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Wojciech Jurczak

Disclosures

WOJCIECH JURCZAK, MD, PHD, ASSOC PROF

CELGENE (RESEARCH FUNDING); EISAI (RESEARCH FUNDING); GILEAD (RESEARCH FUNDING); JANSEN (RESEARCH FUNDING);

MUNDIPHARMA (SCIENTIFIC ADVISORY BOARD); PHARMACYCLICS (RESEARCH FUNDING); PFIZER (RESEARCH FUNDING);

ROCHE (RESEARCH FUNDING); SANDOZ – NOVARTIS (RESEARCH FUNDING, SCIENTIFIC ADVISORY BOARD); SPECTRUM

(RESEARCH FUNDING, SCIENTIFIC ADVISORY BOARD); TAKEDA (RESEARCH FUNDING, SCIENTIFIC ADVISORY BOARD); TEVA

(RESEARCH FUNDING, SCIENTIFIC ADVISORY BOARD).

1

Targeting BCR signaling pathway in B cell

malignancy

[email protected] Department of Haematology, Jagiellonian University, Małopolskie Medical Center, Polish Lymphoma Research Group

Wojciech Jurczak

BCR – signalling in lymphoma cells

BCR is required for B-cell survival and differentiation at several stages of B-cell development from the pre-B cell stage and onwards

Wojciech Jurczak

Inhibition of BCR

BTK

PI3K

PI3K Inhibitors • Idelalisib

BTK Inhibitors • Ibrutynib

Syc Inhibitors • Fostamatinib

Syc

Wojciech Jurczak

Inhibition of BCR

BTK

PI3K

PI3K Inhibitors • Idelalisib

BTK Inhibitors • Ibrutynib

Syc Inhibitors • Fostamatinib

Syc

mTOR Inhibitors • Rapamycin • Temsirolimus • Everolimus

PKC Inhibitors • Enzasturyn

PKC

Proteasom Inhibitors • Bortezomib • Salinosporamid

Wojciech Jurczak

BCR - signalling

Wojciech Jurczak

BTK functions downstream in a variety of receptors

Functions of BTK in B-cell signaling pathways

B-cell receptor (BCR) Regulates apoptosis by mediating PLCγ2 and BAFF/BAFF-R activation

of NF-κB1,2

Chemokine receptor

(CXCR 4/5) Essential for CXCR4/5 chemokine-controlled B-cell migration and

tissue homing2,3

Toll like receptor (TLR) Positive regulation factor in the MyD88 and TRIF-dependent TLR

signaling pathways4

B-cell activating factor

receptor (BAFF-R) Important for proliferation and survival

1. Shinners et al, J Immunol 2007; 179: 3872-80. 2. Buggy and Elias, Int Rev Immunol 2012; 31: 119-132. 3. de Gorter et al, Immunity 2007; 26: 93-104. 4. Liu et al. Nat Immunol 2011; 12: 416-424.

Wojciech Jurczak

BTK: An essential effector of multiple B-cell processes

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.

Toll like receptor TLR1,2

BAFF-R3 BCR4-6 Chemokine receptor CXCR4/57

Wojciech Jurczak

Ibrutinib: Discovery

Ogden Bruton

(1908-2003)

Person

Bruton’s

Agammaglobulinemia,

1952

Disease

Bruton

Tyrosine

Kinase, 1993

Enzyme

Synthesized 2005

First in human 2009

1st approval 2013

Drug

N

ibrutinib

N

O

N

N N

NH2

O

Wojciech Jurczak

Ibrutinib

• Ibrutinib is an oral, once-daily therapy that targets

important pathways in B-cell malignancies

• Ibrutinib covalently (irreversibly) binds to cysteine

4811,2 near the BTK active site with a 2–3-hour half-life3

• Structurally, only 10/ 491 analysed kinases that have a cysteine in the same position making ibrutinib a highly selective inhibitor4

• Fluorescent tagged derivative of ibrutinib was demonstrated to bind predominantly to BTK suggesting a high degree of specificity to B-cells3

1. Honigberg LA, et al. Proc Natl Acad Sci USA. 2010;107:13075-13080. 2. Pan Z, et al. ChemMedChem 2007;2:58-61. 3. Advani RH, et al. J Clin Oncol. 2013;31:88-94. 4. Pan Z et al. ChemMedChem 2007, 2, 58–61

Wojciech Jurczak

Ibrutinib (PCI-32765)

2006 • Pharmacyclics acquires Celera’s BTK program

2007 • Publication describing irreversible inhibitors of BTK (including PCI-32765) in ChemMedChem

• Poster at ASH describing activity in B-cell lymphoma

2009 • Phase I trial in B-NHL initiated, Poster at ASH

2011 • Pharmacyclics partners with Janssen

2013 • Phase I trial results published in JCO • Phase II trials in MCL and CLL published in NEJM

2014 + • >40 trials have been initiated

Wojciech Jurczak

Durable BTK inhibition following an oral dose

Chang B. Oral presentation at the 245th American Chemical Society Meeting (Abstract 250). Advani RH, et al. J Clin Oncol. 2013;31:88-94.

• Ibrutinib has a short pharmacologic half-life (terminal half-life ranging from 4-8 hours in patients with B-cell malignancies)

• Blood plasma levels peak in 1-2 hours after a dose and then decline rapidly • Inhibitory effects at the receptor last for at least 24 hours.

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

Ac

tive

-Sit

e O

cc

up

an

cy

Pla

sm

a C

on

ce

ntr

ati

on

(n

g/m

L)

Time Postdose (h)

Plasma Concentration of Ibrutinib vs. BTK Occupancy (2.5 mg/kg daily)

Plasma Conc

Plasma concentration profile reflects

inhibition profile of reversibly inhibited off

targets

Occupancy indicates irreversible

inhibition of Btk

Wojciech Jurczak

Ibrutinib inhibits BCR activation in B lymphocytes

EC50= 8 nM

Inhibition of B cell activation demonstrated by a dose dependent reduction in the B cell early activation marker CD69 following anti-IgM stimulation with an IC50 of 3.7 nM

. Chang, B et al. Arthritis Research & Therapy 2011, 13:R115

Anti-IgM stimulated CD69 assay in primary B cells2

Wojciech Jurczak

Mechanism of action of BTK inhibitors

• BTK is a critical kinase in regulating B-cell proliferation, survival, adhesion and migration1–4

• Proposed mechanism of action

– Induction of apoptosis 7

– Inhibition of adhesion 8

– Inhibition of migration and homing 9

1. deGorter DJJ, et al. Immunity. 2007;26:93-104. 2. Wiestner A. Blood. 2012;120:4684-4691. 3. Burger JA, et al. Blood. 2009;114:3367-3375. 4. Buggy JJ, Elias L. Int Rev Immunol. 2012;31:119-132. 5. Honigberg LA, et al. Proc Natl Acad Sci USA. 2010;107:13075-13080.

6. Pan Z, et al. ChemMedChem 2007;2:58-61. 7. Herman et al, Blood 117: 6287-6296 8. de Rooij et al, Blood 119: 2590-2594 9. Ponader et al, Blood 119: 1182-1189.

Wojciech Jurczak

Ibrutinib inhibits BCR activation of NF-kB (causing apoptosis)

Herman et al, Blood 117: 6287-6296

CD19 cells from CLL patients (N=10) incubated with various concentrations of PCI-32765 (1M-50M) and with or without 100M z-VAD-fmk for 48 hours. Viability was determined by annexin-V/PI flow cytometry, and is shown relative to time-matched untreated controls. Each symbol represents an individual patient and dark lines represent averages.

z-VAD-fmk = a cell-permeable pan-caspase inhibitor that irreversibly binds to the catalytic site of caspase proteases

Wojciech Jurczak

BTK controls integrin-mediated

migration and adhesion

1. Spaargaren et al J. Exp. Med 198: 1539-1550

2. de Gorter et al Immunity 26: 93-104

WT = Wild type BTK- = BTK deficient SDF-1 = stromal cell-derived factor 1 (CXCL12) VCAM = Vascular cell adhesion protein 1 DT40 = Chicken bursal lymphoma B cell line DT40 PMA = Phorbol 12-myristate 13-acetate

BTK mutant cells lack

integrin-clustering1

WT

BTK-

C αIgM 30 min αIgM 15 min

DT40 cells, either WT or Btk-, not stimulated (C) or stimulated for 15 or 30 min with anti-IgM (a-IgM) or PMA

BTK mutant cells have

reduced migration2

WT or Btk murine pre-B cells allowed to migrate in the absence (C) or presence of 100 ng/ml SDF-1 in transwells coated with 1 mg/ml VCAM-1 (n = 6).

Wojciech Jurczak

Ibrutinib inhibits the anti-IgM–stimulated integrin-mediated adhesion to fibronectin and VCAM-1

CLL cells, pretreated for 1 hour with 1M Ibrutinib, were allowed to adhere to either fibronectin (n=5) or VCAM-1 (n=6) coated plates in the presence of anti-IgM or PMA. C = control; PMA= phorbol 12-myristate 13-acetate (unstimulated); DMSO= Dimethyl sulfoxide. *P .05; ***P .001.

De Rooij et al, Blood 2012;119(11):2590-2594.

mean inhibition 75% mean inhibition 100%

Wojciech Jurczak

Ibrutinib inhibits migration toward chemokines CXCL12 and CLCL13

Mean SEM relative migration of CLL cells from 8 different patients toward CXCL12 and CXCL13 in the presence or absence (medium control) of different concentrations of Ibrutinib. White bars depict background migration toward wells without chemokine. * indicates P=0.05 compared with the control with chemokine; medium.

Ponader et al, Blood 2012;119(5):1182-1189.

Wojciech Jurczak

Ibrutinib proposed mechanism CLL and MCL

integrinBTK

ibrutinib

BCRCXCR4

CXCR5

CCR7

ibrutinib

ibrutinib

CLL LN PB

adhesion + migration survival + proliferation apoptosis

CXCR4

CLL/MCL Lymph Node Peripheral Blood

• Ibrutinib blocks BTK inducing B-cell apoptosis and disruption of B-cell adhesion in lymph nodes

de Rooij MFM, et al. Blood. 2012;119:2590-2594

Wojciech Jurczak

integrinBTK

ibrutinib

BCRCXCR4

CXCR5

CCR7

ibrutinib

ibrutinib

CLL LN PB

adhesion + migration survival + proliferation apoptosis

CXCR4

CLL/MCL Lymph Node Peripheral Blood

• Ibrutinib blocks BTK inducing B-cell apoptosis and disruption of B-cell adhesion in lymph nodes

• B-cells egress into peripheral blood

• Ibrutinib blocks B cells from migrating back to lymph nodes resulting in treatment-related

lymphocytosis

Ibrutinib proposed mechanism CLL and MCL

de Rooij MFM, et al. Blood. 2012;119:2590-2594

Wojciech Jurczak

WBC & nodal reduction after Ibrutynib

Wojciech Jurczak

Ibrutinib: Evolution of Responses Over Time

Achievement of best response was time dependent Proportion with CR/PR increased during follow-up Proportion with PR+L diminished as the lymphocyte count declined over time

Byrd JC, et al. N Engl J Med. Epub Ahead of Print 19 June 2013

Wojciech Jurczak

BTK signaling and its inhibitors

Wojciech Jurczak


PCI-32765 (Ibrutynib) It is an orally available, small molecule covalent inhibitor of BTK with an IC50 of 0.5 nM. It forms a bond with the Cys-481 residue of BTK, which is in the active, allosteric inhibitory site and, therefore, irreversibly blocks its activity

Wojciech Jurczak


CC-292 (AVL-292) - Avila - is a small molecule, orally available, highly selective covalent inhibitor of BTK with an IC50 of <0.5 nM1 and very little cross-reactivity with other kinases involved in B-cell receptor (BCR) signaling. It has been demonstrated that there is a positive correlation with the amount of the drug bound to BTK and the cytotoxicity of CC-292 in vitro.

Wojciech Jurczak


ONO-4059 is a potent and selective Bruton tyrosine kinase (BTK) inhibitor with an IC50 of 22 nM,1 developed by Ono Pharmaceutical Company as an anti-inflammatory agent for the treatment of rheumatoid arthritis, demonstrated activity in DLBCL

Wojciech Jurczak


ACP-196 is a novel second generation Bruton tyrosine kinase (BTK) inhibitor with increased specificity for BTK, so reducing side effects.

‘09 ‘10 ‘11 ‘12 ‘15 ‘14 ‘13 ‘16 ‘17 ‘18

Phase I in B-NHL

PCYC1102 (CLL)

PCYC1104 (MCL)

WM

PCYC1106

MCL3001

FLR2002

DBL3001

MCL3002

PCYC1115

A041202

CLL3001

PCYC1112

PCYC1117

Ibrutinib Clinical Trials

Aug 2013

Jul 2013

MCL „ who received one prior therapy” Nov 2013

CLL „ who received one prior therapy” Feb 2014

CLL with 17 p deletion Jul 2014

Waldenstrom Makroglobulinemia Jan 2015

Targeting BTK with Ibrutinib in Relapsed or Refractory

Mantle Cell Lymphoma

ML Wang, S Rule, P Martin, A Goy, R Auer, BS Kahl, W Jurczak, RH Advani, JE Romaguera, ME Williams, JC Barrientos, E Chmielowska,

J Radford, S Stilgenbauer, M Dreyling, WW Jedrzejczak, P Johnson, SE Spurgeon, L Li, L Zhang, K Newberry, Z Ou, N Cheng, B Fang, J McGreivy,

F Clow, JJ Buggy, BY Chang, DM Beaupre, LA Kunkel, KA Blum

PCYC-1104 Phase 2 Study Schema

Cohort 1

560 mg/d ibrutinib

No prior treatment with bortezomib*

(n = 65)

*no prior bortezomib therapy or less than 2 complete cycles of bortezomib

Cohort 2

560 mg/d ibrutinib

Prior bortezomib treatment†

(n = 50) †prior treatment with at least 2 cycles of bortezomib

Enrolled February 2011March 2012 • Phase 2, open-label,

multicenter international

study (18 sites)

• Patients with relapsed or

refractory MCL (N = 115)

• Patients received a daily

dose of ibrutinib until

disease progression or

unacceptable levels of

adverse events (AEs)

occurred

Wang ML, et al. N Engl J Med. Epub Ahead of Print 19 June 2013

Primary end point

• Overall response rate (ORR)*

– The proportion of patients with a complete response (CR) or a partial response (PR)

according to the Revised International Working Group Criteria for NHL2

Secondary end points

• Response duration

• Progression-free survival (PFS) and overall survival (OS)

• Safety

– Assessed by the frequency and severity of AEs

– Based on reported AEs, clinical laboratory tests (hematologic testing, serum chemical testing,

and urinalysis), measurements of weight and vital signs, physical examinations, and ECOG

performance status

1. Wang ML, et al. N Engl J Med. Epub Ahead of Print 19 June 2013

2. Cheson BD, et al. J Clin Oncol 2007;25:579-86.

PCYC-1104 Phase 2 Study – End Points

41

Baseline Patient and Disease Characteristics

Characteristic All Patients

(N = 111)

Median age, years (range) 68 (40-84)

ECOG performance status, n (%) 0-1 2 2

99 (89%) 11 (10%) 1 (1%)

MIPI score, n (%) Intermediate risk High risk

42 (38%) 54 (49%)

Advanced disease, n (%) Bone marrow involvement Extranodal involvement

54 (49%) 60 (54%)

Refractory disease*, n (%) 50 (45%)

*Defined as failure to achieve at least PR to the last therapy prior to study entry.

Prior Therapies All Patients

(N = 111)

Prior number of regimens Median (range) ≥3 regimens, n (%)

3 (1-5)

61 (55%)

Types of prior regimen, n (%) Bortezomib Lenalidomide Rituximab-containing regimens

48 (43%) 27 (24%) 99 (89%)

Prior high-intensity therapy, n (%) Hyper-CVAD Stem cell transplant

33 (30%) 12 (11%)

Summary of Prior Therapies

Treatment Emergent AEs in > 15% of Patients Regardless of Relationship to Study Therapy Hematological AE

Bleeding events ≥ grade 3 occurred in 5% of patients

Non-Hematological AE

0% 10% 20% 30% 40% 50% 60%

Neutropenia

Thrombocytopenia

Anemia

0% 10% 20% 30% 40% 50% 60%

Diarrhea

Fatigue

Nausea

Oedema peripheral

Dyspnea

Constipation

Upper respiratory tract infection

Vomiting

Decreased appetite

Cough

Pyrexia

Abdominal pain

Contusion

Rash

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

9 PTHiT 2013, PCYC-1104 Jurczak et al.

45

Prevalence of Infections by Time Period and Grade

Prevalence rate of grade ≥3 infections was 27% during the median study period of 27 months

SAE infections occurred in 20% of patients, and both grade ≥3 and SAE infections generally decreased over time

Incidence of grade ≥3 infection was lower (16%) among patients with a complete response (CR) than in non-CR patients (30%)

18% 15%

12% 10%

5%

0

10

20

30

40

50

1-6 months

7-12 months

13-18 months

19-24 months

˃24 months

Grade ≥3

14% 13%

8% 10%

5%

0

10

20

30

40

50

1-6 months

7-12 months

13-18 months

19-24 months

˃24 months

SAE

N = 111 N = 72 N = 51 N = 41 N = 22 N = 111 N = 72 N = 51 N = 41 N = 22

Pe

rce

nta

ge o

f p

atie

nts

wit

h e

ven

t

49

Selected Adverse Events by Grade Over Total Study Period

34% 36%

9%

14%

9%

42%

5% 5%

27%

0

5

10

15

20

25

30

35

40

45

50

Diarrhea Bleeding Infection

Pe

rce

nta

ge o

f p

atie

nts

wit

h e

ven

t

Grade 1 Grade 2 Grade ≥3

With continuous ibrutinib therapy, AEs of infection, diarrhea, and bleeding were mainly grade 1 or 2 in severity

N=111; one patient experienced diarrhea with missing grades, so this event was counted as “any grade”

Responce to therapy

Bortezomib-Naïve (N = 56)

Bortezomib-Exposed (N = 47)

-100 –

50 –

0 –

50 –

100 –

150 –

12

Best Response

19 23 21

49 44 47

0

20

40

60

80

100

Pat

ien

ts, %

Bortezomib- Naïve

(n = 63)

Bortezomib- Exposed (n = 48)

Total (n = 111)

68 67 68

EHA 2013, PCYC-1104 Rule et al.

Efficacy Population n = 111, Estimated Median Follow-up 15.3 months

CR PR

Responce to Ibrutinib increases with time

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

13

CR PR

• Estimated Median PFS (CI 95%) 13.9 months (7.0, NE)

Kaplan-Meier PFS in R/R MCL (N=111)

EHA 2013, PCYC-1104 Rule et al.

100

0

80

20

40

60

24 0 4 12 8 16 20

Pro

gre

ssio

n-F

ree

Su

rviv

al, %

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

15

Wojciech Jurczak

Efficacy of PI3kinase inhibition – Idelalisib - in Relapsed Mantle Cell Lymphoma

• 40 patients with relapsed/refractory MCL

• 17/40 (43%) were refractory to bortezomib

• ORR was 16/40 (40%), with CR in 2/40 (5%) patients.

• ORR 69% in patients getting 150 mg twice daily or higher

• Median DOR was 2.7 months, median PFS was 3.7 months

• 1-year PFS was 22%.

Kahl et al. Blood. 2014; 123(22):3398-405.

• Estimated Median OS was not reached

• Estimated OS of 58% at 18 months

Kaplan-Meier OS in R/R MCL (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



Bortezomib-Exposed

All 111 98 76 51 32 0

48 43 37 21 13 0

63 55 39 30 19 0

5

4

1

16

• Estimated OS of 47% at 24months

Kaplan-Meier OS in R/R MCL (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



Bortezomib-Exposed

All 111 98 76 51 32 0

48 43 37 21 13 0

63 55 39 30 19 0

5

4

1

16

N ALL subjects 111

Age (years) ˂65 years ≥65 years

41 70

Cohort Bortezomib-Naïve Bortezomib-Exposed

63 48

Sex M F

85 26

Prior Number of Regimens ˂3 ≥3

50 61

Simplified MIPI score Intermediate risk (4-5) High risk (6-11)

42 54

Baseline ECOG 0 1 ≥2

51 48 12

Advanced Disease Yes No

80 31

Tumor Bulk (Largest Diameter)

≥5cm 43

Blastoid Histology Yes No

17 94

Refractory Disease Yes No

50 61

Prior High Intensity Therapy Yes No

39 72

Prior Lenalidomide Yes No

27 84

Response to ibrutinib is Independent of Patient Characteristics and Risk Factors

13 0 20 40 60 80 100

MIPI = MCL International Prognostic Index Advanced disease = bone marrow and/or extranodal involvement PTHiT 2013, PCYC-1104 Jurczak et al.

Patient #15: on 4/28/11 subcarinal LAD: 83 x 54 mm 7/15/11 subcarinal LAD: 21 x 13 mm

Complete Remission after 2 Cycles of Ibrutinib

A week later…..

Targeting BTK With Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

JC Byrd, RR Furman, SE Coutre, IW Flinn, JA Burger, KA Blum, B Grant, J Sharman, M Coleman, WG Wierda, JA Jones, W Zhao, NA Heerema, AJ Johnson, J Sukbuntherng, BY Chang, F Clow,

E Hedrick, JJ Buggy, DF James, S O'Brien

N Engl J Med. 2013. .


Study Design

Cohort 1

420 mg/day ibrutinib† (n = 27)

Cohort 2


Cohort 3 (high-risk*)


† continuous schedule until progression or toxicity

*Defined 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. Blood 2012; 120: Abstract 189

Patient Eligibility1

INCLUSION CRITERIA

• Diagnosis of relapsed or refractory CLL/SLL, as defined by the International Workshop on CLL2 and

World Health Organization3 classifications

• A requirement for treatment

• Adequate organ function including creatinine ≤ 1.5 times the upper limit of normal (ULN) and alanine

transaminase ≤ 2.5 times ULN

• Absence of active infection

• At least 2 prior therapies including a purine analog (Cohorts 1 and 2)

• Failure to respond or progression within 24 months of a chemoimmunotherapy regimen (Cohort

3)

• Absolute neutrophil count of ≥ 750/µL and platelet count of ≥ 50,000/µL initially required

(a subsequent amendment allowed for enrolment of 22 patients with any degree of cytopenia if due to

CLL marrow involvement)

EXCLUSION CRITERIA

• Any malignancy limiting survival to < 2 years

• Gastrointestinal disease that may inhibit ibrutinib absorption

• Medicines associated with torsades de points

1. Byrd JC, et al. N Engl J Med. Epub Ahead of Print 19 June 2013

2. Hallek M, et al, Blood 2008;111:5446-56.

3. Jaffe ES, et al. Blood 2008;112:4384-99.

Patient Characteristics

420 mg

(n = 51)

840 mg

(n = 34)

Overall Population (N = 85)

Prior therapies, n (%)

Nucleoside analog

Rituximab

Alkylator

Alemtuzumab

Bendamustine

Ofatumumab

47 (92)

50 (98)

44 (86)

11 (22)

20 (39)

10 (20)

34 (100)

33 (97)

32 (94)

7 (21)

13 (38)

12 (35)

81 (95)

83 (98)

76 (89)

18 (21)

33 (39)

22 (26)

Unmutated IgVH gene, n (%)

Yes

Missing

41 (80)

2 (4)

28 (82)

2 (6)

69 (81)

4 (5)

Interphase cytogenetics+, n (%)*

Del(17p13.1)

Del(11q22.3)

17 (33)

16 (31)

11 (32)

15 (44)

28 (33)

31 (36)

β2M, # (%)

> 3 mg/L

Missing

18 (35)

3 (6)

21 (62)

2 (6)

39 (46)

5 (6)

Bulky nodes, n(%)

≥ 5 cm

≥ 10 cm

24 (47)

4(8)

20 (59)

9 (26)

44(52)

13 (15)

*Cutoff points were defined per the assay specifications as performed in the central laboratory.

Byrd JC, et al. N Engl J Med. 2013. [Suppl. Appendix]

-20% 0% 20% 40% 60%

Oropharyngeal pain

Neutropenia

Vomiting

Contusion

Sinusitis

Nausea

Hypertension

Headache

Dizziness

Constipation

Muscle spasms

Peripheral edema

Pyrexia

Rash

Arthralgia

Cough

Fatigue

URI

Diarrhea

Grade 1-2 Grade 3-4 Total*

49%

33%

32%

31%

27%

27%

27%

21%

20%

18%

18%

18%

18%

18%

18%

16%

16%

15%

15%

*Total 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)


Efficacy: ORR

0

10

20

30

40

50

60

70

80

90

100

71% 71%

20% 15%

420 mg

(Cohorts 1 + 3)

N = 51

840 mg

(Cohort 2)

N = 34

PR

CR

PR+L

Patie

nts

(%

)

Byrd JC, et al. N Engl J Med. Epub Ahead of Print 19 June 2013 PR+L = partial response with persistent lymphocytosis

Efficacy: ORR by Subgroup Analyses

• 4 of the 12 patients (33%) with mutated IgVH gene had a CR/PR; 5 (42%) had PR +L

• 53 of the 69 patients (77%) with mutated IgVH gene had a CR/PR; 9(13%) had PR+L

• The difference in ORR was significant (P=0.005)

• However, the combined rate of ORR + PR+L was similar between the mutated and unmutated subgroups Byrd JC, et al. N Engl J Med. Epub Ahead of

Print 19 June 2013

Efficacy: PFS in Overall Population


Est. PFS at 26 months was 75%

Months on study

Efficacy: PFS (by status of 17p13.1 or 11q22.3 deletion and mutation of IgVH)


Efficacy: OS in Overall Population

Est. OS at 26 months was 83%


Months on study

Efficacy: OS (by status of 17p13.1 or 11q22.3 deletion and mutation of IgVH)


‘09 ‘10 ‘11 ‘12 ‘15 ‘14 ‘13 ‘16 ‘17 ‘18

Phase I in B-NHL

R/R CLL

MCL

R/R R-chemo

FL

MCL 1st line

DLBCL 1st line

PCYC1102 (CLL)

PCYC1104 (MCL)

WM

PCYC1106 (R/R DLBCL)

MCL3001 RAY(Ibru vs Tems)

FLR2002

DBL3001

MCL3002 SHINE (BR+/- Ibrutynib, 1st line)

PCYC1115

A041202

CLL3001

PCYC1112 RESONATE

PCYC1117

WM

R/R non-GC DLBCL

CLL 1st line

Ibrutinib Clinical Trials in MCL

Open-Label Phase 3 Study of Ibrutinib vs. Temsirolimus in Patients With Relapsed or Refractory MCL Who Have

Received at Least 1 Prior Therapy

Disease: Relapsed or Refractory MCL

Schema (N=280):

• Stratification – Number of prior lines of therapy

(1 or 2 vs. ≥ 3)

– Simplified MIPI (low risk) [0-3] vs. intermediate risk [4-5] vs. high risk [6-11]

Primary objective:

– Progression-free survival

Secondary objectives:

– Overall response rate

– Overall survival

– 1-year survival rate

This study is only being conducted outside of the United States and is currently recruiting patients. NCT01646021

ibrutinib 560 mg orally once daily

89

Randomize

temsirolimus 175 mg IV on days 1, 8, 15 of cycle 1

followed by 75 mg on days 1, 8, 15 of each 21 day cycle

MCL 3001 RAY

– Duration of response

– Time-to-next treatment

– Safety

Placebo-Controlled Phase 3 Study of Ibrutinib in Combination With Bendamustine + Rituximab (BR) in

Patients With Newly Diagnosed MCL

91 NCT01776840

This study is currently recruiting patients.

Disease: Newly diagnosed MCL

Schema (N=520):

Primary objective:




– Complete response rate and overall response rate

– Duration or response

– Safety

Placebo orally once daily + bendamustine (90 mg/m2 IV on days 1-2, cycles 1-6) +

rituximab (375mg/m2 IV on day 1, cycles 1-6; if complete response or partial response is achieved, 375 mg/m2 is administered on day 1 of every second cycle for a maximum

of 12 cycles

Randomise

ibrutinib 560 mg orally once daily + bendamustine (90 mg/m2 IV on days 1-2,

cycles 1-6) + rituximab (375mg/m2 IV on day 1, cycles 1-6; if complete response or partial

response is achieved, 375 mg/m2 is administered on day 1 of every second cycle

for a maximum of 12 cycles

MCL 3002 SHINE

Wojciech Jurczak

1st line induction:

(cytarabine

based)

IBRUTINIB maintenance

ASCT

1st line induction:

(cytarabine

based) +

IBRUTYNIB

®

1st line induction:

(cytarabine

based) +

IBRUTYNIB

ASCT

Planned III phase EMCLN „younger“ trial

‘09 ‘10 ‘11 ‘12 ‘15 ‘14 ‘13 ‘16 ‘17 ‘18

Phase I in B-NHL

R/R CLL

MCL

R/R R-chemo

FL

MCL 1st line

DLBCL 1st line

PCYC1102

PCYC1104 (MCL)

WM

PCYC1106

MCL3001

FLR2002

DBL3001

MCL3002

PCYC1115

A041202

CLL3001

PCYC1112 (RESONATE)

PCYC1117 (17 p deletion)

WM

R/R non-GC DLBCL

CLL 1st line

Ibrutinib Clinical Trials In CLL

Ibru vs Ofatumomab R/R CLL

BR +/- Ibru R/R CLL

Ibrutynib – prev treated

Ibrut vs Chlorambucil – CLL de novo in elderly

Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia

JC Byrd, JR Brown, S O’Brien, JC Barrientos, NE Kay, NM Reddy, S Coutre, CS Tam, SP Mulligan, U Jaeger, S Devereux, PM Barr, RR Furman, TJ Kipps, F Cymbalista, C Pocock,

P Thornton, F Caligaris-Cappio, T Robak, J Delgado, SJ Schuster, M Montillo, A Schuh, S de Vos, D Gill, A Bloor, C Dearden, C Moreno, JJ Jones, AD Chu, M Fardis, J McGreivy,

F Clow, DF James, P Hillmen, for the RESONATE Investigators

N Engl J Med. (May 31, 2014)10.1056/NEJMoa1400376

Byrd JC, et al. N Engl J Med. 2014; ePub 31May2014.

• 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 2013

• Phase 3,

open-label,

randomized,

multicenter

study

• Patients with

previously

treated

CLL or SLL;

not appropriate

for purine

analogue

treatment

R

A

N

D

O

M

I

Z

E

Oral ibrutinib 420 mg once daily*

n = 195

*until PD or unacceptable toxicity

IV ofatumumab 12 doses over 24 wks*

n = 196

*initial dose of 300 mg followed by 2000 mg weekly for 7 weeks

and then every 4 weeks for 16 weeks

Crossover to ibrutinib 420 mg

with IRC confirmed PD after end of study

(n = 57)

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


Patient Eligibility: Key Criteria

INCLUSION CRITERIA1,2

• Men and women with CLL or SLL requiring therapy3

• Received at least 1 prior therapy for CLL or SLL and were not appropriate for

purine analogue treatment, defined by at least 1 of the following:

• Failure to respond (stable disease [SD] or PD on treatment), or a progression-free interval of

< 3 years from treatment with a purine analogue–based therapy and anti-CD20–containing

chemoimmunotherapy regimen after at least 2 cycles

• Age ≥ 70 years, or age ≥ 65 years with the presence of comorbidities

• History of purine analogue–associated autoimmune anemia or autoimmune thrombocytopenia

• del17p either alone or in combination with other cytogenetic abnormalities

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Absolute neutrophil count (ANC) ≥ 750 cells/µL, platelets ≥ 30,000 cells/µL

• Adequate liver and kidney function

EXCLUSION CRITERIA1

• Required treatment with warfarin or strong CYP3A4/5 inhibitors

1. Byrd JC, et al. N Engl J Med. 2014; ePub 31May2014

2. Byrd JC, et al. N Engl J Med. 2014; Suppl Appendix. ePub 31May2014.

3. Hallek M, et al. Blood. 2008;111:5446-5456

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


IRC-Evaluated OS*

OS rate for ibrutinib:

90% at 12 mo

vs

OS rate for ofatumumab:

81% at 12 mo

*The survival effect was based on an analysis in

which data were censored at the time of crossover.

57% reduction in risk

of progression or

death with ibrutinib


Disease: Treatment-Naïve CLL /SLL

Schema (N=272):

• Stratification

– ECOG performance status

– Advanced Rai stage

Primary objective


Secondary objectives


– Rate of minimal residual disease–negative complete responses

– Hematologic improvement

– Safety

Open-Label Phase 3 Study of Ibrutinib vs. Chlorambucil in Patients 65 Years or Older With

Treatment-Naïve CLL or SLL

121 NCT01722487 and NCT01724346

This study is currently recruiting patients.

Randomize

chlorambucil 0.5 mg/kg orally on days 1 & 15 of

each 28-day cycle

ibrutinib 420 mg orally once daily until disease

progression

PCYC-1115-CA RESONATETM-2

Disease: Relapsed or Refractory CLL/SLL

Schema (N=580):

• Stratification – Refractory to purine analog

– Number of prior therapies, 1 vs. > 1

Primary objective:



– Overall response rate


– Safety

Placebo-Controlled Phase 3 Study of Ibrutinib in Combination With Bendamustine + Rituximab (BR) for

Patients With Relapsed or Refractory CLL/SLL

124

NCT01611090 This study is currently recruiting patients.

Randomize

placebo orally once daily + bendamustine (70 mg/m2 IV on cycle 1, days 2-3 and cycles 2-6,

days 1-2) + rituximab 375/500 mg/m2 IV on day 1, cycles 1-6) (28 day cycle)

ibrutinib 420 mg orally once daily + bendamustine (70

mg/m2 IV on cycle 1, days 2-3 and cycles 2-6, days 1-2) +

rituximab 375/500 mg/m2 IV on day 1, cycles 1-6) (28 day cycle)

CLL 3001 HELIOS

‘09 ‘10 ‘11 ‘12 ‘15 ‘14 ‘13 ‘16 ‘17 ‘18

Phase I in B-NHL

R/R CLL

MCL

R/R R-chemo

FL

MCL 1st line

DLBCL 1st line

PCYC1102 (CLL)

PCYC1104 (MCL)

WM

PCYC1106 (R/R DLBCL) Ibrutynib

MCL3001 RAY

FLR2002

DBL3001 (R-CHOP +/- Ibrutynib w DLBCL ABC)

MCL3002 SHINE

PCYC1115

A041202

CLL3001

PCYC1112 RESONATE

PCYC1117

WM

R/R non-GC DLBCL

CLL 1st line

Ibrutinib Clinical Trials In DLBCL

Placebo-Controlled Phase 3 Study of Ibrutinib in Combination With R-CHOP in Patients With Newly

Diagnosed Non-GCB DLBCL

Disease: Newly diagnosed DLBCL

Schema (N=800):

• Stratification – Stratify by R-IPI, region, and number

of pre-specified treatment cycles

• Primary objective:

– Event-free survival

• Secondary objectives:



– 1-year survival rate

– Complete response rate

– Safety

This study is soon to be recruiting patients.

DBL 3001

placebo orally once daily + R-CHOP (rituximab 375mg/m2 IV,

cyclophosphamide 750mg/m2 IV, doxorubicin 50mg/m2 IV, vincristine 1.4mg/m2 IV [maximum 2mg], and

prednisolone 100mg orally) for 6 or 8 cycles per site preference (21 day cycle)

129

Randomize

ibrutinib 560 mg orally once daily + R-CHOP

(rituximab 375mg/m2 IV, cyclophosphamide 750mg/m2 IV,

doxorubicin 50mg/m2 IV, vincristine 1.4mg/m2 IV [maximum 2mg], and

prednisolone 100mg orally) for 6 or 8 cycles per site preference (21 day cycle)

1:1

NCT01855750

Wojciech Jurczak

Ibrutinib Future Challenges

• Patient selection – DLBCL: non-GC

– Current trials require central pathology. How will this work in community setting?

• Resistance – BTK mutations (C481S). Role for other BTK inhibitors?

– Other mutations in CLL: PLCg2

– Other mutations in DLBCL: CD79B, not CARD11, MYD88?

– Role for rational combinations?

Wojciech Jurczak

BCR - signalling

Wojciech Jurczak

PI3Kδ inhibition impacts multiple critical

pathways in iNHL ….

Wojciech Jurczak

…where AKT/mTOR is probably the most important one

Wojciech Jurczak

Isoform Idelalisib (Oral) Duvelisib (IPI-145) (Oral) Copanlisib (IV)

P110a 2221 1410 0.5

P110b 135 26.2 3.7

P110g 550 0.36 6.4

P110d 4.9 19.6 0.7

PI3K Inhibitors

Wojciech Jurczak

PI3K-δ and PI3K-γ support the growth and survival of B-cell and T-cell malignancies

• IPI-145 is a potent inhibitor of both δ and γ PI3K isoforms • Early evidence of therapeutic potential across a broad range of

hematologic malignancies

Wojciech Jurczak

PI3Kγ and PI3Kδ inhibition may have complementary effects on malignant B cells

Wojciech Jurczak

Wojciech Jurczak

PiP3 pathway and its inhibitors

Wojciech Jurczak


GS-1101, CAL-101 - Idelalisib is a first-in-class, small molecule Class I phosphatidylinositol 3-kinase-δ (PI3K-δ) specific inhibitor with an IC50 of 2.5 nM for this isoform.1

Wojciech Jurczak


Duvelisib (IPI-145, INK-1197) is a small molecule pan-Class I phosphatidylinositol 3-kinase (PI3K)-δ and -γ inhibitor with an IC50 of 1 and 43 nM, respectively.

Wojciech Jurczak


Copanlisib (BAY 80-6946) is a small molecule pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with IC50 values of 0.5 nM (PI3K-α), 3.7 nM (PI3K-β), 0.7 nM (PI3K-δ), and 6.4 nM (PI3K-γ).

Expression Ubiquitous Ubiquitous Leukocytes Leukocytes

EC50 (nM) >10,000 1419 2500 9

a b g d

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

Idelalisib (CAL-101, GS-1101)

Class I PI3K Isoform

♦ Promising activity in R/R iNHL in phase I study*

*Benson D et al. ASCO 2013, abstr 8526

Wojciech Jurczak

Idelalisib (CAL-101, GS-1101)

2005 • Patent filed for PI3Kd inhibitor

2008 • Phase I trial initiated

2011 Gilead acquires Calistoga Pharmaceuticals

2013 • Gilead submits NDA for indolent NHL

• Gilead halts phase III CLL trial, everyone crosses over to idelalisib

http://en.wikipedia.org/wiki/File:Idelalisib_skeletal.svg

Wojciech Jurczak

Previously treated iNHL Phase 3 combination immuno or chemoimmunotherapy

124 Study: R ± GS-1101 125 Study: BR ± GS-1101

iNHL Full

Approval

Additional studies – lymphoid malignancies Exploration & Indication Expansion

Healthy Volunteer Trials

• Dose-ranging

• Metabolism

Hematologic Cancer Trials

• Single-agent (101-02 Study)

• Combination (101-07 Study)

• Combination (101-08 Study)

Full Development 2011-2016

Early Development 2008-2010

Refractory iNHL Phase 2 single-agent (101-09 Study)

iNHL Accelerated

Approval Previously treated CLL

Phase 3 combination with CD-20 mAb 116/117 Study: R ± GS-1101

119 Study: Ofa ± GS-1101 CLL Full

Approval Previously treated CLL

Phase 3 combination with chemoimmunotherapy 115 Study: BR ± GS-1101

Idelalisib Study Context

PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma

Ajay K. Gopal, M.D.1, Brad S. Kahl, M.D.2, Sven de Vos, M.D., Ph.D.3, Nina D. Wagner-Johnston, M.D.4, Stephen J. Schuster, M.D.5, Wojciech J. Jurczak, M.D., Ph.D.6, Ian W. Flinn, M.D., Ph.D.7, Christopher R. Flowers, M.D.8, Peter Martin, M.D.9, Andreas Viardot, M.D.10, Kristie A. Blum, M.D.11, Andre H. Goy, M.D.12, Andrew J. Davies, M.R.C.P., Ph.D.13, Pier Luigi Zinzani, M.D., Ph.D.14, Martin Dreyling, M.D.15, Dave Johnson, M.D.16, Langdon L. Miller, M.D.16, Leanne Holes16, Daniel Li, Ph.D.16, Roger D. Dansey, M.D.16, Wayne R. Godfrey, M.D.16, Gilles A. Salles, M.D., Ph.D.17

Wojciech Jurczak

Study 101-09: Key Eligibility Criteria

• Previously treated iNHL: (FL, SLL, MZL, LPL/WM)

• Refractory to BOTH rituximab and an alkylating agent:

– Defined as less than PR on therapy, or progression

within 6 months of completion of therapy

– Refractoriness documented radiologically

• Measureable disease - minimum ≥ 2 cm lymph node diameter

• ECOG 0-2/Karnofsky PS ≥ 60

• Organ function:

– Neutrophils ≥ 1000 cells/μl, Hgb ≥ 8 gm/dL, platelets ≥ 50K/ul

– Serum transaminases ≤ 2.5x ULN, bilirubin ≤ 1.5x ULN

– Serum creatinine < 1.5x ULN

Wojciech Jurczak

Idelalisib Monotherapy

in Refractory iNHL (Study 101-09)

Idelalisib 150 mg BID

Therapy

maintained until

progression

Single-Arm Study (N=125)

Disease assessments using

Cheson and WM criteria:

– Weeks 0, 8, 16, 24, 36, 48

– Every 12 weeks thereafter

– Evaluated by Independent Review

Committee

– 2 independent radiologists with

adjudication by a 3rd if needed

– clinical review by

hematologist/oncologist

Primary endpoint:

– Overall Response Rate (ORR)

Secondary endpoints:

– Duration of Response (DOR)

– Progression Free Survival (PFS)

– Overall Survival (OS)

– Safety

– Quality of life

Enrolled

April 2011 to

October 2012

Lo

ng

Term

fo

llo

w-u

p

Wojciech Jurczak

Rituximab

Alkylating agent

Regimens:

R-alkylating agent

R-Bendamustine

R-CHOP

R-CVP

125/125 (100%)

124/125 (99%)

106/112 (95%)

47/60 (78%)

40/56 (71%)

29/36 (81%)

Refractory to ≥ 2 regimens

Refractory to last regimen

99 (79%)

112 (90%)

Prior Therapy Refractoriness

Wojciech Jurczak

Hematologic Laboratory Abnormalities

Baseline Any Grade Grade ≥ 3

Neutrophils decreased 30 (24%) 6 (5%)

Hemoglobin decreased 64 (51%) 1 (1%)

Platelets decreased 43 (34%) 4 (3%)

On Study Any Grade Grade ≥ 3

Neutrophils decreased 70 (56%) 34 (27%)

Hemoglobin decreased 35 (28%) 2 (2%)

Platelets decreased 32 (26%) 8 (6%)

Wojciech Jurczak

Transaminases, n (%) Grade 1-

2 Grade 3 Grade 4 Any Grade

ALT or AST elevated 44 (35%) 13 (10%) 3 (2%) 60 (48%)

Transaminase Elevations

Subjects Rechallenged (N=14, out of 16 ≥ Grade 3)

No recurrence 10 (71%)

Recurrence of ≥ Grade 3 4 (29%)

Grade 1-2 resolved with continued idelalisib treatment

Grade ≥ 3 reversible with drug interruption

Wojciech Jurczak

AE Any Grade

N, %

Grade ≥ 3

N, %

Diarrhea 54 (43%) 16 (13%)

Fatigue 37 (30%) 2 (2%)

Nausea 37 (30%) 2 (2%)

Cough 36 (29%) None

Pyrexia 35 (28%) 2 (2%)

Dyspnea 22 (18%) 4 (3%)

Decreased appetite 22 (18%) 1 (1%)

Abdominal pain 20 (16%) 3 (2%)

Vomiting 19 (15%) 3 (2%)

URI 18 (14%) None

Decreased weight 17 (13%) None

Rash 16 (13%) 2 (2%)

Asthenia 14 (11%) 3 (2%)

Night Sweats 14 (11%) None

Pneumonia 14 (11%) 9 (7%)

Adverse Events > 10%

Wojciech Jurczak

Black Box - Grade 5 Toxicity

Grade 5

Hepatotoxicity 1/1192 = 0.1%

Diarrhea 1/1192 = <0.1%

Pneumonitis 3/760 = 0.5%

Perforation 2/1192 = 0.2%

Referenced from: https://www.zydelig.com/hcp/

Wojciech Jurczak

aCriterion for lymphadenopathy response [Cheson 2007] b 3 subjects no post baseline evaluation: □ 2 subjects NE ■ 1 subject PD by Lymph Node biopsy

Waterfall Plot Lymph Node Response

-100

-75

-25

0

-50a

+25

+50

Individual Patients (N=125)

SP

D o

f M

easu

red

Lym

ph

No

des,

Best

% C

han

ge f

rom

Baselin

e•90% had improvement in lymphadenopathy

•57% had ≥50% decrease from baseline

Wojciech Jurczak

Duration Of Response (DOR)

Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to IRC assessments

Median DOR = 12.5 months

0

25

50

75

100

0?(71)

3(54)

6(34)

9(17)

12(9)

15(0)

18(0)

Time from Response, Months

(N, Patients at Risk)

% C

on

tin

ued

Resp

on

se

Wojciech Jurczak

0

25

50

75

100

0(125)?

3?(100)

6 (59)?

9 (39)?

12?(20)

15(13)

18(0)

Time from Start of Idelalisib, Months

(N, Patients at Risk)

% P

rog

ressio

n-F

ree

Median PFS = 11 months

Progression Free Survival

Wojciech Jurczak

Idelalisib CLL Registration Study

Wojciech Jurczak

“…in patients for whom Rituximab alone would be considered appropriate therapy due to other comorbidities”

Characteristic Percentage Median

Age > 65 78% 71

Cr Clearance < 60 40% 64 ml/min

Grade 3 Marrow 35%

CIRS > 6 85% 8

Wojciech Jurczak


Wojciech Jurczak

Outcomes (PFS & OS)

Coutre et al ASCO 2014

Wojciech Jurczak Sharman et al ASCO 2014

Study arm +/- 17P Study arm +/- 11Q


Wojciech Jurczak

Frontline Idelalisib + Rituximab

O’Brien et al ASCO 2013

Wojciech Jurczak

Therapeutic Selection

Idelalisib with rituximab

Ibrutinib

• On blood thinners (atrial fibrillation)

• Renal insufficiency

• Abnormal liver function • History of bowel difficulties • Lung issues • Monotherapy preferred

• CLL, CLL del 17 & iNHL • CLL, CLL del 17, iNHL, WM, MCL • DLBCL ABC

Wojciech Jurczak

1942 1948 1959 1970 1975 1978 2003 2014

Louis Goodman,

Alfred Gilman

Nitrogranulogen in HD

Sydney Farber

antymetabolites inALL

FDA registers

Cyklophosphamide

NCI ‘gang of five’: George

Canellos, Bruce Chabner, Phillip

Schein, Vincent DeVita i Robert

Young

Polichemotherapy: 1970 MOPP,

1973 CHOP (Doxorubicin)

Gianni Bonadonna ABVD

FDA registers Cisplatin

Volker Diehl – HD

Escalated BEACOPP

Bertrand Coiffier –

R-CHOP in DLBCL

Instead of summary ….

Michael Wang, Ajay Gopal &

J Byrd– Ibrutynib &

Idelalisib

Brentuximab

Vedotin in HD

[email protected] Department of Haematology, Jagiellonian University, Małopolskie Medical Center, Polish Lymphoma Research Group

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