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 Nat Rev Immunol 2:945 Syk (spleen tyrosine kinase): R406, PRT 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 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 mg BID: 5 cycles (16) mg BID: 18 cycles (39) Cycles (28 days) % Progression-Free

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

Kinase PCI IC 50 (nM) Kinase PCI IC 50 (nM) Btk0.46FGR2.31 Ikt10.70Fyn95.55 Bmx/Etk0.76HCK3.67 TEC77.76Lyn EGFR5.55ABL86.12 JAK316.13Brk3.34 BLK0.52JAK2>10,000 LCK33.24SYK>10,000 IC50 Values of PCI 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 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

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

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) β 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)

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 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%)

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  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

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)

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)

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)

CLL Patients Treated with Idelalisib 150 mg BID Brown J. ASCO 2013 ALC SPD

Single Agent Idelalisib in CLL Brown J. ASCO 2013

Improvement in Baseline Cytopenias Brown J. ASCO 2013

Idelalisib in CLL Brown J. ASCO 2013 Median PFS = 17.1 monthsMedian OS not reached Progression Free SurvivalOverall Survival

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

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

Idelalisib Pivotal Study Schema: GS-US

IPI-145 IPI-145: Potent Inhibitor of PI3K-  and  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

Complete Inhibition of PI3K-  and >50% Inhibition of  at Doses > 25 mg BID Patel. ASCO 2013.

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