IBRUTINIB IN NHL Simon Rule Professor of Clinical Haematology - - PowerPoint PPT Presentation

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

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

Durable Btk inhibition, despite rapid drug elimination

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 10 20 30 40 50 60 70

4 8 12 16 20 24 28

Btk Active-Site Occupancy Plasma Concentration (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)

SINGLE AGENT

Btk inhibitor PCI-32765 Phase I

Fowler, ASH 2010 #964

% Change in SPD

PCYC-1104-CA PHASE 2 STUDY OF IBRUTINIB IN R/R MCL

48,7 53,2 50,5 47,8 46,0 47,3 10 20 30 40 50 60 70 80 90 100 2 4 6 9 12 15 Response rate, % 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 80 20 40 60 Overall Survival, % 24 4 12 8 16 20 Months From First Dose

Number at risk:

Bortezomib-Naïve Bortezomib-Exposed All

111 98 76 51 32 48 43 37 21 13 63 55 39 30 19 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

• bserved 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

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)

% alive without progression 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 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 perpendicula diameters

• 100
• 50

50 100

Maximum % Improvement from Baseline SPD 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

10 20 30 40 50 60 70 80 90 100 SD

Best Response (%)

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

• bserved in this set
• f 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