Research Focus: Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies This program is supported by an educational grant from Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC Image: 3D4Medical/Copyright©2013 Phototake All Rights Reserved

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Non-Hodgkin’s Lymphoma Epidemiology  NHL is a leading form of new cancer among US men and women with B-cell lymphomas accounting for 80% to 85% of cases [1,2] –Estimated > 69,000 new diagnoses expected in the US in 2013 –Estimated > 19,000 deaths expected in the US in 2013  Incidence rose dramatically from 1970 to the mid-1990s [2]  Incidence rates between 1991 and 2009 have begun to stabilize [3] –Potentially due to decline in AIDS-related NHL (HIV RR: 100) [4]  Probability of developing NHL is higher in men than women and in white patients compared with black patients [1] 1. Siegel R, et al. CA Cancer J Clin. 2013;63: NCCN. Clinical practice guidelines in oncology: non- Hodgkin’s lymphoma. v SEER. Stat fact sheets: non-Hodgkin’s lymphoma Stebbing J, et al. J Clin Oncol. 2004;22:

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Overview of Current Therapy Options for B-Cell Malignancies  Chemoimmunotherapy combinations: –Multidrug regimens: R-CHOP, R-CVP, R-ESHAP, FCR, etc –Bendamustine + R –Lenalidomide + R  Single-agent immunotherapy: rituximab, ofatumomab  Proteosome inhibitor–based therapy: bortezomib + CT  Radiation  Radioimmunotherapy: ibritumomab tiuxetan, tositumomab  Autologous and allogeneic hematopoietic SCT

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Risk GroupFactors, nPatient Distribution, % 5-Yr OS, % 10-Yr OS, % Low Intermediate High≥ Follicular Lymphoma International Prognostic (FLIPI) Index 6. Solal-Céligny P, et al. Blood. 2004;104:

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies LYN SYK BCR BTK PLCγ2 PKC PI3K Delta AKT mTOR p70s6kelf4E GSK-3 NF-kβ Pathway Critical Signaling Pathways and New Targeted Agents in B-Cell Malignancies  B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation  BCR signaling up- regulated in B-cell malignancies  New inhibitors are targeting multiple components of BCR signaling including PI3K delta, BTK, and Syk Ibrutinib AVL-292 ┬ ┬ Idelalisib IPI-145 TGR-1202 ┬ Fostamatinib GS-9973

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies PI3K-δ Inhibitors Currently in Development TGR-1202 Idelalisib (CAL-101, GS-1101) IPI-145 Selectivity, Fold Change Isoform αβγδ TGR-1202 [8] > 10000> 50> 481 Idelalisib [9] > 300> 200> 351 IPI-145 [10] > 1000> 60> Vakkalanka S, et al. ASH Abstract Lannutti BJ, et al. Blood. 2011;117: DiNitto J, et al. Keystone Symposium Abstract 1032.

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Idelalisib Results in CLL Tumor Shrinkage Including Those With del(17p) 11. Sharman J, et al. ASH Abstract Hallek M, et al. Blood. 2008;112: Best on Treatment Change in Tumor Size [11] (ITT Analysis, N = 55) % Change in Lymph Node Area * Unevaluable (patients without a follow-up tumor assessment) Patients with del(17p) *Criterion for response. [12]

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Idelalisib Shows Nodal Activity as Mono- or Combination Therapy in CLL % Change in Lymph Node Area Best On-Treatment Change in Tumor Size (ITT Analysis) Unevaluable (patients without a follow-up tumor assessment) a IWCLL 2008 criteria for nodal response Mono (n = 55) I + R (n = 19) I + F (n = 7) I + B (n = 14) I + BR (n = 14) 13. Sharman J, et al. ASH Abstract Hallek M, et al. Blood. 2008;111:

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies 15. de Vos S, et al. ASH Abstract Cheson BD, et al. J Clin Oncol. 2007;25: Idelalisib Active as Mono- or Combination Therapy in Indolent NHL Single Agent (n = 59) Combination (n = 52) Best On-Treatment Change in Tumor Size (ITT Analysis) % Change in Tumor Size a 2007 criteria for lymphoma response Unevaluable (patients without a follow-up tumor assessment)

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Early Clinical Activity of IPI-145 Across Dose Cohorts and Diseases  Reduction in tumor mass observed in all indications and all dose levels –Measurable disease between CT scan and ≥ 1 on-treatment CT assessment are shown, including pts (n = 2) who have not had a response assessment –Pts off-study with PD before first CT (n = 2) or disease not assessed by CT (n = 4) not included 17. Flinn IW, et al. ASH Abstract mg BID Best Percent Change in Tumor Mass to Date Cancer Diagnosis T-cell lymphoma (n = 7) HL (n = 2) aNHL (n = 2) CR by PET (n = 3) MCL (n = 3) iNHL (n = 11) CLL/SLL (n = 10) Off study (n = 9)

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Toxicities Associated With PI3K-δ Inhibitors  Predominantly mild adverse events  Grade ≥ 3 toxicities include pneumonia, febrile neutropenia, myelosuppression, transaminase elevation, and diarrhea –Transaminase elevations resolved with holding of therapy and reinitiation at a reduced dose  No additional toxicities observed in combination with rituximab, bendamustine, or both 19. Byrd JC, et al. ASCO 2012 Educational Book. 20. Flinn IW, et al. ASH Abstract 3663.

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies 21. Flinn IW, et al. ASH Abstract Rapid Asymptomatic Lymphocyte Redistribution With Idelalisib Absolute Lymphocyte Count and Changes in Lymph Node 0 (52, 51)1 (52, 51)2 (51, 44)4 (38, 34)6 (32, 27)8 (31, 24) 10 (25, 18)12 (22, 20) Blood lymphocyte count Lymph node area Cycle (28 Days) (N ALC, N Lymph Nodes) Mean SPD Change ± SEM (%) Mean ALC ± SEM (K/mL)

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies PI3K-δ Inhibitors in B-Cell NHL: Key Ongoing Trials IdentifierSettingN (Planned)TherapyPrimary Endpoint NCT Advanced Heme200IPI-145Safety NCT Relapsed/refractory NHL, CLL, PTCL 60TGR 1202MTD NCT Relapsed FL30 Idelalisib + R-Len MTD NCT Relapsed iNHL450Idelalisib + BR vs BRPFS NCT Relapsed/refractory B- cell Lymphomas 200GS idelalisibPFS NCT Relapsed CLL160 Idelalisib + R vs placebo + R PFS NCT Relapsed CLL210 Idelalisib + ofatumumab vs ofatumumab PFS ClinicalTrials.gov.

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Bruton’s Tyrosine Kinase: A Critical Kinase for Lymphoma Growth, Survival  BCR signaling is required for tumor expansion and proliferation  BTK is an essential element of the BCR signaling pathway [28]  Inhibitors of BTK block BCR signaling and induce apoptosis [29]  Targeted inhibition of BTK is a novel approach for the treatment of B-cell malignancies LYN SYK BCR BTK PLCγ2 PKC PI3K Delta AKT mTOR p70s6kelf4E GSK-3 NF-kβ Pathway 29. Herman SEM, et al. Blood. 2011;117: Davis RE, et al. Nature. 2010;463:88-92.

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Ibrutinib (PCI-32765): A Selective Inhibitor of BTK  Forms a specific bond with cysteine-481 in BTK  Highly potent BTK inhibition at IC 50 = 0.5 nM [30]  Orally administered with once-daily dosing resulting in 24-hr target inhibition [31]  No cytotoxic effect on T cells or NK cells [32]  In CLL cells, promotes apoptosis and inhibits CLL cell migration and adhesion [33,34] 31. Honigberg LA, et al. Proc Natl Acad Sci U S A. 2010;107: Advani R, et al. J Clin Oncol. 2013;31: Herman SE, et al, Blood. 2011;117: Ponader S, et al. Blood. 2012;119: de Rooij MF, et al. Blood. 2012;119: N N N N N O NH 2 O

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Treatment Naive ≥ 65 yrs Ibrutinib 420 mg/day or 840 mg/day (n = 31) Relapsed/Refractory Ibrutinib 420 mg/day or 840 mg/day (n = 61) Patients with CLL/SLL treated with ibrutinib monotherapy* and ECOG PS ≤ 2 (N = 116) Enrolled May July Byrd JC, et al. ASH Abstract 189. PCYC-1102-CA: Single-Agent Ibrutinib in CLL/SLL  A multicohort phase Ib/II trial High-risk † Relapsed/Refractory Ibrutinib 420 mg/day (n = 24) 20.3 mos median follow-up 22.1 mos median follow-up 14.7 mos median follow-up *Patients with SLL not included in current analysis † Defined as progression of disease < 24 mos after initiation of a chemoimmunotherapy regimen or failure to respond.

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Single-Agent Ibrutinib in CLL Patients: Common All-Cause Adverse Events Treatment Naive (n = 31)R/R and High-Risk R/R (n = 85) Grade 3Grade 1Grade 2Grade Byrd JC, et al. ASH Abstract %20%40%60%80% Urinary tract Gastroreflux URI Vomiting Hypertension Constipation Arthralgia Peripheral Edema Dyspepsia Dizziness Rash Fatigue Nausea Diarrhea 0%20%40%60%80% Nausea Headache Dizziness Constipation Hypertension Sinusitis Muscle spasms Peripheral Edema Rash Pyrexia Arthralgia Cough Fatigue URI Diarrhea

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Single-Agent Ibrutinib in CLL Patients: Best Response  Single-agent ibrutinib active across CLL patient populations 38. Byrd JC, et al. ASH Abstract 189. Response or Survival Outcome, % Treatment-Naive Patients ≥ 65 Yrs of Age (n = 31) Relapsed/Refractory and High-Risk Relapsed/Refractory Patients (n = 85) ORR  CR  PR PR with lymphocytosis1318 SD134 PD02

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Single-Agent Ibrutinib in CLL Patients: Survival Outcomes  OS (estimated 26 mo): 96% vs 83% (treatment naive vs relapsed/refractory and high-risk relapsed/refractory; P =.0937) PFS by Previous TherapyPFS by del(17p) status 39. Byrd JC, et al. ASH Abstract 189. Naive (n = 31) Relapsed/refractory (n = 85) + Censored PFS Probability Mos on Study Relasped del(17p): no (n = 52) Relasped del(17p): yes (n = 28) + Censored PFS Probability Mos on Study

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Pattern of Response: Blood Lymphocytes vs Lymph Nodes ALC Mo Mean Percent Change from Baseline SPD Mo 40. Byrd JC, et al. ASH Abstract 189.

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Syk Is a Key Target in B-Cell Malignancies  Syk is overexpressed and activated in many NHL tumors including DLBCL and in CLL  Syk as a target has been extensively validated in preclinical models  Inhibitors of BCR signaling have demonstrated activity in early clinical trials LYN SYK BCR BTK PLCγ2 PKC PI3K Delta AKT mTOR p70s6kelf4E GSK-3 NF-kβ Pathway 41. Friedberg JW, et al. Blood. 2010;115:

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Fostamatinib in Relapsed/Refractory B- Cell NHL  Phase I cohort (N = 13) –MTD: 200 mg PO BID –DLT: neutropenia, thrombocytopenia, diarrhea  Phase II cohort (N = 68) –Toxicities (> 20%) included diarrhea, fatigue, cytopenias, HTN, nausea –ORR –DLBCL: 5/23 (22%) –FL: 2/21 (10%) –CLL/SLL: 6/11 (55%) –MCL: 1/9 (11%) –Median PFS: 4.2 mos 42. Friedberg JW, et al. Blood. 2010;115:

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies BTK Inhibitors and Syk Inhibitors in B-Cell NHL: Key Ongoing Trials IdentifierSettingN (Planned) TherapyPrimary Endpoint NCT Refractory FL110IbrutinibORR NCT CD20+ B-cell NHL33Ibrutinib + R-CHOPMTD NCT MCL post- bortezomib 110IbrutinibORR NCT Relapsed DLBCL, MCL, iNHL 48Ibrutinib + BRMTD NCT WM33IbrutinibORR NCT Relapsed/refractory B-cell lymphomas 200GS idelalisibPFS NCT DLBCL60FostamatinibORR ClinicalTrials.gov.

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Future Development of BCR Targets  Untested targets in the BCR pathway –NF-kB –JAK-STAT –Others  Combination trials using inhibitors targeting the BCR pathway as initial therapy  Duration of response  Long-term toxicities of inhibitors to PI3K-δ and BTK

clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Conclusion  Therapy for B-cell malignancies has improved since the development of rituximab with both refinement of immunotherapy and with combination of chemotherapy and antibody therapy  Despite advances in these therapies, long-term DFS is still significantly diminished for many patients  Antagonists of the BCR pathway have shown remarkable early activity in patients who have poor prognostic features and who are refractory to multiple lines of standard therapy  Further development of BCR pathway targets may lead to a change in the approach to patients with B-cell malignancies