Transcript of Primer on Kinase Inhibitors Richard R. Furman Directory, CLL Research Center Weill Cornell Medical...
- Slide 1
- Primer on Kinase Inhibitors Richard R. Furman Directory, CLL
Research Center Weill Cornell Medical College / New York
Presbyterian Hospital
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- BCR-associated Kinases: Proven Effective Therapeutic Targets
Nat Rev Immunol 2:945 Syk (spleen tyrosine kinase): R406, PRT062070
Btk (Brutons tyrosine kinase): ibrutinib, CC-292, ACP-196 PI3K
(phosphatidyl 3-kinase: idelalisib(GS-1101), IPI-145
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- Targeting the BCR++ Antigen Pathway:
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- 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
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- Issues with Novel Agents Need to revise Response Criteria
Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide
therapeutic window Differences
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- Issues with Novel Agents Need to revise Response Criteria
Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide
therapeutic window Differences
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- Lymphocytosis + Nodal Reduction with BCR Antagonists
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- Redefining Clinical End Points Cheson 2012 Standard response
criteria: measure of treatment efficacy For novel agents, response
criteria dont 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.
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- 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
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- Issues with Novel Agents Need to revise Response Criteria
Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide
therapeutic window Differences
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- Idelalisib Doses >150 mg BID Associated with Longer PFS PFS
-- By Idelalisib Dosing Regimen 50-100 mg BID: 5 cycles (16)
150-350 mg BID: 18 cycles (39) Cycles (28 days) %
Progression-Free
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- Issues with Novel Agents Need to revise Response Criteria
Dosing: No more MTD dosing Threshold dosing Fixed dosing / wide
therapeutic window Differences
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- Kinase PCI-32765 IC 50 (nM) Kinase PCI-32765 IC 50 (nM)
Btk0.46FGR2.31 Ikt10.70Fyn95.55 Bmx/Etk0.76HCK3.67
TEC77.76Lyn200.45 EGFR5.55ABL86.12 JAK316.13Brk3.34
BLK0.52JAK2>10,000 LCK33.24SYK>10,000 IC50 Values of
PCI-32765 and Related Kinases
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- Brutons Tyrosine Kinase (Btk) B-cell antigen receptor (BCR)
signaling required for B cell survival Brutons Tyrosine Kinase
(Btk) is an essential element of the BCR signaling pathway
Inhibitors of Btk block BCR signaling and induces apoptosis
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- Ibrutinib: Inhibitor of Brutons Tyrosine Kinase Forms an
irreversible bond with cysteine-481 in Btk Potent Btk inhibition IC
50 =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 N N NH 2 O N O
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- Ibrutinib in CLL: PCYC-1102 Furman RR. iWCLL 2013
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- PCYC-1102: Patient Demographics Furman RR. iWCLL 2013
Characteristic TN 65 Years n = 31 R/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)
2 M > 3.0 mg/L, n (%)8 (26)39 (46) Rai stage III/IV, n (%) 17
(55) 52 (61) Prognostic markers, n (%) IgV H unmutated del(17p)+
del(11q)+ 15 (48) 2 (6) 1 (3) 65 (76) 29 (34)
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- PCYC-1102: Patient Disposition Furman RR. iWCLL 2013 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 2 (6) 1 (3) 0 10 (12) 1 (1) 1
(1) a Disease progression b 1 (3)10 (12) SCT (while in response)
Investigator decision (not SCT) Patient decision Lost to Follow-up
0 2 (6) 0 4 (5) 3 (4) 1 (1) a Cryptococcal pneumonia b 7 patients
(1 TN and 6 R/R) had disease progression with Richters
transformation
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- 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%)
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- 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
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- PI 3 Kinase Signaling in B Cells Lannutti, B. Blood, 2011 BCR
PI3K Delta CD40 STAT T308S473 AKT JAK TRAF6 NF-k pathway JAK mTOR
BTK PLC 2 PKC GSK-3 LYN SYK LYN/SYK T-cell Signalingstimulus gp130
STAT BTK PLC 2 p70s6k elf4E B-cell membrane CXCR4/5 BAFFR Stromal
cell IL-6R CXCL12/13 BAFF IL-6
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- Idelalisib: Specific Inhibitor of p110 Tyrosine Phosphorylation
PI3K Isoforms ExpressionBroad Leukocytes Gene KO effectLethal
Benign Physiological role Insulin signaling Angiogenesis unknown
B-cell signaling, development & survival Neutrophil, T-cell
development IC50 (nM)21544278182
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- Phase I Study of Idelalisib in Patients with Hematologic
Malignancies Idelalisib 50 mg to 350 mg BID Continuous 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)
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- CLL Patients Treated with Idelalisib 150 mg BID Brown J. ASCO
2013 Response Rate Nodal Response 39% 33% 81% 72% Overall Response
Decrease by 50% of nodal SPD PR with lymphocytosis (Cheson 2012) PR
by IWCLL criteria (Hallek 2008)
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- CLL Patients Treated with Idelalisib 150 mg BID Brown J. ASCO
2013 ALC SPD
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- Single Agent Idelalisib in CLL Brown J. ASCO 2013
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- Improvement in Baseline Cytopenias Brown J. ASCO 2013
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- Idelalisib in CLL Brown J. ASCO 2013 Median PFS = 17.1
monthsMedian OS not reached Progression Free SurvivalOverall
Survival
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- Adverse Events (> 15%) and Selected Lab Abnormalities (N=54)
Brown J. ASCO 2013 AE, n (%)Any Grade (%) Grade 3 (%) Fatigue17
(32)1 (2) Diarrhea16 (30)3 (6) Pyrexia16 (30)2 (4) Cough13 (24)2
(4) Back pain12 (22)0 Rash12 (22)0 URI12 (22)0 Pneumonia11 (20)10
(19) Night sweats10 (19)0 Chills 9 (17)0 Laboratory abnormality, n
(%) AST, increased*13 (24)1 (2) ALT, increased*10 (19)1 (2) *15
subjects total with transaminase elevations
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- Idelalisib + Coutre S. ASH 2012, Abs 191 LNR = Nodal Response
OR = Response by IWCLL criteria (Hallek 2008) Response Rate 95% CI
LNRORLNROR +R +B +BR LNROR
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- Idelalisib Pivotal Study Schema: GS-US-312-0116
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- IPI-145 IPI-145: Potent Inhibitor of PI3K- and Potent oral
inhibitor of both PI3K- and PI3K- Selective for PI3Ks over other
protein and lipid kinases Inhibits malignant B and Tcell survival
Affects tumor cells directly Disrupts tumor cell interactions
within the microenvironment Patel et al ASCO 2013
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- Complete Inhibition of PI3K- and >50% Inhibition of at Doses
> 25 mg BID Patel. ASCO 2013.
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- IPI-145: Clinical Response Patel, et al. ASCO 2013