Primer on Kinase Inhibitors

Richard R. FurmanDirectory, CLL Research CenterWeill Cornell Medical College /New York Presbyterian Hospital

BCR-associated Kinases:Proven Effective Therapeutic Targets

Nat Rev Immunol 2:945

• Syk (spleen tyrosine kinase): R406, PRT062070

• Btk (Bruton’s tyrosine kinase): ibrutinib, CC-292, ACP-196

• PI3K (phosphatidyl 3-kinase: idelalisib(GS-1101), IPI-145

Targeting the “BCR++” Antigen Pathway:

Novel BCR Acting Agents

BTK:Ibrutinib (PCI-32765)CC-292 (AVL-292)ACP-196

PI 3 Kinase:Idelalisib (GS-1101, CAL-101)IPI-145

SYK:Fostamatinib (R935778)PRT062070

Issues with Novel Agents

• Need to revise Response Criteria

• Dosing:– No more MTD dosing– Threshold dosing– Fixed dosing / wide therapeutic window

• Differences

Issues with Novel Agents

• Need to revise Response Criteria

• Dosing:– No more MTD dosing– Threshold dosing– Fixed dosing / wide therapeutic window

• Differences

Lymphocytosis + Nodal Reductionwith BCR Antagonists

Redefining Clinical End Points“Cheson 2012”

• Standard response criteria: measure of treatment efficacy• For novel agents, response criteria don’t measure effect:

– Thalidomide / lenalidomide: tumor flare– BCR Antagonists: lymphocytosis (Not tumor flare)

• Need to provide means for determining need for treatment discontinuation

• LRF sponsored committee: May 2011

Cheson BD. JCO 2012.

Cheson 2012: Recommendations

1. For IMID compounds: Assessment of PD should use repeat observations and incorporate indicators of PD not associated with tumor flares

2. For BCR-targeted agents: lymphocytosis alone should not be considered an indicator of PD. Need to demonstrate other CLL-related signs or symptoms of PD

3. Lymphocytosis is distinct from tumor flare

Issues with Novel Agents

• Need to revise Response Criteria

• Dosing:– No more MTD dosing– Threshold dosing– Fixed dosing / wide therapeutic window

• Differences

Idelalisib Doses >150 mg BID Associated with Longer PFS

PFS -- By Idelalisib Dosing Regimen

0 2 4 6 8 10 12 14 16 18 20 22 240

25

50

75

100

50-100 mg BID: 5 cycles (16)150-350 mg BID: 18 cycles (39)

Cycles (28 days)

% P

rogr

essi

on-F

ree

Issues with Novel Agents

• Need to revise Response Criteria

• Dosing:– No more MTD dosing– Threshold dosing– Fixed dosing / wide therapeutic window

• Differences

Kinase PCI-32765 IC50 (nM) Kinase PCI-32765

IC50 (nM)

Btk 0.46 FGR 2.31

Ikt 10.70 Fyn 95.55

Bmx/Etk 0.76 HCK 3.67

TEC 77.76 Lyn 200.45

EGFR 5.55 ABL 86.12

JAK3 16.13 Brk 3.34

BLK 0.52 JAK2 >10,000

LCK 33.24 SYK >10,000

IC50 Values of PCI-32765 and Related Kinases

Bruton’s Tyrosine Kinase (Btk)

B-cell antigen receptor (BCR) signaling required for B cell survival

Bruton’s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway

Inhibitors of Btk block BCR signaling and induces apoptosis

Ibrutinib: Inhibitor of Bruton’s Tyrosine Kinase

• Forms an irreversible bond with cysteine-481 in Btk

• Potent Btk inhibitionIC50=0.5 nM

• Orally bioavailable• Daily dosing resulting in 24-hr target

inhibition• No impact on T-cells or NK cells• Possible impact upon bmx, blk, and

platlets

N

N

NN

NH2

O

N

O

Ibrutinib in CLL: PCYC-1102

Furman RR. iWCLL 2013

PCYC-1102: Patient Demographics

Furman RR. iWCLL 2013

CharacteristicTN ≥ 65 Years

n = 31R/R

n = 85

Median age, years (range)≥ 70 years, n (%)

71 (65, 84)23 (74)

66 (37, 82)30 (35)

Male, n (%) Female, n (%)

19 (61) 12 (39)

65 (76)20 (24)

Prior Therapies, n (%) < 3> 3

NA

Median = 4 (1-12) 24 (28)61 (72)

β2M > 3.0 mg/L, n (%) 8 (26) 39 (46)

Rai stage III/IV, n (%) 17 (55) 52 (61)

Prognostic markers, n (%) IgVH unmutated del(17p)+del(11q)+

15 (48)

2 (6)1 (3)

65 (76)29 (34)29 (34)

PCYC-1102: Patient Disposition

Furman RR. iWCLL 2013

TN ≥ 65 Yearsn = 31

R/R n = 85

Median time on treatment, months (range) 21.3 (0.3, 26.6) 16.3 (0.3, 28.7)

Median time on study, months (range) 22.1 (2.5, 28.9) 22.1 (0.7, 29)

Patients still on treatment, n (%) 26 (84) 53 (62)

Patients discontinuing treatment, n (%) 5 (16) 32 (38)

Reasons for treatment discontinuation, n (%) AE

Treatment-related AE Death due to AE

2 (6)1 (3)

0

10 (12)1 (1)1 (1)a

Disease progressionb 1 (3) 10 (12) SCT (while in response) Investigator decision (not SCT) Patient decision Lost to Follow-up

00

2 (6)0

4 (5)4 (5)3 (4)1 (1)

aCryptococcal pneumoniab7 patients (1 TN and 6 R/R) had disease progression with Richter’s transformation

PCYC-1102: Overall Response

• Among those patients whose initial response was PR-L, the majority achieved classic response by iwCLL criteria:

TN: 9/13 (69%) R/R: 38/49 (78%)

• Combined ORR + (PR-L) in TN (84%) and R/R (88%)Censored

Ibrutinib Pivotal Study Schema:PCYC-1112

Patients will be randomized 1:1 to either arm A or B

Treatment Arm A: Ofatumumab IV12 IV doses over 24 weeks or until PD

Week 1: 300 mg initial doseWeek 2 through 8: 2,000 mg (once weekly)Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)

Treatment Arm B: Ibrutinib PO420 mg (3 x 140mg) orally daily until PD

PI 3 Kinase d Signaling in B Cells

Lannutti, B. Blood, 2011

BCR

PI3KDelta

CD40

STAT

T308 S473AKT

JAKTRAF6

NF-kpathway

JAK

mTOR

BTK

PLC2

PKC GSK-3

LYN

SYK LYN/SYK

T-cell Signalingstimulus

gp130 gp130

STAT BTK

PLC2

p70s6k elf4E

B-cell membraneCXCR4/5BAFFR

Stromal cell

IL-6R

CXCL12/13BAFFIL-6

Idelalisib: Specific Inhibitor of p110d

Tyrosine Phosphorylation

PI3K Isoforms

Expression Broad Broad Leukocytes Leukocytes

Gene KO effect Lethal Lethal Benign Benign

Physiological role Insulin signalingAngiogenesis unknown

B-cell signaling, development & survival

Neutrophil, T-cell development

IC50 (nM) 2154 427 8 182

Phase I Study of Idelalisib in Patients with Hematologic Malignancies

Idelalisib 50 mg to 350 mg BIDContinuous oral dosing (28-day cycles)

48 weeks

Endpoints:• Phase 2 dose• Safety• Pharmacodynamics• Pharmacokinetics• Antitumor activity

Previously treated hematologic malignancies:

CLL (N=54)iNHL (N=30)MCL (N=21)DLBCL (N=9)myeloma (N=12)AML (N=12)

CLL Patients Treated withIdelalisib 150 mg BID

Brown J. ASCO 2013

0

20

40

60

80

100

Res

pons

e R

ate

NodalResponse

39%

33%

81%72%

OverallResponse

Decrease by 50% of nodal SPD PR with lymphocytosis (Cheson 2012)PR by IWCLL criteria (Hallek 2008)

CLL Patients Treated withIdelalisib 150 mg BID

Brown J. ASCO 2013

ALCSPD

0 2 4 6 8 12 16 20 24 32 40 480

20

40

60

80

-80

-60

-40

-20

0

Time from Start of Idelalisib, Weeks

ALC,

Mea

n

SEM

, x10

9 /L

Change in SPD

from B

aselineM

ean SEM

, %

Single Agent Idelalisib in CLL

Brown J. ASCO 2013

Best On-Treatment Change in Tumor Size(ITT Analysis, N=55)

-100

-75

-25

0

-50*

+25

+50

+75

+100

Inevaluable (patients without a follow-up tumor assessment)Patients with del (17p)

* Criterion for response [Hallek 2008]

% C

hang

e in

Lym

ph N

ode

Area

Improvement in Baseline Cytopenias

Brown J. ASCO 2013

0 2 4 6 8 12 16 20 24 32 40 480 0

2

4

6

50

70

90

110

90

100

110

120

Hemoglobin (N=25)Platelet Count (N=34)

Time from Start of Idelalisib, Weeks

Hem

oglo

bin,

Mea

nSE

M, g

/LC

ell Nu m

ber, Mean

SEM, x 10

9/L

ANC (N=15)

Idelalisib in CLL

Brown J. ASCO 2013

PFS (N=54)

0

25

50

75

100

Time from Start of Idelalisib, Months

% P

rogr

essi

on-F

ree

0  6  12  18  24  30  36  42 

OS (N=54)

0

25

50

75

100

Time from Start of Idelalisib, Months

% S

urvi

ving

0  6  12  18  24  30  36  42 

Median PFS = 17.1 months Median OS not reached

Progression Free Survival Overall Survival

Adverse Events (> 15%) and Selected Lab Abnormalities (N=54)

Brown J. ASCO 2013

AE, n (%) Any Grade (%) Grade 3 (%)

Fatigue 17 (32) 1 (2)Diarrhea 16 (30) 3 (6)Pyrexia 16 (30) 2 (4)Cough 13 (24) 2 (4)Back pain 12 (22) 0Rash 12 (22) 0URI 12 (22) 0Pneumonia 11 (20) 10 (19)Night sweats 10 (19) 0Chills 9 (17) 0

Laboratory abnormality, n (%)AST, increased* 13 (24) 1 (2)ALT, increased* 10 (19) 1 (2)*15 subjects total with transaminase elevations

Idelalisib +

Coutre S. ASH 2012, Abs 191

0

20

40

60

80

100

90%79% 78% 78%

87% 87%

LNR = Nodal ResponseOR = Response by IWCLL criteria (Hallek 2008)

Res

pons

e R

ate

95

% C

I

LNR OR LNR OR

+R +B +BR

LNR OR

Idelalisib Pivotal Study Schema:GS-US-312-0116

IPI-145

IPI-145: Potent Inhibitor of PI3K-d and

PI3K Isoform PI3K-δ PI3K-

Expression Primarily Leukocytes

Primarily Leukocytes

Biochemical Activity (KD) 23 pM 243 pM

Whole Blood Assay (IC50)

96 nMAnti-FcƐR1

1028 nM fMLP

• Potent oral inhibitor of both PI3K-δ and PI3K-γ • Selective for PI3Ks over other protein and lipid kinases• Inhibits malignant B and T cell survival‐ ‐

– Affects tumor cells directly – Disrupts tumor cell interactions within the

microenvironmentPatel et al ASCO 2013

O

N

Cl

NHN

N

HNN

Complete Inhibition of PI3K-d and >50% Inhibition of at Doses > 25 mg BID

Patel. ASCO 2013.

IPI-145: Clinical Response

Patel, et al. ASCO 2013

Population

Best Observed Response (n) Median Time to IWCLL Response

(range)Pts (n) CR PR nPR SD PD

Overall CLL 22 0 12 7 2 1 1.9 (1.8, 5.6)

≤ 25 mg BID 19 0 10 7 1 1 2.9 (1.8, 5.6)

CD38+ 5 0 2 3 0 0 5.5 (5.5, 5.6) 17p del 4 0 2 0 1 1 1.9 (1.8, 1.9) TP53 mut 6 0 4 2 0 0 2.9 (1.8, 4.7) 75 mg BID 3 0 2 0 1 0 1.8 (1.8, 1.9)

PR + Nodal R = 19/22 (86%)