1. 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

2. 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;63:11-30. 2. NCCN. Clinical practice guidelines in oncology: non- Hodgkin’s lymphoma. v.1.2013. 3. SEER. Stat fact sheets: non-Hodgkin’s lymphoma. 2012. 4. Stebbing J, et al. J Clin Oncol. 2004;22:2177-2183.

3. 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

4. clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Risk GroupFactors, nPatient Distribution, % 5-Yr OS, % 10-Yr OS, % Low0-1369171 Intermediate2377851 High≥ 3275336 Follicular Lymphoma International Prognostic (FLIPI) Index 6. Solal-Céligny P, et al. Blood. 2004;104:1258-1265.

5. 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

6. 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> 101 8. Vakkalanka S, et al. ASH 2012. Abstract 2610. 9. Lannutti BJ, et al. Blood. 2011;117:591-594. 10. DiNitto J, et al. Keystone Symposium 2013. Abstract 1032.

7. 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 2011. Abstract 1787. 12. Hallek M, et al. Blood. 2008;112:5446-5456. Best on Treatment Change in Tumor Size [11] (ITT Analysis, N = 55) % Change in Lymph Node Area 100 75 50 25 0 -25 -50* -75 -100 Unevaluable (patients without a follow-up tumor assessment) Patients with del(17p) *Criterion for response. [12]

8. 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 2011. Abstract 1787. 14. Hallek M, et al. Blood. 2008;111:5446-5456. -100 -75 -25 0 -50 25 50 75 100

9. clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies 15. de Vos S, et al. ASH 2011. Abstract 2699. 16. Cheson BD, et al. J Clin Oncol. 2007;25:579-586. 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 -100 -75 -25 0 -50 25 50 75 100 a 2007 criteria for lymphoma response Unevaluable (patients without a follow-up tumor assessment)

10. 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 2012. Abstract 3663. mg BID Best Percent Change in Tumor Mass to Date 80 60 40 20 0 -20 -40 -60 -80 -100 257550607560 3550351525 501525 8 1525 15 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)

11. 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 2012. Abstract 3663.

12. clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies 21. Flinn IW, et al. ASH 2012. Abstract 3663. 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) 0 20 40 60 80 -80 -60 -40 -20 0 Blood lymphocyte count Lymph node area Cycle (28 Days) (N ALC, N Lymph Nodes) Mean SPD Change ± SEM (%) Mean ALC ± SEM (K/mL)

13. 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 NCT01476657 Advanced Heme200IPI-145Safety NCT01767766 Relapsed/refractory NHL, CLL, PTCL 60TGR 1202MTD NCT01644799 Relapsed FL30 Idelalisib + R-Len MTD NCT01732926 Relapsed iNHL450Idelalisib + BR vs BRPFS NCT01796470 Relapsed/refractory B- cell Lymphomas 200GS-9973 + idelalisibPFS NCT01539512 Relapsed CLL160 Idelalisib + R vs placebo + R PFS NCT01659021 Relapsed CLL210 Idelalisib + ofatumumab vs ofatumumab PFS 22-28. ClinicalTrials.gov.

14. 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;117:6287-6296. 30. Davis RE, et al. Nature. 2010;463:88-92.

15. 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;107:13075-13080. 32. Advani R, et al. J Clin Oncol. 2013;31:88-94. 33. Herman SE, et al, Blood. 2011;117:6287-6296. 34. Ponader S, et al. Blood. 2012;119:1182-21189. 35. de Rooij MF, et al. Blood. 2012;119:2590-2594. N N N N N O NH 2 O

16. 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 2010 - July 2011 36. Byrd JC, et al. ASH 2012. 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.

17. 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 4 37. Byrd JC, et al. ASH 2012. Abstract 189. 0%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

18. 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 2012. 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 68 10 58 71 2 68 PR with lymphocytosis1318 SD134 PD02

19. 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 2012. Abstract 189. Naive (n = 31) Relapsed/refractory (n = 85) + Censored 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 PFS Probability Mos on Study 024246810141618202212 Relasped del(17p): no (n = 52) Relasped del(17p): yes (n = 28) + Censored 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 PFS Probability Mos on Study 024246810141618202212

20. clinicaloptions.com/oncology Agents Targeting Novel B-Cell Pathways in Hematologic Malignancies Pattern of Response: Blood Lymphocytes vs Lymph Nodes 012 3 4 5 6 7 8 91011 550 450 350 250 150 50 -50 ALC Mo Mean Percent Change from Baseline 012 3 4 5 6 7 8 91011 25 0 -25 -50 -75 -100 SPD Mo 40. Byrd JC, et al. ASH 2012. Abstract 189.

21. 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;115:2578-2585.

22. 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;115:2578-2585.

23. 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 NCT01779791 Refractory FL110IbrutinibORR NCT01569750 CD20+ B-cell NHL33Ibrutinib + R-CHOPMTD NCT01599949 MCL post- bortezomib 110IbrutinibORR NCT01479842 Relapsed DLBCL, MCL, iNHL 48Ibrutinib + BRMTD NCT01614821 WM33IbrutinibORR NCT01796470 Relapsed/refractory B-cell lymphomas 200GS-9973 + idelalisibPFS NCT01499303 DLBCL60FostamatinibORR 44-50. ClinicalTrials.gov.

24. 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

25. 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