New agents for recurrent FL

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1 Lymphoma and Myeloma 2015 Meeting New agents for recurrent FL Sven de Vos, MD, PhD Director, UCLA Lymphoma Program Los Angeles, CA

Indolent Lymphoma Percent Survival Year 60 mos 120 mos 1944-54 29.3 17.2 1955-64 41.5 23.2 1965-74 54.1 31.9 1975-84 63.

2 Indolent Lymphoma Percent Survival Year 60 mos 120 mos (Neelapu S. 60 Years of Survival Outcomes at the MDACC. Springer pp )

3 Survival Advantage in inhl (Fowler & Dunleavy; 2013 Dublin Summit on Immune Microenvironment)

4 Bcl-2 family of proteins (Mg and Davids, Clinical Advances in Hematology & Oncology 2014;12: )

Mechanism of Action of Venetoclax 1 An Increase in BCL-2 Expression Allows

Overexpressed BCL-2 Venetoclax 3 Apoptosis is Initiated Active Caspase

(BCL-2) BH3-only APAF-1 Cytochrome c Procaspase BAK BAX BCL-2 BCL-2

5 Mechanism of Action of Venetoclax 1 An Increase in BCL-2 Expression Allows the Cancer Cell to Survive 2 Venetoclax Binds to and Inhibits Overexpressed BCL-2 Venetoclax 3 Apoptosis is Initiated Active Caspase Apoptosome Pro-apoptotic Proteins (BAX, BAK) Anti-apoptotic Proteins (BCL-2) BH3-only APAF-1 Cytochrome c Procaspase BAK BAX BCL-2 BCL-2 Mitochondria Mitochondria Mitochondria BH3-only family member proteins include BIM, BAD, PUMA, and NOXA

$Phase I Study of ABT-199 in Patients with Relapsed/Refractory NHL RT = Richter s$

6 Phase I Study of ABT-199 in Patients with Relapsed/Refractory NHL RT = Richter s Transformation 27/50 (54%) of patients had 50% reduction in nodal size (Davids et al., EHA 2014 meeting)

7 Overall Reponses in ABT-199 Treated NHL Patients Histology Overall Response (CR + PR) Complete Response n (%) Partial Response n (%) Stable Disease n (%) Progressive Disease n (%) D/C Prior to Response n (%) Total evaluable (n=59) 48% 3 (5) 25 (42) 15 (26) 12 (20) 4 (7) MCL (n=19) 68% 1 (5) 12 (63) 4 (21) 1 (5) 1 (5) DLBCL (n=18) 28% 1 (6) 4 (22) 1 (6) 9 (50) 3 (5) FL (n=13) 31% 1 (8) 3 (23) 9 (69) - - WM (n=4) 75% - 3 (75) 1 (25) - - MZL (n=3) 67% - 2 (67) 1 (33) - MM (n=1) (100) - PMBCL (n=1) 100% - 1 (100) FL = All responses occurred at doses 600 (4/8 pts, 50%) DLBCL = 3 responses at 600 mg (1 RT), 2 responses at 400 mg (2 RT) MCL and WM responses observed across dose cohorts (Davids et al., EHA 2014 meeting)

$Phase 1 study of Venetoclax (ABT-199) plus BR in relapsed/refractory NHL: Dosing Schedule$ Cycles: B (90 mg/m 2 ) and R (375 mg/m 2 ) Venetoclax monotherapy a a Following completion

Cycles: B (90 mg/m 2 ) and R (375 mg/m 2 ) Venetoclax monotherapy a a Following completion

last patient) at the highest dose cleared in another phase 1 single agent venetoclax study

8 Phase 1 study of Venetoclax (ABT-199) plus BR in relapsed/refractory NHL: Dosing Schedule Patients were treated on a 28-day Cycle with 3 venetoclax schedules The BR regimen was 6 Cycles: B (90 mg/m 2 ) and R (375 mg/m 2 ) Venetoclax monotherapy a a Following completion of BR, patients could continue venetoclax monotherapy up to 2 years (after enrollment of last patient) at the highest dose cleared in another phase 1 single agent venetoclax study 1, with continued tolerability in the absence of disease progression (de Vos et al., ICML Lugano 2015)

9 Adverse Events (AEs) All Grade AEs (in 20% patients), n (%) Total N=35 Any AE 34 (97) Nausea 21 (60) Thrombocytopenia 18 (51) Anemia 16 (46) Diarrhea 16 (46) Hyperglycemia 15 (43) Neutropenia 15 (43) Lymphocyte count decreased 14 (37) Constipation 12 (34) Fatigue 12 (34) Hypokalemia 11 (31) Hypocalcemia 10 (29) Vomiting 10 (29) Headache 8 (23) Leukopenia 8 (23) Grade 3/4 AEs (in 3 patients), n (%) Total N=35 Any Grade 3/4 AE 27 (77) Lymphocyte count decreased 13 (34) Neutropenia 11 (31) Leukopenia 7 (20) Thrombocytopenia 7 (20) Anemia 6 (17) Serious Adverse Events (in 2 patients), n (%) Total N=35 Any SAE 13 (37) Febrile neutropenia 3 (9) Dyspnea 2 (6) Malignant neoplasm progression 2 (6) Syncope 2 (6) There were no SAEs of febrile neutropenia during monotherapy maintenance (de Vos et al., ICML Lugano 2015)

10 Most Patients Responded Prior to First Assessment Median time on study is 4.9 months (range: ) 50 mg (3/28d) 100 mg (3/28d) 100 mg (7/28d) 100 mg (28/28d) 200 mg (28/28d) 200 mg (7/28d) 400 mg (7/28d) 400 mg (28/28d) FL FL MZL FL FL MZL DLBCL DLBCL FL DLBCL DLBCL DLBCL FL FL DLBCL FL FL FL FL FL FL FL DLBCL MZL FL FL DLBCL FL DLBCL FL DLBCL FL FL DLBCL FL Active Time to first assessment Time on study, months As of April 2, 2015 CR PR PD Stable disease Discontinued without assessment

11 Preliminary Efficacy: Histology Subgroups Response, n (%) DLBCL n=11 Follicular Lymphoma n=21 Marginal Zone Lymphoma n=3 Objective response 5 (45) 15 (71) 3 (100) Complete response, CR 1 (9) 6 (29) 1 (33) Partial response, PR 4 (36) 9 (43) 2 (67) Stable disease, SD 2 (18) 2 (10) 0 (0) Progressive disease, PD 4 (36) 2 (10) 0 (0) Discontinued without assessment 0 (0) 2 (10) 0 (0) As of April 2, 2015 (de Vos et al., ICML Lugano 2015)

12 Best Percent Change from Baseline in Nodal Size DLBCL Follicular Lymphoma Marginal Zone B-Cell Lymphoma *n=3 did not have post-baseline tumor assessment (de Vos et al., ICML Lugano 2015)

13 Preliminary Biomarker Results Biomarker DLBCL (n=2) Follicular Lymphoma (n=6) Marginal Zone Lymphoma (n=3) Best Response PR PD CR CR CR CR PR PD CR PR PR Best % Change in Tumor Size Bcl-2 IHC Pos Neg Pos Pos Pos Neg Pos Pos Pos Pos Pos Bcl-XL IHC Neg Pos Pos Neg Pos Neg Neg Neg Pos Neg ND Mcl-1 IHC Neg Pos ND Neg Neg Pos Neg Neg Neg Neg ND c-myc IHC Pos Pos ND Neg Pos Neg Neg Neg Neg Neg ND t(14;18) FISH ND Pos ND ND Neg Pos Pos Pos BCL-2 Amp FISH c-myc trans FISH ND Neg ND ND Pos Neg Neg Neg ND Neg ND ND Neg Neg Neg Neg Cell of Origin ABC GCB Days on Venetoclax Bcl-2 family IHC: (Pos) 50% tumor cell staining 2+ intensity; Myc IHC: (Pos) 40% positive nuclear staining of any intensity; (ND) not determined; (GCB) Germinal Center B-cell-like; (ABC) Activated B-cell-like (de Vos et al., ICML Lugano 2015)

14 ABT Active Studies in Lymphoma Study (Phase) Patients Design N Active M (Ph 1) R/R NHL ABT BR 35 GO27878/CAVALLI (Ph 1/2 ) 1 st line DLBCL or B-cell NHL R/G-CHOP-ABT BO29337/CONTRALO (Ph 2) R/R FL Gr 1-3a RB vs RB-ABT-199 or R- ABT-199 ~150 (chemo-free)

, PNAS 2014;111 : 2349) Synergy between ABT-199 and ibrutinib or idelalisib primary WM cells

15 ABT-199 in vitro combination data Synergy between ABT-199 and ibrutinib in ABC DLBCL cell lines Cell viability Synergy between ABT-199 and ibrutinib in MCL cell lines Apoptosis (Griner et al., PNAS 2014;111 : 2349) Synergy between ABT-199 and ibrutinib or idelalisib primary WM cells Apoptosis (Zhao et al., British Journal of Haematology 2015;168:757) (Cao et al., Br J Haematol [Epub ahead of print])

16 ABT-199 Mechanisms of resistance in vitro model MCL-1 and BCL-XL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies (Choudhary et al., Cell Death and Disease (2015) 6, e1593; doi: /cddis )

17 Rationale for BCL-2 antagonist combinations Tipping the balance of pro-survival and pro-apoptotic BCL-2 family members Bcl-2 + PI3K inhibitor ABT IPI-145 (DLBCL, inhl, CLL) (David A. Fruman and Christian Rommel, Nature Reviews Drug Discovery 2014;13: )

18 Bcl-2 inhibitor combinations Chemo / Immuno thx BCR signaling Anti-CD20 R-Bendamustine R-CHOP DA-EPOCH-R BCR-inhibitors PI3K-inhibitors c-myc signaling Microenvironment Checkpoint inhibitors Lenalidomide Anti PD-1

19 PI3K-d and PI3K-g Inhibition May Have Complementary Effects on Malignant B-Cell Growth and Survival Inhibition of PI3K-g may block migration and/or differentiation of supportive T-cells and myeloid cells, eliminating key support cells within the tumor microenvironment (Peluso et al., ASH 2014)

$Idelalisib: Selective PI3K Inhibitor Phase II in Refractory inhl Long Term follow-up Ritux + Alkylator Refractory Indolent NHL Single-Arm Study$ thereafter Evaluated by Independent Review Committee 2 radiologists with adjudication if needed clinical review Primary endpoint: Overall

thereafter Evaluated by Independent Review Committee 2 radiologists with adjudication if needed clinical review Primary endpoint: Overall

20 Idelalisib: Selective PI3K Inhibitor Phase II in Refractory inhl Long Term follow-up Ritux + Alkylator Refractory Indolent NHL Single-Arm Study (N=125) Idelalisib 150 mg BID continuously Therapy maintained until progression Tumor assessments: Weeks 0, 8, 16, 24, 36, 48 Every 12 weeks thereafter Evaluated by Independent Review Committee 2 radiologists with adjudication if needed clinical review Primary endpoint: Overall Response Rate (ORR) Secondary endpoints: Duration of Response (DOR) Progression Free Survival (PFS) Safety Quality of life (Gopal A, et al. NEJM 2014)

21 Tumor Response (Gopal A, et al. NEJM 2014)

22 Progression Free Survival Historical Control: Bendamustine: DOR 10mo (Gopal A, et al. NEJM 2014)

23 Adverse Events (Gopal A, et al. NEJM 2014)

24 Idelalisib Phase 1b Combination Study in inhl 3 groups, non-randomized Durable response - Median PFS 37 months, DOR at 36 months 55% Manageable safety profile with treatment up to >3 years with no unexpected toxicities in combination (de Vos et al., ASH 2014)

25 PI3K INHIBITORS IN NHL Drug single agent Target ORR (%) in relapsed lymphoid malignancies DLBCL FL MCL SLL/CLL PTCL HL Idelalisib PI3K-δ IPI-145 PI3K-γδ 0 69 (2 in 3) (55) higher dose level BAY PI3K-αδ (1 in 2) TGR-1202 PI3K-δ (1 in 9) 42 (1 in 3) 63 - (1 in 8) Approved indication Gopal A. et al., NEJM 2014 Flinn I. et al, ASH , O'Brien et al, ASH 2014 Dreyling M. et al., ASH 2013 Burris H. et al., ASCO 2015

26 CURRENT & ON-GOING TRIALS Drug Target Idelalisib PI3K-δ Duvelisib PI3K-δ,γ Trial Design n Regimen Primary Objective YOSEMITE Phase 3, rand 2:1, Relapsed inhl BRIDALVEIL Phase 3, rand 2:1, Relapsed inhl DYNAMO Phase 2 Refractory inhl DYNAMO+R Phase 3, rand 1:1, Relapsed FL CONTEMPO Phase 1b/2, rand 1:1 Thx naïve FL Duration 375 Rit +/- Idelalisib PFS 48 wks 450 RB +/- Idelalisib PFS 48 wks 120 Duvelisib ORR 1-2 yrs 400 Rit +/- Duvelisib 120 Duvelisib + Rit vs. Duvelisib + Obinotuzumab PFS Safety CR rate 2 yrs 2 yrs

27 CURRENT & ON-GOING TRIALS Drug Target TGR PI3K-δ Copanlisib PI3K-δ,α Trial Design n Regimen Prim Objective Triple Combination (Fowler, ASCO 2015) Phase 1 dose esc rel/refr NHL, HL, CLL Phase 1/1b rel/refr NHL, CLL CHRONOS-1 Phase 2 A: rel/refr indol/aggr NHL B: rel/refr FL 60 TGR-1202 Safety MTD 80 (Ublituximab + TGR-1202) +/- Ibrutinib Copanlisib (BAY ) (iv dosing) Safety MTD ORR Duration 1 yr

28 PI3K-inhibitor combinations

29 PI3K/BTK inhibitors in rel/ref inhl (de Vos et al., Whistler 2015)

30 PI3K inhibitor for first line treatment of follicular lymphoma Phase 1b Safety Lead in: duvelisib + Obinutuzumab duvelisib + Rituximab R Phase 2: Duvelisib + Obinutuzumab Phase 2: Duvelisib + Rituximab Phase 1b/2 study in ~120 patients with previously untreated FL Primary objectives: Confirm safety of the combinations Assess clinical activity (de Vos et al., Whistler 2015)

31 Ibrutinib inhibits both BTK and ITK resulting in modulation of both B- and T-cell function (Ansell. Blood 2013;122: )

32 Phase III Study of R-Chemo +/- Ibrutinib in Relapsed Indolent NHL 400 pts with Relapsed Follicular or Marginal Zone Lymphoma Randomize BR or R-CHOP x 6 Ibrutinib* BR or R-CHOP x 6 Placebo* Objectives: *Continue until progression Primary: Progression free survival Secondary: Overall Survival, complete response rate, safety

33 Frontline Ibrutinib + Rituximab Follicular Lymphoma Untreated Ibrutinib Follicular 560 mg PO Daily Lymphoma N=60 Rituximab 375mg IV x 4 Objectives Primary Evaluate the ORR (CR+PR) Secondary Duration of response, PFS Safety *Continue until progression Enrolment complete, submitted to ASH 2015.

pathway may be co-opted by tumors to evade immune attack Nivolumab is a

34 (Timmerman et al., ICLM Lugano 2015) Checkpoint inhibitors The PD-1 immune checkpoint pathway may be co-opted by tumors to evade immune attack Nivolumab is a fully human anti-pd1 IgG4 mab which can restore anti-tumor immune activity MHC T-cell receptor PD-L1 Nivolumab Tumor cell PD-L2 PD-1 T cell

35 Pre-Clinical Results Multiple Myeloma PD-L1 expression by malignant plasma cells Animal models of PD-1 blockade Non-Hodgkin Lymphoma Variable PD-1 biology Follicular lymphoma PD-1 in microenvironment, no PD-L1 on tumor cells Diffuse Large B-Cell Lymphoma PD-L1 expression in subset of tumors Andorsky, et al. Clin Cancer Res. 2011; 17: Liu, et al. Blood. 2007;110: Chen, et al. Clin Cancer Res. 2013;19: Paiva, et al. Leukemia. 2015; Mar 17 [Epub] (Timmerman et al., ICLM Lugano 2015)

36 (Timmerman et al., ICLM Lugano 2015) Study Design CA : Phase 1 study of nivolumab in lymphoid malignancies Relapsed or Refractory Lymphoid Malignancies (n=105) Dose Escalation (n=13) 1 mg/kg 3 mg/kg Dose Expansion (n=92) 3 mg/kg Endpoints Primary Safety and Tolerability No autoimmune disease No organ/stem cell allograft No prior checkpoint blockade Wk 1,4 then q2wk until PD, toxicity, CR or 2y Classical Hodgkin (n=23) B-cell NHL (n=31) T-cell NHL (n=23) Myeloma (n=27) CML (n=1) Secondary Best Overall Response Objective Response Duration of Response Progression-free survival Biomarker studies August 2012 Start June 2014 (ASH 2014) April 2015 (EHA 2015)

37 (Timmerman et al., ICLM Lugano 2015) Best Response Tumor Type # pts ORR CR PR SD Multiple Myeloma 27 1 (4) 1 (4) 0 17 (63) B-Cell Non-Hodgkin Lymphoma 31 8 (26) 3 (10) 5 (16) 16 (52) Diffuse Large B-Cell 11 4 (36) 2 (18) 2 (18) 3 (27) Follicular NHL 10 4 (40) 1 (10) 3 (30) 6 (60) Mantle Cell Lymphoma (75) Primary Mediastinal B-Cell (100) Other B-NHL (50) T-Cell Non-Hodgkin Lymphoma 23 4 (17) 0 4 (17) 10 (43) CTCL/MF 13 2 (15) 0 2 (15) 9 (69) Peripheral T-Cell 5 2 (40) 0 2 (40) 0 Other T-NHL (20) Hodgkin Lymphoma (87) 6 (26) 14 (61) 3 (13)

38 (Timmerman et al., ICLM Lugano 2015) Durability of Response Tumor type n ORR Median Follow-up in weeks Median Response Duration in weeks Ongoing Responses Multiple Myeloma 27 1 (4%) (100%) DLBCL 11 4 (36%) (6, 77+) 1 (25%) Follicular NHL 10 4 (40%) 91 NR (27+, 82+) 3 (75%) CTCL/MF 13 2 (15%) 43 NR (24+, 50+) 2 (100%) PTCL 5 2 (40%) 31 NR (11, 79+) 1 (50%) Hodgkin Lymphoma (87%) 86 NR (2, 91+) 10 (50%)

39 Percent Change From Baseline Percent Change From Baseline (Timmerman et al., ICLM Lugano 2015) DLBCL and Follicular NHL 600 DLBCL 600 Follicular NHL X 0 X X X 0 X X Time Since First Dose, Weeks Time Since First Dose, Weeks First response X First occurrence of new lesion

40 Proportion of Progression-Free Survival Proportion of Overall Survival (Timmerman et al., ICLM Lugano 2015) DLBCL and Follicular NHL PFS OS Follicular Non-Hodgkin Lymphoma Follicular Non-Hodgkin Lymphoma 0.0 Diffuse Large B-Cell Lymphoma 0.0 Diffuse Large B-Cell Lymphoma Baseline Time Since First Dose, Weeks Baseline Time Since First Dose, Weeks

41 Phase III Study (GADOLIN): Bendamustine vs Bendamustine + Obinutuzumab (Cheson, B et al. Lugano 2015)

42 GADOLIN primary outcome: IRF-assessed PFS (Cheson, B et al. Lugano 2015)

43 Lenalidomide + GA101 in Relapsed inhl

44 1 st line DLBCL Follicular Lymphoma 1 st line 1 st line Hodgkin Multiple NHL R-CHOP + ABT-199 Vs. G-CHOP + ABT-199 (all types of DLBCL) 2 nd line Duvelisib (IPI-145) + Ritux or Obinutuzumab ABVD vs. AVD + SGN-35 2 nd line Waldenstrom s 2 nd line 2 nd line Ibrutinib + Lenalidomide +/- Rituximab MOR00208 (CD19 moab) + Lenalidomide ACP-196 (BTK inhibitor) Ibrutinib + Lenalidomide + DA-EPOCH-R KTE-C19 CD19 CAR T-cells IMO-8400 (TLR inhibitor) Selinexor (SINE XPO1 antagonist) Lenalidomide + Obinutuzumab + Pembrolizumab 1 st line 2 nd line BR +/- ABT-199 or Rituximab + ABT-199 Nivolumab (Anti-PD1) CLL/SLL Idela + Gazyva vs. Leukeran + Gazyva ACP-196 vs. ACP Gazyva vs. Leukeran + Gazyva Ublituximab + Ibrutinib vs. Ibrutinib ABT-199 (for rel after BCR inhibitor) ACP-196 (BTK inhib) (CLL, Richter s, PLL) Selinexor (Richter s) 2 nd line 2 nd line 2 nd line Ibrutinib IMO-8400 MCL Palbociclib + Idelalisib KTE-C19 CD19 CAR T-cells PTCL Fenretinide (retinoid derivate) CTCL Mogamulizumab (anti-ccr4) vs. Vorinostat MRG1106 (targets mir-155) RB +/- Idelalisib (inhl) Nivolumab (Anti-PD1) + anti-kir moab (FL, PTCL, MM) Urelumab (anti-cd137) + Rituximab - rituximab refractory - ACP ACP-319 (BTK and PI3K inhibitors) ACP Pembrolizumab (BTK inhib + anti-pd1) ABT IPI-145 (DLBCL, inhl, CLL) IGN002 (anti-cd20-ifn) INCB (PIM-kinase inhibitor) In start up TRIO - US trial

Follicular Lymphoma New Agents. Idelalisib

Indolent Lymphoma Workshop Bologna 2017 Follicular Lymphoma New Agents Idelalisib Sven de Vos, MD, PhD Director, UCLA Lymphoma Program Los Angeles, CA Disclosures of Sven de Vos Company name Research support