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Primer on Kinase Inhibitors

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.

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Primer on Kinase Inhibitors

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  1. Primer on Kinase Inhibitors Richard R. Furman Directory, CLL Research Center Weill Cornell Medical College / New York Presbyterian Hospital

  2. BCR-associated Kinases:Proven Effective Therapeutic Targets • Syk (spleen tyrosine kinase): R406, PRT062070 • Btk (Bruton’styrosine kinase): ibrutinib, CC-292, ACP-196 • PI3K (phosphatidyl 3-kinase: idelalisib(GS-1101), IPI-145 Nat Rev Immunol 2:945

  3. Targeting the “BCR++” Antigen Pathway:

  4. 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

  5. Issues with Novel Agents Need to revise Response Criteria Dosing: • No more MTD dosing • Threshold dosing • Fixed dosing / wide therapeutic window Differences

  6. Issues with Novel Agents Need to revise Response Criteria Dosing: • No more MTD dosing • Threshold dosing • Fixed dosing / wide therapeutic window Differences

  7. Lymphocytosis + Nodal Reductionwith BCR Antagonists

  8. 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.

  9. Cheson 2012: Recommendations For IMID compounds: Assessment of PD should use repeat observations and incorporate indicators of PD not associated with tumor flares 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 Lymphocytosis is distinct from tumor flare

  10. Issues with Novel Agents Need to revise Response Criteria Dosing: • No more MTD dosing • Threshold dosing • Fixed dosing / wide therapeutic window Differences

  11. Idelalisib Doses >150 mg BID Associated with Longer PFS PFS -- By IdelalisibDosing Regimen 100 75 % Progression-Free 50 25 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Cycles (28 days) 150-350 mg BID: 18 cycles (39) 50-100 mg BID: 5 cycles (16)

  12. Issues with Novel Agents Need to revise Response Criteria Dosing: • No more MTD dosing • Threshold dosing • Fixed dosing / wide therapeutic window Differences

  13. IC50 Values of PCI-32765 and Related Kinases

  14. 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

  15. Ibrutinib: Inhibitor of Bruton’s Tyrosine Kinase • 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 O NH 2 N N N N N O

  16. Ibrutinib in CLL: PCYC-1102 Furman RR. iWCLL 2013

  17. PCYC-1102: Patient Demographics Furman RR. iWCLL 2013

  18. PCYC-1102: Patient Disposition aCryptococcal pneumonia b7 patients (1 TN and 6 R/R) had disease progression with Richter’s transformation Furman RR. iWCLL 2013

  19. 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

  20. 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

  21. PI 3 Kinase d Signaling in B Cells Stromal cell T-cell Signaling stimulus IL-6 BAFF CXCL12/13 BCR IL-6R CD40 CXCR4/5 B-cell membrane BAFFR LYN gp130 gp130 JAK TRAF6 JAK SYK  LYN/SYK   PI3K Delta STAT STAT BTK BTK PLC2 PLC2 AKT T308 S473 NF-k pathway PKC GSK-3 mTOR p70s6k elf4E Lannutti, B. Blood, 2011

  22. Idelalisib: Specific Inhibitor of p110d Tyrosine Phosphorylation

  23. Phase I Study of Idelalisib in Patients with Hematologic Malignancies Idelalisib 50 mg to 350 mg BID Continuous oral dosing (28-day cycles) Previously treated hematologic malignancies: 48 weeks CLL (N=54) iNHL (N=30) MCL (N=21) DLBCL (N=9) myeloma (N=12) AML (N=12) • Endpoints: • Phase 2 dose • Safety • Pharmacodynamics • Pharmacokinetics • Antitumor activity

  24. CLL Patients Treated withIdelalisib 150 mg BID 81% Response Rate 72% Decrease by 50% of nodal SPD PR with lymphocytosis (Cheson 2012) PR by IWCLL criteria (Hallek 2008) 33% 39% Nodal Response Overall Response Brown J. ASCO 2013

  25. CLL Patients Treated withIdelalisib 150 mg BID ALC SPD Brown J. ASCO 2013

  26. Single Agent Idelalisib in CLL Brown J. ASCO 2013

  27. Improvement in Baseline Cytopenias Brown J. ASCO 2013

  28. Idelalisib in CLL Progression Free Survival Overall Survival Median PFS = 17.1 months Median OS not reached Brown J. ASCO 2013

  29. Adverse Events (> 15%) and Selected Lab Abnormalities (N=54) Brown J. ASCO 2013

  30. Idelalisib + +B +BR +R Response Rate 95% CI LNR OR LNR OR LNR OR LNR = Nodal Response OR = Response by IWCLL criteria (Hallek 2008) CoutreS. ASH 2012, Abs 191

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

  32. IPI-145: Potent Inhibitor of PI3K-d and g • 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

  33. Complete Inhibition of PI3K-d and >50% Inhibition of g at Doses > 25 mg BID Patel. ASCO 2013.

  34. IPI-145: Clinical Response Patel, et al. ASCO 2013

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