignancies
Targets of B-Cell Receptor Signaling
Antigen
CK
B Cell Receptor
Cytokine Receptor
C
D
7
9
B
SYK
P
TLR
C
D
1
9
C
D
7
9
A
PI3K
LYN
BTK P
Cal 101
P
PIP3
JAK1
DAG
AKT
fostamatinib
PLCγ
MYD88
IP3--Ca++
BLNK
PKCβ
CARD11
ERK
Bcl10
MALT1
IkB
IkB
NFkB
Transcriptional Activation
Proteosomal
Degradation
Mature Response Data from a Phase 2
Study of PI3K-Delta Inhibitor Idelalisib
in Patients with Double (Rituximab and
Alkylating Agent)-Refractory Indolent
B-Cell Non-Hodgkin Lymphoma (iNHL)
A Gopal,1 B Kahl,2 S de Vos,3 N Wagner-Johnston,4 S Schuster,5 K Blum,6 W Jurczak,7 I Flinn,8 C Flowers,9 P Martin,10 A Viardot,11
A Goy,12 A Davies,13 PL Zinzani,14 M Dreyling,15 L Holes,16 D Li,16 R Dansey,16 Wayne Godfrey,16 and G Salles17
1University
of Washington School of Medicine, Seattle, WA, USA; 2University of Wisconsin Carbone Cancer Center, Madison, WI, USA; 3David Geffen School of Medicine at UCLA, Los Angeles, Los
Angeles, CA, USA; 4Washington University School of Medicine, St. Louis, MO, USA; 5Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA; 6Ohio State University
Wexner Medical Center, Columbus, OH, USA; 7Jagiellonian University, Krakow, Poland; 8Sarah Cannon Research Institute, Nashville, TN, USA; 9Winship Cancer Institute of Emory University,
Atlanta, GA, USA; 10Weill Cornell Medical College, New York, NY, USA; 11University Hospital of Ulm, Ulm, Germany; 12Hackensack University Medical Center, Hackensack, NJ, USA; 13University of
Southampton, Southampton, United Kingdom; 14University of Bologna, Bologna, Italy; 15University Hospital Grosshadern, LMU Munich, Germany; 16Clinical Research Oncology,
Gilead Sciences, Seattle, WA, USA; 17Hospices Civils de Lyon, University Claude Bernard, Pierre Benite, France
American Society of Hematology
December 8, 2013
New Orleans, LA
Oral No 85.
Idelalisib
 Selective, oral inhibitor of PI3K-delta
 Inhibits proliferation and induces apoptosis in many
B-cell malignancies
 Inhibits homing and retention of malignant B-cells
in lymphoid tissues reducing B-cell survival
Class I PI3K
Isoform
Expression
EC50 (nM)
a
b
g
d
Ubiquitous
Ubiquitous
Leukocytes
Leukocytes
>10,000
1419
2500
9
♦ Promising activity in R/R iNHL in phase I study*
*Benson D et al. ASCO 2013, abstr 8526
Slide 21
Study 101-09 Waterfall Plot Lymph Node Response
SPD of Measured Lymph Nodes,
Best % Change from Baseline
+50
•90% had improvement in lymphadenopathy
•57% had ≥50% decrease from baseline
+25
0
-25
-50a
-75
-100
Individual Patients (N=125)
aCriterion
b
for lymphadenopathy response [Cheson 2007]
3 subjects no post baseline evaluation:
□ 2 subjects NE
■ 1 subject PD by Lymph Node biopsy
Slide 22
Study 101-09: Duration Of Response (DOR)
% Continued Response
Median DOR = 12.5 months
100
75
50
25
0
0
(71)
3
(54)
6
(34)
9
(17)
12
(9)
15
(0)
18
(0)
Time from Response, Months
(N, Patients at Risk)
Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to IRC assessments
Slide 23
Study 101-09: Adverse Events > 10%
AE
Diarrhea
Fatigue
Nausea
Cough
Pyrexia
Dyspnea
Decreased appetite
Abdominal pain
Vomiting
URI
Decreased weight
Rash
Asthenia
Night Sweats
Pneumonia
Any Grade
N, %
54 (43%)
37 (30%)
37 (30%)
36 (29%)
35 (28%)
22 (18%)
22 (18%)
20 (16%)
19 (15%)
18 (14%)
17 (13%)
16 (13%)
14 (11%)
14 (11%)
14 (11%)
Grade ≥ 3
N, %
16 (13%)
2 (2%)
2 (2%)
None
2 (2%)
4 (3%)
1 (1%)
3 (2%)
3 (2%)
None
None
2 (2%)
3 (2%)
None
9 (7%)
Slide 24
Idelalisib
• I think there is a good chance idelalisib will
get FDA approval in this patient population
Targets of B-Cell Receptor Signaling
Antigen
CK
B Cell Receptor
Cytokine Receptor
C
D
7
9
B
SYK
P
TLR
C
D
1
9
C
D
7
9
A
PI3K
LYN
BTK P
Cal 101
P
PIP3
JAK1
DAG
AKT
PLCγ
fostamatinib
MYD88
IP3--Ca++
ibrutinib
BLNK
PKCβ
CARD11
ERK
Bcl10
MALT1
IkB
IkB
NFkB
Transcriptional Activation
Proteosomal
Degradation
PCI-32765: First-in Class Inhibitor of BTK
O
NH 2
N
N
N
•
Forms a specific and irreversible bond with
cysteine-481 in BTK
•
Highly potent BTK inhibition at
IC50 = 0.5 nM
•
Orally administered with once daily dosing
resulting in 24-hr target inhibition
•
In CLL cells promotes apoptosis, inhibits
ERK1/AKT phosphorylation, NF-κB DNA
binding, CpG mediated proliferation
•
Inhibits CLL cell migration and adhesion
•
No cytotoxic effect on T-cells or NK-cells
N
N
O
PCI-32765
Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010
Herman SEM et al: Blood 117: 6287-6296, 2011
Ponader, et al., ASH Meeting Abstracts 116:45, 2010
27
Original Article
Targeting BTK with Ibrutinib in Relapsed or
Refractory Mantle-Cell Lymphoma
Michael L. Wang, M.D., Simon Rule, M.D., Peter Martin, M.D., Andre Goy, M.D.,
Rebecca Auer, M.D., Ph.D., Brad S. Kahl, M.D., Wojciech Jurczak, M.D., Ph.D.,
Ranjana H. Advani, M.D., Jorge E. Romaguera, M.D., Michael E. Williams, M.D.,
Jacqueline C. Barrientos, M.D., Ewa Chmielowska, M.D., John Radford, M.D.,
Stephan Stilgenbauer, M.D., Martin Dreyling, M.D., Wieslaw Wiktor Jedrzejczak, M.D.,
Peter Johnson, M.D., Stephen E. Spurgeon, M.D., Lei Li, Ph.D., Liang Zhang, M.D.,
Ph.D., Kate Newberry, Ph.D., Zhishuo Ou, M.D., Nancy Cheng, M.S., Bingliang Fang,
Ph.D., Jesse McGreivy, M.D., Fong Clow, Sc.D., Joseph J. Buggy, Ph.D., Betty Y.
Chang, Ph.D., Darrin M. Beaupre, M.D., Ph.D., Lori A. Kunkel, M.D., and Kristie A.
Blum, M.D.
N Engl J Med
Volume 369(6):507-516
August 8, 2013
Best Response to Therapy.
Wang ML et al. N Engl J Med 2013;369:507-516
Duration of Response, Progression-free Survival, and Overall Survival.
Wang ML et al. N Engl J Med
2013;369:507-516
Backround
• Limited options for R/R CLL
• Bruton’s tyrosine kinase
– Essential component of B cell receptor signaling
• Ibrutinib (PCI-32765)
– 1st in class oral BTK inhibitor
• Phase 1b-2 multicenter trial
– 420 mg/day N = 51
– 840 mg/day N = 34
Figure 1:
lymphocyte count vs. nodal response
Figure 1: Response over time
Figure 3: PFS and OS
Conclusions
• Unprecedented single agent activity in
relapsed MCL and CLL
• Durable responses
• Side effect profile tolerable
– Lack of myelosuppression
– Infection risk similar to background
• FDA approval
– Nov 2013 MCL
– Feb 2014 CLL
Ongoing Research
• BCR pathway inhibitors are:
– Most active: CLL/SLL, MCL
– Moderate: FL, MZL, MALT, DLBCL
• Extensive ongoing research
– In other lymphoma types
– In combination with chemotherapy and other
targeted agents
BCL-2 targeting
Introduction
• Bcl-2 overexpression is fundamental in the pathophysiology of
NHL
(Sawas et al, Curr Opin Hematol, 2011)
• BH3 mimetic Navitoclax (ABT-263) is active in indolent NHL and
CLL (Wilson et al, Lancet Oncology, 2010 and Roberts et al, J Clin Oncol, 2012)
O S
NO2 H
N
2
O
– Inhibits Bcl-2, Bcl-xL and Bcl-w
O
O
– Thrombocytopenia due to Bcl-xL inhibition is dose-limiting
• ABT-199: a small molecule, orally-bioavailable secondgeneration BH3-mimetic (Souers et al., Nature Medicine in press)
NH
N
N
N
H
N
Cl
ABT-199
• >100-fold selectivity for Bcl-2 over Bcl-xL in tumor cell line assays
39
Adverse Events (AEs)
All Grades
Diarrhea
≥20% of pts
n (%)
29 (43)
Nausea
27 (40)
Neutropenia
25 (37)
Fatigue
22 (33)
Upper respiratory tract infection
22 (33)
Cough
15 (22)
≥ 3 pts
n (%)
24 (36)
Grades 3/4
Neutropenia
Anemia
6 (9)
Thrombocytopenia
6 (9)
Tumor lysis syndrome*
6 (9)
Febrile neutropenia
Hyperglycemia
Hypophosphatemia
5 (7)
5 (7)
3 (4)
*TLS includes 3 events from Cohort 1; 2 clinical events and 1 laboratory TLS
occurred in Cohorts 4, 8, and 2
40
NHL Maximal % Reduction in Nodal Size
* = Confirmed Partial Remission**
CR = Complete Remission
20
MCL MCL MCL DLBCL MCL
WM
MCL
MCL
WM
FL
MCL
FL
FL
FL DLBCL WM
% Change From Baseline
0
FL
FL
DLBCL
FL
FL
-20
-40
Dose (cohort)
-60
*
-80
CR
*
-100
*
*
200 mg (1)
300 mg (2)
400 mg (3)
600 mg (4)
600 mg (5)
n = 21 evaluable (at minimum 6 week assessment)
**Confirmed = response verified at 2nd consecutive assessment
Median Time to 50% Reduction = 43 days (range 36 to 113; n=11)
Best Percent Change from Baseline in SPD of Nodal Mass
by CT Scan
• 50/57 (88%) patients had at least a 50% reduction in sum of the product of diameters (SPD) of
nodal masses.
• The median time to 50% reduction was Week 6.
17p del (17p)
FR Fludarabine
refractory
»
del(17p) and FR
SPD = Sum of the product of diameters; SE = safety expansion.
N = 57 evaluable (at minimum, Week 6 assessment)
42
Conclusions for ABT-199
• ABT-199 highly active, acceptable safety profile
• Once daily oral dosing
• Tumor lysis syndrome is a risk
• Response rate in CLL/SLL is 79% (84 patients)
– Phase II dose 400 mg/day
• Response rate in NHL is 48% (44 patients)
– Phase II dose 1200 mg/day
• ABT-199 is highly promising as a single agent and in should
be studied in combination
Efficacy in CLL/SLL
• 45 year old male with CLL/SLL, diagnosed in 2007
• Prior therapies:
–
–
–
–
–
FCR x 6 cycles (PR for 9 months)
Bendamustine-Rituximab x 6 cycles (PR for 12 months)
R-CHOP x 3 cycles (minor response. Stopped for toxicity)
BR for 3 cycles (minor response)
High dose steroids (minor response)
• November 2nd 2013, began ABT-199
February
8 2012
Oct
25, 2013
Baseline
March
2012
Dec
10,27
2013
Week 6
May
9 14
2012
January
2013
Feb
17,
2014
Week 16
Conclusions
• Not truly ready to discard chemotherapy…
• However,
– Targeted agents are finally showing highly promising
results in B cell malignancies
– BCR inhibitors, BCL-2 inhibitors
• Challenge is to develop rational combinations of
targeted agents
– Disrupt several key survival pathways simultaneously
– Delay/prevent emergence of resistance
• I am optimistic 
Questions?