Primer on Kinase Inhibitors

Report
Primer on Kinase Inhibitors
Richard R. Furman
Directory, CLL Research Center
Weill Cornell Medical College /
New York Presbyterian Hospital
BCR-associated Kinases:
Proven Effective Therapeutic Targets
• 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
Nat Rev Immunol 2:945
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 Reduction
with 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
% Progression-Free
100
75
50
25
0
0
2
4
6
8
10
12
14
16
Cycles (28 days)
150-350 mg BID: 18 cycles (39)
50-100 mg BID: 5 cycles (16)
18
20
22
24
Issues with Novel Agents
• Need to revise Response Criteria
• Dosing:
– No more MTD dosing
– Threshold dosing
– Fixed dosing / wide therapeutic window
• Differences
IC50 Values of PCI-32765 and Related Kinases
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
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
•
O
•
NH 2
N
•
•
N
N
N
N
O
•
•
Forms an irreversible bond with
cysteine-481 in Btk
Potent Btk inhibition
IC50=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
Ibrutinib in CLL: PCYC-1102
Furman RR. iWCLL 2013
PCYC-1102: Patient Demographics
Characteristic
Median age, years (range)
≥ 70 years, n (%)
Male, n (%)
Female, n (%)
Prior Therapies, n (%)
<3
>3
TN ≥ 65 Years
n = 31
R/R
n = 85
71 (65, 84)
23 (74)
66 (37, 82)
30 (35)
19 (61)
12 (39)
65 (76)
20 (24)
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)
Furman RR. iWCLL 2013
PCYC-1102: Patient Disposition
TN ≥ 65 Years
n = 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
Disease progressionb
2 (6)
1 (3)
0
1 (3)
10 (12)
1 (1)
1 (1)a
10 (12)
0
0
2 (6)
0
4 (5)
4 (5)
3 (4)
1 (1)
SCT (while in response)
Investigator decision (not SCT)
Patient decision
Lost to Follow-up
aCryptococcal
b7
pneumonia
patients (1 TN and 6 R/R) had disease progression with Richter’s transformation
Furman RR. iWCLL 2013
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%)
Ibrutinib Pivotal Study Schema:
PCYC-1112
Patients will be randomized 1:1 to either arm A or B
Treatment Arm A: Ofatumumab IV
12 IV doses over 24 weeks or until PD
Week 1: 300 mg initial dose
Week 2 through 8: 2,000 mg (once weekly)
Week 12, 16, 20 and 24: 2,000 mg (every 4 weeks)
Treatment Arm B: Ibrutinib PO
420 mg (3 x 140mg) orally daily until PD
PI 3 Kinase d Signaling in B Cells
Stromal cell
T-cell
Signaling
stimulus
IL-6 BAFF
IL-6R
BCR
CD40
BAFFR
B-cell membrane
LYN
JAK
TRAF6
CXCL12/13
CXCR4/5
gp130
gp130
JAK
SYK
LYN/SYK
STAT
PI3K
Delta
BTK
PLC2
PKC
T308 AKT
STAT

BTK
PLC2
S473
NF-k
pathway
GSK-3
mTOR
p70s6k
elf4E
Lannutti, B. Blood, 2011

Idelalisib: Specific Inhibitor of p110d
Tyrosine Phosphorylation
PI3K Isoforms
Expression
Broad
Broad
Leukocytes
Leukocytes
Gene KO effect
Lethal
Lethal
Benign
Benign
Insulin signaling
Angiogenesis
unknown
B-cell signaling,
development &
survival
2154
427
8
Physiological role
IC50 (nM)
Neutrophil,
T-cell
development
182
Phase I Study of Idelalisib in Patients with
Hematologic Malignancies
Previously treated
hematologic
malignancies:
CLL (N=54)
iNHL (N=30)
MCL (N=21)
DLBCL (N=9)
myeloma (N=12)
AML (N=12)
Idelalisib 50 mg to 350 mg BID
Continuous oral dosing (28-day cycles)
48 weeks
Endpoints:
• Phase 2 dose
• Safety
• Pharmacodynamics
• Pharmacokinetics
• Antitumor activity
CLL Patients Treated with
Idelalisib 150 mg BID
100
81%
72%
Decrease by 50% of nodal SPD
PR with lymphocytosis (Cheson 2012)
PR by IWCLL criteria (Hallek 2008)
Response Rate
80
60
33%
40
20
39%
0
Nodal
Overall
Response Response
Brown J. ASCO 2013
0
60
-2 0
40
-4 0
20
-6 0
9
80
-8 0
0 2 4 6 8
12 16 20 24
32
40
M ean  SEM , %
0
C h a n g e in S P D f r o m B a s e lin e
A LC, M ean  SEM , x10 / L
CLL Patients Treated with
Idelalisib 150 mg BID
ALC
SPD
48
T im e f r o m S t a r t o f Id e la lis ib , W e e k s
Brown J. ASCO 2013
Single Agent Idelalisib in CLL
Best On-Treatment Change in Tumor Size
(ITT Analysis, N=55)
+100
% Change in Lymph Node Area
+75
+50
+25
0
-25
-50*
-75
-100
Inevaluable (patients without a follow-up tumor assessment)
Patients with del (17p)
* Criterion for response [Hallek 2008]
Brown J. ASCO 2013
120
110
110
90
70
100
P la te le t C o u n t ( N = 3 4 )
H e m o g lo b in ( N = 2 5 )
50
90
6
A N C (N = 1 5 )
4
2
0
0
2
4
6
8
12
16
20
24
32
40
48
9
0
C e ll N u m b e r , M e a n  S E M , x 1 0 /L
H e m o g lo b in , M e a n  S E M , g /L
Improvement in Baseline Cytopenias
T im e f r o m S t a r t o f Id e la lis ib , W e e k s
Brown J. ASCO 2013
Idelalisib in CLL
Progression Free Survival
Overall Survival
P F S (N = 5 4 )
O S (N = 5 4 )
100
75
% S u r v iv in g
% P r o g r e s s io n - F r e e
100
50
25
75
50
25
0
0
0
6
12
18
24
30
36
42
0
6
12
18
24
30
36
42
T im e f r o m S t a r t o f Id e la lis ib , M o n t h s
T im e f r o m S t a r t o f Id e la lis ib , M o n t h s
Median PFS = 17.1 months
Median OS not reached
Brown J. ASCO 2013
Adverse Events (> 15%) and
Selected Lab Abnormalities (N=54)
AE, n (%)
Any Grade (%) Grade  3 (%)
Fatigue
Diarrhea
Pyrexia
Cough
Back pain
Rash
URI
Pneumonia
Night sweats
Chills
17 (32)
16 (30)
16 (30)
13 (24)
12 (22)
12 (22)
12 (22)
11 (20)
10 (19)
9 (17)
1 (2)
3 (6)
2 (4)
2 (4)
0
0
0
10 (19)
0
0
13 (24)
10 (19)
1 (2)
1 (2)
Laboratory abnormality, n (%)
AST, increased*
ALT, increased*
*15 subjects total with transaminase elevations
Brown J. ASCO 2013
Idelalisib +
+B
Response Rate 95% CI
+R
+BR
100
80
90%
79%
78%
78%
OR
LNR
OR
87%
87%
LNR
OR
60
40
20
0
LNR
LNR = Nodal Response
OR = Response by IWCLL criteria (Hallek 2008)
Coutre S. ASH 2012, Abs 191
Idelalisib Pivotal Study Schema:
GS-US-312-0116
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 nM
Anti-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
microenvironment
Patel et al ASCO 2013
IPI-145
Complete Inhibition of PI3K-d and >50% Inhibition of
 at Doses > 25 mg BID
Patel. ASCO 2013.
IPI-145: Clinical Response
Best Observed Response (n)
CR
PR
nPR
SD
PD
Population
Pts
(n)
Median Time
to IWCLL
Response
(range)
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)
3
0
2
0
1
0
1.8 (1.8, 1.9)
75 mg BID
PR + Nodal R = 19/22 (86%)
Patel, et al. ASCO 2013

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