IBRUTINIB IN NHL
Simon Rule
Professor of Clinical Haematology
Consultant Haematologist
Derriford Hospital and Peninsula Medical School Plymouth
OUTLINE
• BTK Inhibition
• Ibrutinib
• MCL data
– Single agent
– Toxicity
• Combination data
• Resistance
IBRUTINIB
BRUTON’S TYROSINE KINASE (BTK): A CRITICAL KINASE FOR LYMPHOMA CELL SURVIVAL AND
PROLIFERATION
EHA 2013, PCYC-1104 Rule et al. 2
• Bruton’s tyrosine kinase (BTK) is an essential element of the BCR signaling pathway (Niiro, NRI 2002)
• Inhibitors of BTK block BCR signaling and induce apoptosis
• BTK also acts downstream of certain chemokine receptors impacting integrin molecules that help in promoting egression from the lymph node environment
PCI-32765: FIRST-IN CLASS INHIBITOR OF BTK
• 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
• Blocks 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 2010
Chang, D et al. Proc ASH 2011
N
N
N
N
N H 2
O
N
O
PCI-32765
13/06/2013
3
Ibrutinib: A potent BTK inhibitor
• Ibrutinib (PCI-32765) forms a bond with cysteine-481 in BTK
• Highly potent BTK inhibition at IC50 = 0.5 nM
• High degree of specificity for hematopoietic cells
• Orally administered once daily dosing until PD or no longer tolerated by patient
EHA 2013, PCYC-1104 Rule et al. 3
13/06/2013
6
Durable Btk inhibition, despite rapid drug
elimination
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0
10
20
30
40
50
60
70
0 4 8 12 16 20 24 28
Btk
Acti
ve-S
ite O
ccu
pan
cy
Pla
sm
a C
on
cen
trati
on
(ng
/mL
)
Time Postdose (h)
Plasma concentrations of ibrutinib vs. BTK occupancy
Plasma Conc
% Active-Site Occupancy
Patients dosed at 2.5
mg/kg/day
Advani et al. J Clin Oncol 28:15s, 2010 (suppl; abstr 8012)
Objective response in evaluable patients (n = 48)
*2 CLL pts had nodal response with lymphocytosis
9/13*
7/9
2/3
1/44/13
2/7
0
20
40
60
80
100
Be
st
Re
sp
on
se
Ra
te (
%)
CR
PR
ORR (evaluable) 52%ORR (ITT) 45%
Advani et al. J Clin Oncol 28:15s, 2010 (suppl; abstr 8012)
SINGLE AGENT
Btk inhibitor PCI-32765 Phase I
Fowler, ASH 2010 #964
% C
han
ge in
SP
D
PCYC-1104-CA PHASE 2 STUDY OF IBRUTINIB IN
R/R MCL
48,7
53,2 50,5 47,8
46,0 47,3
0
10
20
30
40
50
60
70
80
90
100
2 4 6 9 12 15
Re
spo
nse
rat
e, %
Time, months
66.7 68
52.3
62.2 64 64.9
3.6 9.0
13.5 17.1 20.7 20.7
CR PR
Rule et al. Oral presentation at EHA 2013, Abstract S1178. Wang et al. Poster presentation at ICML 2013, Abstract 293.
10
• 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 survival (n=111)
All Bortezomib-Exposed
Bortezomib-Naïve
Censored
100
0
80
20
40
60
Ove
rall
Surv
ival
, %
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.
CONFIDENTIAL & PROPRIETARY -- NOT TO BE
DISTRIBUTED. 11
SPARK trial Wang et al ASH 2015
0% 10% 20% 30% 60% 50% 40%
Grade 1/2
Grade 3/4
Grade 5
Thrombocytopenia
Neutropenia
Anemia
Fatigue Diarrhea
Cough
Nausea
Muscle spasms
Pyrexia
Dyspnea
Rash
Upper respiratory tract infection
Vomiting
Arthralgia
Pneumonia
Contusion
Constipation
Sinusitis
Stomatitis
Back pain
Decreased appetite
Hypokalemia
Hypertension
Atrial fibrillation Myalgia
Abdominal pain
Urinary tract infection
Pain in extremity
Headache
SPARK trial Wang et al ASH 2015
RESULTS: SAFETY ANALYSIS - INFECTIONS
Rule S, et al. EHA 2014; Poster/Abstract P461.
Prevalence of infections by time period and grade
27%
20%
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 time
MCL3001 (RAY): PHASE 3 OPEN-LABEL STUDY
Rule et al., ASH 2015 (abstract 469, oral presentation)
Patients
with
previously
treated
MCL
Enrollment dates:
Dec 2012 – Nov 2013
1:1 Stratified by number of prior lines of therapy and by sMIPI
Ibrutinib (N = 139)
Oral ibrutinib 560 mg daily
starting Cycle 1, Day 1
Treat to PD or unacceptable
toxicity
Temsirolimus
(N = 141)
175 mg on cycle 1, days 1, 8, 15;
then 75 mg on days 1, 8, 15
subsequent cycles
R
A
N
D
O
M
I
Z
E
Primary end point:
• IRC-assessed PFS
Secondary end points included:
• IRC-assessed ORR (CR + PR)
• Overall survival
• Duration of response
• Time to next treatment
• Safety
• Patient-reported outcomes (FACT-Lym)
Jul14
Crossover to ibrutinib
(after IRC-confirmed
PD; n = 32)
Treat to PD or
unacceptable toxicity
• At a 2-year landmark, the PFS rate was 41% for ibrutinib versus 7% for temsirolimus
• Investigator-assessed HR for ibrutinib versus temsirolimus was 0.43 (95% CI, 0.32-0.58)
PRIMARY END POINT: IRC-ASSESSED PFS
ITT population Median follow-up: 20 months
17
Ibrutinib Temsirolimus
Median PFS (months) 14.6 6.2 Hazard ratio (HR) 0.43 95% confidence interval (CI)
0.32-0.58
Log-rank p value < 0.0001
0
20
40
60
80
100
CR PR
Number of prior lines of therapy
1 2 ≥3
71.9
39.5
48.0
68.4 71.9
33.3
I I I T T T
PFS by number of lines of therapy
(IRC assessed) Overall Response Rate
RAY: Ibrutinib vs Temsirolimus in R/R MCL
Rule et al., ASH 2015 (abstract 469, oral presentation)
% a
live
with
ou
t p
rog
ressio
n
Months
0 3 6 9 12 15 18 21 24 27 30
Ibrutinib Prior Line1
Ibrutinib Prior Line ≥2
Temsirolimus Prior Line 1
Temsirolimus Prior Line ≥2
Waldenstroms Macroglobulinaemia
COMBINATION DATA
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 2014
BEST RESPONSE
125
100
75
50
25
0
25
50
75
100
125
150
175
%
PD
SD
PR
CR
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)
IBRUTINIB PLUS RITUXIMAB IN
TREATMENT-NAÏVE PATIENTS WITH
FOLLICULAR LYMPHOMA: RESULTS FROM
A MULTICENTER, PHASE 2 STUDY
Nathan H. Fowler, MD1, Loretta Nastoupil, MD1, Sven De Vos, MD, PhD2, Mark Knapp, MD3, Ian W. Flinn, MD, PhD4, Robert Chen, MD5, Ranjana H.
Advani, MD6, Sumeet Bhatia, MD7, Peter Martin, MD8, Raul Mena, MD9, Samuel Suzuki, MS, MBA10, Darrin M. Beaupre, MD, PhD10, Jutta K. Neuenburg, MD,
PhD10, M. Lia Palomba, MD11
1University of Texas MD Anderson Cancer Center, Houston, TX; 2David Geffen School of Medicine at UCLA,
Los Angeles, CA; 3Mid Ohio Oncology/Hematology, Inc., Columbus, OH; 4Sarah Cannon Research Institute, Nashville, TN; 5City of Hope National Medical Center, Duarte, CA; 6Stanford University School of Medicine, Stanford, CA; 7Community Health Network, Indianapolis, IN; 8Weill Cornell
Medical College, New York, NY; 9Providence Saint Joseph Medical Center/Disney Family Cancer Center, Burbank, CA; 10Pharmacyclics LLC,
an AbbVie Company, Sunnyvale, CA; 11Memorial Sloan Kettering Cancer Center, New York, NY
MAXIMUM PERCENTAGE IMPROVEMENT FOR
TARGET LESION SPD – ARM 1
26
Median target lesion SPD at baseline: 23.7 cm2 (range, 2.9-135.5)
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; SPD, sum of the products of the greatest perpendicular
diameters
-100
-50
0
50
100
Max
imu
m %
Imp
rove
me
nt
fro
m B
ase
line
SP
D
CR PR
N=60
*
*Response recorded in database is SD; unresolved
query
SD
27
Median follow-up 13.8 months (range, 5.8-19.3)
ORR 82% in all treated patients (49 of 60)
Median time to best response: 2.7 months (range, 1.1-13.6)
Median duration of ibrutinib treatment: 12.55 months (range, 0.8, 19.6)
30%
52%
18%
Best Response – Arm 1
0
10
20
30
40
50
60
70
80
90
100
SD
Best
Resp
on
se (
%)
CR
PR
18%
30%
52%
82%
PHASE I STUDY OF RITUXIMAB,
LENALIDOMIDE, AND IBRUTINIB IN
PREVIOUSLY UNTREATED FOLLICULAR
LYMPHOMA (ALLIANCE 051103)
Chaitra S. Ujjani, Sin-Ho Jung, Brandelyn
Pitcher, Peter Martin, Steven I. Park, Kristie A. Blum, Sonali M. Smith, Myron S.
Czuczman, Matthew S. Davids, John P. Leonard and Bruce D. Cheson.
RESULTS
22 patients (16 at max dose)
ORR 91% (CR/CRu 63%)
12 month PFS 84%
Toxicity:
Rash 73% (32% Gd III)
Neutropenia 18% Gd III
11 dose reductions, 8 due to rash
Mutational Analysis of Patients With
Primary Resistance to Single-Agent
Ibrutinib in Relapsed or Refractory
Mantle Cell Lymphoma (MCL)
Sriram Balasubramanian1, Michael Schaffer1, William Deraedt2, Cuc Davis1,
Emily Stepanchick1, Regina Aquino1, Zhilong Yuan3, Britte Kranenburg4, Irit Avivi5,
Martin Dreyling6, Simon Rule7, Michael Wang8, Sen Hong Zhuang3,
Mark Wildgust3, Aleksandra Rizo3, and Georg Lenz9
1Janssen 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; 7Derriford Hospital, Plymouth, United Kingdom; 8The University of Texas MD Anderson Cancer Center, Houston, TX; 9Charité – Universitätsmedizin, Berlin, Germany
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 genes
AND FINALLY
IBRUTINIB FOR CNS MANTLE CELL NHL
CONCLUSION
• Highly active agent
– Especially MCL / WM
• Potential to fundamentally change treatment approaches
• Challenge to chemotherapy