IBRUTINIB IN NHL - ercongressi.it · Zhang, MD, PhD, Maria Badillo, BS, Maria Rosa, Alicia Addison,...

34
IBRUTINIB IN NHL Simon Rule Professor of Clinical Haematology Consultant Haematologist Derriford Hospital and Peninsula Medical School Plymouth

Transcript of IBRUTINIB IN NHL - ercongressi.it · Zhang, MD, PhD, Maria Badillo, BS, Maria Rosa, Alicia Addison,...

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

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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