primer on kinase inhibitors
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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. - PowerPoint PPT PresentationTRANSCRIPT
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%)