Simon Rule Professor of Clinical Haematology Consultant Haematologist Derriford Hospital and Peninsula Medical School Plymouth DISCLOSURES OF COMMERCIAL SUPPORT Name of Company Research support ID: 709465
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Slide1
Btk inhibition in Mantle cell Lymphoma & CLL
Simon Rule
Professor of Clinical
Haematology
Consultant
Haematologist
Derriford
Hospital and Peninsula Medical School PlymouthSlide2
DISCLOSURES OF COMMERCIAL SUPPORT
Name of Company
Research support
Employee
Consultant
Stockholder
Speaker
’
s Bureau
Advisory Board
Other
J&J
+
+
PCYC
+
Roche
+
Celgene
+
+Slide3
Outline
BTK Inhibition
Ibrutinib CLL data
combinations
MCL
data
Combinations
Long term toxicity
Lymphocytosis
Other BTK inhibitors
ONO-4059
CC-292
ACP-196Slide4
BCR signaling promotes proliferation, differentiation, and survival
1-5
1. Murphy et al,
Janeway’s Immuno Biol 7
th
Ed 2008; 240
-1. 2
. Brunner et al, Histol Histopathol 2005; 20:945-55. 3. Wiestner, Blood; 120: 4686-4691. 4. Sharma et al, J Immunol 2009; 182:329-339. 5. Young and Staudt, Nature Rev Drug Discov. 2013; 12: 229-243.Slide5
BTK: An essential effector of multiple B-cell processes
5
1. Liu et al,
Nat
Immunol
2011; 12: 416-425
. 2.
Treon et al, NEJM 2012; 367: 826-33. 3.
Shinners
et al,
J Immunol 2007; 179: 3872-80. 4. Murphy et al, Janeway’s Immuno Biol 7th Ed 2008; 240. 5. Buggy and Elias, Int Rev Immunol 2012; 31: 119-132 . 6. Wiestner, Blood; 120: 4686-4691. 7. de Gorter et al, Immunity 2007; 26: 93-104.
TLR
1,2
BAFF-R
3
BCR4-6
CXCR4/57Slide6
PCI-32765:
First-in Class Inhibitor of
Btk
Forms a specific and irreversible bond with cysteine-481 in Btk
Highly potent Btk inhibition at IC
50
= 0.5 nM
Orally administered with once daily dosing resulting in 24-hr target inhibitionBlocks mantle cell migration and adhesion
Blocks
pERK
,
pJNK, and NF-kB pathways in mantle cell lymphoma lines. Honigberg LA et al: Proc Natl Acad Sci
2010Chang, D et al. Proc ASH 2011
N
N
N
N
N
H
2
O
N
O
PCI-32765Slide7Slide8Slide9
Btk
inhibitor PCI-32765 in MCL
Fowler, ASH 2010 #964
% Change in SPDSlide10
Time on Study (N=56)
DLBCL
Indolent
CLL/SLL
MCL
10Slide11
Summary of Ibrutinib Data in CLL
Study
Treatment
Patients
ORR
PFS/OS
1102/1103
2,3
Ibrutinib alone
r/r
1
Tx naïve2 71%; CR 3% PR 68% (+20% PR Lym)71%; CR 13% PR 55% (+13% PR
Lym)
75% PFS @26
mo, OS 83%
96% PFS @24 mo
, OS 96.6%
11121
Phase III study
Ibrutinib alone vs.
Ofar/r
43%*;
PR 43% (+20%PR
Lym
) vs 4%
Ofa
88% PFS at 6
mo
vs 65%
Ofa
,
OS
90% at 12 mo
vs
81%
Ofa
IISs
:
Weistner
7
Ibrutinib alone
Elderly
Tx
naive
del17p
(naïve and r/r)
PR 81%
(+9% PR
Lym
)
PR 53%
(+43% PR
Lym
)93%
EFS at 14 mo
Burger4
Ibrutinib + R
High risk95%; CR 8% PR 87%
80% PFS @ 14 mo
Jaglowski5
Ibrutinib + Ofa
r/r
100%; CR 4% PR 96%
>90% PFS @12mo
Brown6
Ibrutinib + BR
r/r93%;
CR 17% PR 77%
>90% PFS @
12mo
1. Byrd et al. N
Engl J Med. 2014; ePub
31May2014; 2.
Byrd J, et al. N Engl J Med. 2013; 369:32-42 ; 3.
O’Brien S, et al. Lancet Oncol
. 2014; 15(1): 48-58; 4.
Burger J, et al. Oral presentation at ASH 2013 (abstract 675); 5 Jaglowski
et al. ASCO 2012; 6.
Brown J et al. Oral presentation at ASH 2013. (abstract 525); 7. Wiestner A et al.
Blood.
2012; 120(24): 4684-4691.
* As
assessed by the Independent Review
Committee.
Investigator-assessed responses were 70% (2% CR/CRi and 68% PR)
with
+15% PR
LymSlide12
Study Design of Trial 1102/ 1103
†
continuous schedule until progression or toxicity
*
D
efined as progression
of disease within 24 months of
initiation of
a regimen containing at least a
nucleoside analog
or bendamustine in combination with
a monoclonal antibody, or failure to respond to such a regimen.Enrolled May 2010August 2011
Phase 1b/2, open-label,
multicenter study
Patients with relapsed or
refractory CLL/SLL (N
= 85)
Patients received a fixed daily dose of ibrutinib until disease
progression/unacceptable toxicity
Based on early data from
cohort 1, a third cohort was added to gain additional experience in patients with high-risk disease*
Study included an additional treatment
cohort for treatment-naïve patients over 65 years of age (n = 31) who received
420
mg/d or 840 mg/d
ibrutinib
. Results from this cohort
are not reported in this slide kit.
Byrd JC, et al. N
Engl
J Med. 2013; 369:32-42.
Byrd JC et al. Blood 2012; 120: Abstract 189.
Primary
endpoint:
safetySlide13
Grade
1-2
Grade
3-4
Total*
16%
49%
33%
32%
31%
27%
27%
27%
21%
20%
18%
18%
18%
18%
18%
18%
16%
15%
15%
*
T
otal percentage may not equal sum of Grade 1-2 and Grade 3-4 percentages due to rounding
.
URI, upper respiratory infection.
Neutropenia
did not lead to treatment discontinuation and was often managed with growth
factors (6/13 patients).
Safety: Common AEs in Overall Population
(
occurring
in
≥ 15% of
patients, regardless of causality
)
Byrd JC, et al. N
Engl
J Med. 2013; 369:32-42 Slide14
Efficacy: ORR
(Investigator assessed)
71%
71%
20%
15%
420 mg
(Cohorts 1 + 3)
N = 51
840 mg
(Cohort 2)
N = 34
PR
C
R
PR+L
Patients (%)
PR+L = partial response with persistent
lymphocytosis
Byrd JC, et al. N
Engl
J Med. 2013; 369:32-42Slide15
Response Over Time
Best response to ibrutinib improves over time
*Cumulative response as assessed by investigator
O’Brien S,
et al.
Oral Presentation ASCO 2014Slide16
0
0.2
0.4
0.6
0.8
1.0
Progression-Free Survival (Proportion)
0
6
12
18
24
30
36
42
Months From Initiation of Study Treatment
Progression-Free Survival by
Cytogenetics
(FISH) in Relapsed/Refractory Population
Del17p
R/R
Del11q
R/R
No del17p/
11q
30-month
PFS
45.9%
74.2%
89.0%
(95% CI)
(25.0–64.6)
(53.3–86.8)
(69.0–96.4)
Median
PFS
28.1
months
Not reached
Not reached
del17p
del11q
No del17p or del11q
+
Censored
O’Brien S,
et al.
Oral Presentation ASCO 2014Slide17
Stratification according
to:
Disease
refractory to purine analog
chemoimmunotherapy
(no
response or relapsed within 12
months)
Presence
or absence of
the 17p13.1 deletion (del17p)
Enrolled June 2012 April 2013Phase 3, open-label, randomized, multicenter studyPatients with previously treated
CLL or SLL; not
appropriate for purine analog
ue treatment
1:1
RESONATE (PCYC-1112) Study Design
IRC, independent review committee;
IV, intravenous; PD, progressive disease.
N=391
E
N
D
O
F
S
T
U
D
Y
Byrd JC, et al.
N Engl J Med
. 2014;
ePub
31May2014
.Slide18
Primary End Point: IRC-Evaluated PFS
Median PFS not reached
(PFS rate:
88% at 6
mo)
Median PFS of 8.1 mo
(PFS rate: 65%
at 6
mo)
78%
reduction in risk of progression or death
with ibrutinib
Byrd JC, et al.
N Engl J Med
. 2014;
ePub 31May2014.Slide19
Primary endpoint
Safety
Secondary endpoints
ORR
PFS
19
PCYC 1108
A
Phase 1b Study of
Ibrutinib
With BR or FCR in Patients With Relapsed/Refractory CLL/SLL
I
brutinib
420 mg orally, once daily in 28d
cycles +
BR (70 mg/m
2 d1-d2 [B]; 375 mg/m2
cycle 1, 500 mg/m2
cycles 2-6 [R]) for 6 cycles
N = 30
I
brutinib
420 mg orally, once
daily in
28d cycles +
FCR
(25 mg/m
2
d1-3 [F
]; 250
mg/m
2
d1-
3 [
C
]; 375
mg/m
2
cycle
1, 500
mg/m
2
cycles 2-6 [R
]) for 6 cycles
N = 3
Investigator ChoiceSlide20
Median treatment duration on this study was 16 months, with an ORR of 93.4%
(28 responding patients [5 CR, 3
nPR
])
1 patient achieved a PR with lymphocytosis (not included in ORR)
20
PCYC 1108
Overall Response Rate (ORR)Slide21
21
PCYC 1108
Treatment-Emergent AEs (TEAEs) in ≥ 20% of Patients Regardless of Attribution
70%
67%
47%
40%
37%
33%
30%
30%
30%
27%
27%
23%
23%
23%
23%
20%
20%
20%Slide22Slide23Slide24Slide25
PCYC-1104-CA Phase 2 Study of Ibrutinib in R/R MCL
52.3
62.2
64
64.9
3.6
9.0
13.5
17.1
20.7
20.7
CR
P
R
Rule et al.
Oral presentation at EHA 2013, Abstract S1178
.
Wang et al. Poster presentation at
ICML 2013, Abstract
293.
25Slide26Slide27
Estimated Median PFS (CI 95%) 13.9 months (7.0, NE)
PCYC-1104-CA Phase 2 Study of Ibrutinib in R/R MCL
Kaplan
-Meier
progression-free survival
(n=111)
100
0
80
20
40
60
24
0
4
12
8
16
20
Progression-Free
Survival, %
Months From First Dose
All
Bortezomib
-Exposed
Bortezomib
-Naïve
Censored
Number at risk:
Bortezomib
-Naïve
Bortezomib
-Exposed
All
111
81
57
33
22
0
48
37
29
14
10
0
63
44
28
19
12
0
2
2
0
Rule et al.
Oral presentation at EHA 2013, Abstract S1178
.
Wang et al. Poster presentation at
ICML 2013, Abstract
293.
27Slide28
Estimated Median OS was not reached
Estimated OS of 58% at 18 months
PCYC-1104-CA Phase 2 Study of Ibrutinib in R/R MCL
Kaplan
-Meier
overall
s
urvival
(n=111)
All
Bortezomib
-Exposed
Bortezomib
-Naïve
Censored
100
0
80
20
40
60
Overall Survival, %
24
0
4
12
8
16
20
Months From First Dose
Number at risk:
Bortezomib
-Naïve
Bortezomib
-Exposed
All
111
98
76
51
32
0
48
43
37
21
13
0
63
55
39
30
19
0
5
4
1
Rule et al.
Oral presentation at EHA 2013, Abstract S1178
.
Wang et al. Poster presentation at
ICML 2013, Abstract
293.
28Slide29
Ibrutinib and Rituximab are an Efficacious and Safe Combination in relapsed Mantle Cell Lymphoma: Preliminary Results from a Phase II Clinical Trial
Michael Wang, MD
Professor
Director, Mantle Cell Lymphoma Program of Excellence
Co-Director, Clinical Investigation and Translational Research for Clinical Trials
Michael Wang, MD , Fredrick Hagemeister, MD, Jason Westin, MD, Luis Fayad, MD, Felipe Samaniego, MD, MPH, Francesco Turturro, MD, Wendy Chen, Liang Zhang, MD, PhD, Maria Badillo, BS, Maria Rosa, Alicia Addison, Larry Kwak, MD, PhD and Jorge Romaguera, MD
Department of Lymphoma/Myeloma
Department of Stem Cell Transplantation and Cellular Therapy
ASH 2014Slide30
Study Design and Eligibility
Single Center Phase II, target enrollment (50)
From 7/2013-7/2014
, 50 patients were enrolled
in 12
months.
Tissue diagnosis of MCL, CD20+,Cyclin D1+
Relapsed MCL no upper limit of prior therapies
Good performance and organ functionSlide31
Incidence
(%)
All Treatment-Emergent Hem AEs: Incidence %Slide32
Treatment-Emergent Non-Hema AEs: Incidence > 15%Slide33
Best Response
12
1
** Ki67 N/A for 4 patients **
p
= 0.0001
p = 0.006Slide34
Best Response
Ki-67: 60%, blastoid
Ki-67: 100%, blastoid
Ki-67: 60%, nodular
SD 1. Ki-67: 70% (diffuse); SD 2: Ki-67: 60% (blastoid); SD 3: Ki-67 60% (nodular)Slide35
Overall PFS (n=50)
PFS by Ki67
Months
Probability
Months
Probability
PFS:
Median Follow up 11 months
(4-16
months)
Median = 13.6 monthsSlide36Slide37Slide38
Phase 2 Study of Ibrutinib in Patients With Mantle Cell Lymphoma Who Have
Received at Least One Prior Therapy:
Updated Safety Analysis on Prevalence of Infection, Diarrhea, and Bleeding Over Time
Rule S, et al. EHA 2014; Poster/Abstract P461.
S Rule,
1
ML Wang,
2
P Martin,
3 R Auer,4 BS Kahl,5
W Jurczak,6 RH Advani,7
J Romaguera,
2 M Williams,8 JC Barrientos,9
E Chmielowska,10 JA Radford,11
S Stilgenbauer,12 V Truong,13 M Cheng,
13 DM Beaupre,13 A Goy,14 KA Blum
15
1
Derriford Hospital, Plymouth, UK,
2
University of Texas MD Anderson Cancer Center, Houston, USA,
3
Weill Cornell Medical College, New York, NY, USA,
4
Barts Health NHS Trust, London, UK,
5
University of Wisconsin, Madison, WI, USA,
6
Jagiellonian University, Krakow, Poland,
7
Stanford University Medical Center, Stanford, CA, USA,
8
University of Virginia School of Medicine, Charlottesville, VA, USA,
9
Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA,
10
Oddzial Kliniczny Onkologii, Centrum Onkologii, Bydgoszcz, Poland,
11
The University of Manchester and the Christie NHS Foundation Trust, Manchester, UK,
12
Universitatsklinikum Ulm, Klinik fur Innere Medizin II, Ulm, Germany,
13
Pharmacyclics, Inc., Sunnyvale, CA, USA,
14
John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA,
15The Ohio State University, Columbus, OH, USASlide39
Results: Patient Disposition
Median duration of treatment was 8.3 months (range, 1-30 months)
46% of patients were treated for > 12 months, and 26% of patients continue treatment
The most common reason for treatment discontinuation (56%) was progressive disease
Rule S, et al. EHA 2014; Poster/Abstract P461.Slide40
Results: Safety Analysis - Infections
Rule S, et al. EHA 2014; Poster/Abstract P461.
Prevalence of infections by time period and grade
27%
20%Slide41
Results: Safety Analysis - Immunoglobulins
No substantial changes in serum Ig levels (IgA, IgG, IgM) were observed over time
Rule S, et al. EHA 2014; Poster/Abstract P461.
Immunoglobulin levels over timeSlide42
Lymphocytosis in MCLSlide43
Lymphocytosis and Ibrutinib in MCL
Furtado
et al.
in press
BJHaemSlide44
Next generation BTK Slide45Slide46
A Phase I Study Of The Oral
Btk
Inhibitor ONO-4059
In Patients With Relapsed/Refractory B-Cell Lymphoma
1
Department of Haematology,
Derriford Hospital, Plymouth, United Kingdom, 2
Hospices
Civils
de Lyon;
Université Claude Bernard Lyon 1, Lyon, France, 3Centre Hospitalier Lyon Sud/Hospices Civils de Lyon, Pierre-Bénite, France, 4Service Maladies du Sang, CHRU - Hôpital
Claude Huriez, Lille, France
,
5Hôpital Claude Huriez
, Lille, France, 6
Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom,
7Department Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom
, 8Department of Haematology, Cardiff University, Cardiff, United Kingdom
, 9Département d’Hématologie Clinique, CHU Montpellier,
Monpellier, France, 10
Orion
Clinical Services, Slough, United Kingdom
,
11
Wright
Dose Limited, Manchester, United Kingdom
,
12
Linden
Oncology, Edinburgh, United Kingdom
,
13
ONO
Pharma
UK LTD, London, United Kingdom
,
14
Ono
Pharmaceutical CO., LTD, Osaka, Japan
,
15
Ono
Pharmaceutical Co., Ltd., Osaka, Japan
,
16Clinical
Science Oncology, Ono Pharma UK Ltd., London, United
Kingdom
Simon Rule1
, Nimish Shah
1, Gilles Andre Salles
2, Lionel Karlin
3, Franck Morschhauser
4, Louis
Terriou5, Martin JS
Dyer6, Claire
Hutchinson7
, Chris Fegan8
, Guillaume Cartron9
, Tomasz Knurowski
10,
James G Wright
11, Andrew J Saunders
12, Hideyuki
Honda13, Andrew
Mazur13, Toshio
Yoshizawa14
,
Kazuhito Kawabata15
, and Joseph TP Birkett16
Rule
et al., ASH 2013; abstract 4397 (poster presentation)Slide47
Change from baseline SPD (%)
# the largest diameter is
<
15 mm
#
#
Best Overall Response of 43 %
#
■
DLBCL
■MCL■WM■MZL■
FL■
SLL
Max % Reduction in Tumour Burden (
N=16*){20-320mg}
M
aximum percentage reduction in tumor
burdenRule et al., ASH 2013; abstract 4397 (poster presentation)Slide48Slide49Slide50
PHASE 1 STUDY OF SINGLE AGENT CC-292,
A HIGHLY SELECTIVE
BRUTON
’
S TYROSINE KINASE (BTK) INHIBITOR,
IN RELAPSED/REFRACTORY
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND
B-CELL NON-HODGKIN LYMPHOMA (B-NHL)
Jennifer R. Brown
1
,
Wael
A. Harb
2
, Jeff P. Sharman
3, Brian T. Hill
4, Shuo Ma5, Thomas P. Miller6, Marshall T. Schreeder
7, Paul M. Barr8, James M. Foran9, Janice L. Gabrilove10, Kevin R. Kelly
11, Jan A. Burger12, Evelyn Barnett13, Jeffrey Marine13, Pilar Nava-Parada
13, Ada Azaryan14, Jay Mei13, Thomas J. Kipps15
1Dana-Farber Cancer Institute, Boston, MA; 2Horizon Oncology Center, Lafayette, IN; 3Willamette Valley Cancer Institute and Research Center/US Oncology Research, Eugene, OR; 4Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic
Taussig
Cancer Institute, Cleveland, OH;
5
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL;
6
University of Arizona Cancer Center, Tucson, AZ,
7
Clearview Cancer Institute, Huntsville, AL;
8
Hematology/Oncology, University of Rochester Medical Center, Rochester, NY;
9
Division of Hematology and Medical Oncology, Mayo Clinic Florida, Jacksonville, FL;
10
Mount Sinai School of Medicine, New York, NY;
11
CTRC Institute for Drug Development, University of Texas Health Science Center at San Antonio, San Antonio, TX;
12
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX;
13
Clinical R&D, Hematology/Oncology, Celgene Corporation, Summit, NJ; 14
Global Drug Safety and Risk Management, Celgene Corporation, Berkeley Heights, NJ; 15Division of Hematology-Oncology and Central Office of CLL Research Consortium,
Moores Cancer Center, University of California San Diego, La Jolla, CA, USASlide51
Efficacy Assessment
Dose level
N
(Evaluable)
Total Responders
PR
Nodal Response w/ increased ALC
Median Treatment Cycles (n)
Median Follow-up (Months)
750 mg QD
29
14 (48%)
9 (31%)
5 (17%)
9.4
10.5
1000 mg QD
7
4 (57%)
3 (43%)
1 (14%)
7.9
8.3
375 mg BID
6
4 (67%)
4 (67%)
0
8.5
8.5
500 mg BID
5
3 (60%)
2 (40%)
1 (20%)
3.9
3.9Slide52Slide53Slide54
Mechanisms of Resistance to Ibrutinib
Chang et al., ASCO 2013Slide55
Mutational Analysis of Patients
With
Primary
Resistance to Single-Agent Ibrutinib in Relapsed or Refractory
Mantle
Cell Lymphoma (MCL
)
Sriram Balasubramanian
1
, Michael
Schaffer
1, William Deraedt2, Cuc Davis1, Emily Stepanchick1, Regina Aquino1, Zhilong Yuan
3, Britte Kranenburg4
, Irit Avivi
5, Martin Dreyling6, Simon Rule
7, Michael Wang8, Sen Hong Zhuang3,
Mark Wildgust3, Aleksandra Rizo3, and
Georg Lenz91Janssen Research & Development, LLC, Springhouse, PA;
2Janssen Research & Development, LLC, Beerse, Belgium; 3Janssen Research & Development, LLC, Raritan, NJ; 4Janssen Biologics B.V
., South Holland, Netherlands; 5Tel Aviv Medical Center, Tel Aviv, Israel; 6Klinikum der Universität München-Campus Grosshadern, Munich, Germany; 7
Derriford Hospital, Plymouth, United Kingdom; 8The University of Texas MD Anderson Cancer Center, Houston, TX; 9Charité – Universitätsmedizin
, Berlin,
GermanySlide56
Responders
Patients With Durable Response Have Few
or No Mutations in These Genes
Primary resistant
Individual Patients
Moderate benefit
In patients with long durable responses, few mutations are observed in this set of genesSlide57
conclusion
BTK inhibitors highly active in CLL + MCL
Well toleratedNo long term toxicityCombinations being evaluated
Newer BTK inhibitors in trials
Resistance emerging