New developments in the treatment of FL. Massimo Federico University of Modena and Reggio Emilia Italy

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1 New developments in the treatment of FL Massimo Federico University of Modena and Reggio Emilia Italy

2 Common Questions Asked by The Patient I would like to know what is the best therapeutic option and why. What can you tell me about my disease? How long can therapeutic intervention/treatment be delayed? What is the prognosis of my disease? How does this disease typically respond to treatment? Is recovery a realistic goal?

3 Follicular NHL - Common indolent NHL 10-22% of B-NHL 2-3 cases / people M: F W: B Incidence increases with age Stable incidence trend between 1992 and 2001 except for elderly people (+ 1.8 % per y.)

4 Outcome of FL from SEER Data Swenson WT, et al. J Clin Ocol 2005;23:

5 How we used to look at FL 1. Indolent B-cell lymphoma 2. Watch and wait is a treatment option 3. Good response to treatment 4. Constant relapses 5. Shorter duration of remissions after every recurrence 6. Risk of transformation into aggressive NHL 7. Incurable disease

6 Overall Survival (1057) Median FU 38 months 89% at 60 mos 65% at 60 mos 60 Swenson WT, et al. J Clin Ocol 2005;23: , Federico unpublished data

7 Which Endpoint Should Be Used for Studying Prognosis in FL? Overall survival and progression-free survival of 832 patients used for Follicular Lymphoma International Prognostic Index 2 development Federico M, et al. J Clin Oncol 2009;27:

8 FLIPI2 Score score 0 score 1 Age 60 yrs > 60 yrs Hemoglobin level 12 g/dl < 12 g/dl B2-microglobulin level ULN > ULN LoDLIN* 6 cm > 6 cm BM involvement absent present * Longest Diameter of Largest Involved Node Low risk 0 Intermediate risk 1-2 High risk 3-5

9 (A) PFS and (B) OS of the training sample (832 patients) according to the FLIPI2 (C) PFS and (D) OS of the validation sample (231 patients) according to FLIPI2 Federico M, et al. J Clin Oncol 2009;27:

10 Treatment Options in FL

11 FL Treatment Depends on Stage and Extent of Disease After Staging Evaluation Low tumor burden Localized Advanced Stage Observation or therapy IFRT: 24 Gy or Rituximab

12 The Publications Follicular Lymphoma: the First-Line Treatment Regimen Phase III studies with Rituximab in FL N patients Median follow-up (mo) CVP ± R vs 10 CHOP ± R vs 17 MCP ± R vs 25 CHVP ± R vs 44 R-Chemo versus Chemo* CR/CRu(%) ORR (%) Efficacy 81 vs vs vs vs 86 TTP: 32 vs 15 mo 2-yr PFS: 84% vs 63% 2-yr EFS: 83% vs 43% 2.5-yr EFS: 78% vs 63% * P < 0.05 for all comparisons between R-Chemo and Chemo Patients subsequently received interferon or autologous transplant 1. Marcus R, et al. Blood 2005; 105: Hiddemann W, et al. Blood 2005;106: Herold M, et al. J Clin Oncol 2007;25: Salles G, et al. Blood 2008;112:4824..

13 FOLL05 Arm 1 R-CVP > PR molecular biology samples shipment R A N D O M every 21 days Arm 2 R-CHOP every 21 days Arm 3 R-FM R E - A S S E S S M E N T > PR every 21 days every 21 days + 2 Rituximab every 21 days > PR + 2 Rituximab every 21 days every 21 days every 21 days ClinicalTrials.gov Identifier: NCT

14 Kaplan-Meier Analysis of Probability of (A) Time to Treatment Failure and (B) Progression-Free Survival according to Intention-To-Treat Principle 2013 by American Society of Clinical Oncology Federico M, et al. J Clin Oncol 2013;31:

15 Grade 3-4 Toxicities by Arm (%) Anemia P = Neutropenia P < Thrombocytopenia P < Infections P = Anemia Neutropenia Thrombocytopenia Infections R-CVP R-CHOP R-FM Federico M, et al. J Clin Oncol 2013;31:

16 Second Malignancies (not Censored as Events) R-CVP (N=4) Breast GI tract Genitourinary Kaposi R-CHOP (N=5) Genitourinary 3 x Lung Glioblastoma * R-FM (N=14) 4 x AML/MDS * * 1x HL 3 x Genitourinary* Lung 2 x Skin GI tract * Parotid Breast P = PRESENTED BY: M. Federico

17 Conclusions R-CHOP and R-FM are both superior to R-CVP in terms of TTF (Primary endpoint of the study) R-CHOP and R-FM have similar anti-lymphoma activity R-CHOP and R-CVP are less toxic than R-FM Maintenance therapy could improve the PFS (indirect conclusion) R-CHOP is associated with the best risk/benefit ratio PRESENTED BY: M. Federico

18 UPDATE FOLL05 Median Follow-up 54 months (range 1-90) Function Overall survival PFS TTF Median FU Personyears Rate x100 prs-years % at 3 yrs JCO 34 (1-70) (CI ) 95 (92-97) Update 54 (1-90) (CI ) 95 (93-96) JCO (CI ) 61 (56-66) Update (CI ) 63 (59-67) JCO ( ) 56 (50-60) Update ( ) 58 (53-62)

19 Update - TTF TTF% at 5-yrs R-CVP 43 (CI ) R-CHOP 56 (CI ) R-FM 56 (CI ) Months R-CVP R-CHOP R-FM R-CVP JCO R-CHOP JCO R-FM JCO

20 Update - PFS PFS% at 5-yrs R-CVP 47 (CI ) R-CHOP 62 (CI ) R-FM 60 (CI ) Months R-CVP R-CHOP R-FM R-CVP JCO R-CHOP JCO R-FM JCO

21 Update - OS OS 91 (CI ) # dead JCO: 31 # dead (2014): 47 (+16) 0.00 OS OS JCO Months

22 Bendamustine-Rituximab (B-R) vs CHOP-R StiL NHL Follicular Waldenström Marginal zone Small lymphocytic Mantle cell R Bendamustine-Rituximab CHOP-Rituximab Bendamustine 90 mg/m 2 day R day 1, max 6 cycles, q 4 wks. CHOP-R, max 6 cycles, q 3 wks. Rummel MJ, et al. Lancet 2013;381:

23 Hematotoxicity grades 3+4 B-R (n=1.450) CHOP-R (n=1.408) (% of cycles) (% of cycles) P value Leukocytopenia 12,1 38,2 < Neutropenia 10,7 46,5 < G-CSF administered 4,0 20,0 < Thrombocytopenia 0,7 1,2 Anemia 1,4 1,9 Rummel MJ, et al. Lancet 2013;381:

24 Toxicities (all CTC-grades) B-R (n=261) CHOP-R (n=253) (no. of pts) (no. of pts) P value Alopecia < Paresthesias < Stomatitis < Skin (erythema) = Allergic reaction (skin) = Infectious complications = Sepsis 1 8 = Rummel MJ, et al. Lancet 2013;381:

25 PFS: Follicular (n=279) Median (months) B-R n. y. r. CHOP-R Hazard ratio, 0.61 (95% CI ) 0.1 p = Months Rummel MJ, et al. Lancet 2013;381:

26 902 An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin s Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study Flinn IW et al.blood (ASH) 2012; abstract randomized patients with inhl and MCL, never treated Bendamustine 90 mg/m 2 /day on days 1 and 2 + Rtx 375 mg/m 2 on day 1 of a 28-day cycle CHOP/CVP 21 dd for 6/8 cycles + Rtx 375 mg/m 2 dd 1 every cycle The randomized groups were well matched for: Age (median 60 and 58 years), Sex (male, 61% and 59%), ECOG status (64% performance status 0, both groups), Lymphoma type (83% indolent NHL, both groups) Ann Arbor stage (62% stage IV, both groups).

27 Response Rate and Treatment Outcomes BR (n = 213) R-CHOP/R-CVP (n = 206) Overall response rate 94% 84% Progressive/relapsed disease or death* 8% 4% Completed 6 treatment cycles with >96% dose intensity 92% 91% Dose delays 35% 19% Dose reductions 22% 29% * At time of data cutoff Independent review committee and INV differed mainly in quality of response (CR versus partial response) rather than in whether a patient was a responder. Time-to-event data are immature at time of present analyses. Flinn IW et al. Proc ASH 2012;Abstract 902

28 WHAT IS NEXT? R CHT? NO CHT?

29 GA101

30 A PHASE III RANDOMIZED STUDY IN PREVIOUSLY UNTREATED PATIENTS WITH ADVANCED INDOLENT NHL EVALUATING THE BENEFIT OF GA101 PLUS CHT COMPARED WITH R PLUS CHT FOLLOWED BY GA101 OR R MAINTENANCE THERAPY IN RESPONDERS

31 Update of January 17th, 2014 BO21223/GALLIUM 1400 Patients Randomized Enrollment Metrics n. Total screened 1605 In screening 1 Randomized 1400 Randomized and active 1214 Discontinued 186 CHOP 433 CVP 141 Bendamustine 826 Follicular 1201 Non follicular 199 Hep B DNA undetectable 89

32 Frontline Combination of Lenalidomide and Rituximab (R2) for FL: Clinical Response SLL (N = 24) Marginal (N = 24)* Follicular (N = 45)* *7 patients inevaluable for response: 5 due to adverse event in cycle 1 1 due to non-compliance 1 due to withdrawal of consent Eval (N = 93) All patients Fowler N, et al. Ann Oncol 2011;22 suppl 4:[abstract 137]. Updated data presented at ICML 2011 ITT (N = 100) ORR, n (%) 20 (83) 21 (88) 44 (98) 85 (91) 85 (85) CR/Cru 6 (25) 16 (67) 38 (85) 60 (65) 60 (60) PR 14 (59) 5 (21) 6 (13) 25 (27) 25 (25) SD, n (%) 2 (8) 3 (13) 1 (2) 6 (6) 6 (6) PD, n (%) 2 (8) (2) 2 (2)

33 R2 for FL: Tumor Burden, Molecular Response Response: by GELF criteria, N = 45 GELF high tumor burden, N = 22 (49%) GELF low tumor burden, N = 23 (51%) SD PR CR/CRu ORR SD PR CR/CRu ORR 0 1 (5%) 21 (95%) 100% 1(5%) 4 (17%) 18 (78%) 95% Response: by bulk of disease, N = 45 Bulky, N = 13 (29%) Non-bulky N = 32 (71%) SD PR CR/CRu ORR SD PR CR/CRu ORR 0 1 (8%) 12 (92%) 100% 1 (3%) 4 (13%) 27 (84%) 97% Response: by PCR, (BM + PB), N = 43 Positive Negative Pre-treatment 17 (40%) 26 (60%) Post-cycle 3 5 (12%) 38 (88%) Post-cycle 6 2 (5%) 40 (95%) Bone marrow and peripheral blood for major or minor breakpoint Fowler N, et al. Ann Oncol 2011;22 suppl 4:[abstract 137]. Updated data presented at ICML 2011

34 RELEVANCE: Phase 3 Study Design (Rituximab and LEnalidomide Versus ANy ChEmotherapy, FL-001) International, multi-centre, randomized study (Frank Morchhauser, Nathan Fowler) R-Chemo R investigator choice of R-CHOP, R-CVP, R-B Lenalidomide 20 mg x 6 cycles, if CR then 10 mg Co-primary end-points 1 st -line FL n = 1,000 R 2 R-Chemo CR, CRu, PR CR, CRu, PR R 2 maintenance Rituximab maintenance surrogate end-point: CR/CRu rate at 1.5 years PFS NCT Available from: Accessed March 2012.

35 Fondazione Italiana Linfomi (FIL) FOLL12 A multicenter, phase III, randomized study to evaluate the efficacy of a response-adapted strategy to define maintenance after standard chemoimmunotherapy in patients with advancedstage Follicular Lymphoma

36 OBJECTIVES Primary objective Evaluate whether a PET and MRD response-based maintenance therapy is more effective in terms of PFS than a standard maintenance therapy with R in patients with untreated, advanced FL

37 Progression-free survival in 202 patients with follicular lymphoma according to post-induction positron emission tomography Luminari S et al. Ann Oncol 2014;annonc.mdt562 The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oup.com.

38 PFS OS PRIMA (med 42mo f/u) FOLL05 (med 28mo f/u) PET Folliculaire (med 24mo f/u)

39 Induction therapy TRIAL DESIGN Standard arm Salvage <PR LF st II-IV Age >18 Active disease FLIPI2>O RANDOMIZATION 4 x R-CHOP 2x R-CHOP + 2R Experimental arm PET MRD

40 Manteinance TRIAL DESIGN Standard arm CR,PR <PR R Maintenance every 2 months x 2yrs Salvage INDUCTION therapy Patients with no molecular markers Neg Observation Experimental arm PET- MRD Pos Rituximab weekly x 4 PET+ (90)Y Ibritumomab Tiuxetan + R Maintenance every 2 months x 2yrs <PR Salvage

41 FIL_FOLL12 ACCRUAL 28/01/ sites authorized 109 patients 101 randomized 5 screening 3 screening failure 53 standard arm 48 experimental arm

42 Salvage therapy New drugs R-CHT RIT HDT

43 Freedom from progression for patients with follicular lymphoma treated with high-dose cyclophosphamide (CY) and total-body irradiation (TBI) followed by autologous stem-cell transplantation in second remission compared with results of a historical control g... Cabanillas F. J Clin Onol 2013;31: by American Society of Clinical Oncology

44 A PHASE III MULTICENTER, RANDOMIZED STUDY COMPARING CONSOLIDATION WITH 90 YTTRIUM-LABELED IBRITUMOMAB TIUXETAN (ZEVALIN ) RADIOIMMUNOTHERAPY VS AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) IN PATIENTS WITH RELAPSED FOLLICULAR LYMPHOMA (FL) AGED YEARS 3x R-chemo regimens CR,PR Randomization ARA-C with R in vivo purging ARA-C with R in vivo purging consolidation with RIT consolidation with ASCT (BEAM) R maintenance R maintenance

45 FLAZ12 Zevalin vs ASCT for refractory and relapse FL MRD 3 R-CHEMO REGIMENS (R-CHOP, R-DHAP, R-FM, R-ICE, R-IEV, R-B) MRD CR-PR SD-PD BLIND RANDOMIZATION Pts stratified based on Center characteristics and response ARA-C 2g/sqm b.i.d. 2 days with Rituximab in vivo purging PBSC harvest MRD Randomization unblinding Arm A consolidation with RIT MRD Arm B: consolidation with ASCT Rituximab maintenance every three months for 8 courses (starting three months after consolidation) Rituximab maintenance every three months for 8 courses (starting three months after consolidation) At relapse MRD At relapse ASCT With Previously collected PBSC Any salvage treatment

46 RENOIR A RANDOMIZED PHASE III MULTICENTER TRIAL ASSESSING EFFICACY AND TOXICITY OF A COMBINATION OF RITUXIMAB AND LENALIDOMIDE (R2) VS RITUXIMAB ALONE AS MAINTENANCE AFTER CHEMOIMMUNOTHERAPY WITH RITUXIMAB-BENDAMUSTINE FOR RELAPSED/REFRACTORY FL PATIENTS NOT ELIGIBLE FOR AUTOLOGOUS TRANSPLANTATION Primary Objective To evaluate in patients responsive to induction whether the R2-MANT program may improve PFS compared to patients treated with R-MANT

47 Renoir: treatment design PCR analysis for Bcl-2 rearrangement on PB/BM REALPSED/REFRACTORY FOLLICULAR LYMPHOMA NEED TO THERAPY R-Bendamustine x 4 once a month Rituximab 375 mg/m 2 day 0 or 1 (day 8 on cycle 1) Bendamustine 90 mg/m 2 iv days 1-2 Restaging and PCR analysis for Bcl-2 rearrangement on PB/BM CR/PR NR OFF Random R2 Rituximab 375 mg/m2 day 1 q 90 days (8 cycles) Lenalidomide (10 mg dd 1-21 q 28) (24 cycles) R alone Rituximab 375 mg/m2 day 1 q 90 days (8 cycles) Clinical and molecular follow-up months 12, 18, 24 and 30 (end of study)

48 FIL centres: 44 Renoir Study Expected accrual time: 36 months Random will be done in 1:1 ratio and stratified by enrolling center characteristics and the clinical response (PR or CR) after induction Lenalidomide supplied by Celgene MRD will be assessed by both qualitative nested PCR and quantitative real time PCR, to better define the kinetics of minimal residual disease MRD analysis centralized according to FIL-MRD network Start up: February 2014

49 Follicular Lymphoma Treatment First line Localized radiotherapy Staging evaluation Advanced indolent Advanced with symptoms W&W Rituximab FOLL12

50 Follicular Lymphoma Salvage Treatment Relapsed/ Refractory First or second relapse > Second relapse or elderly High dose, FLAZ 12 ( 65 yrs) RENOIR New drugs

51 Selected Novel Agents in FL

52 Protocol MO25455: R subcutaneous In Italy enrollment closed for FL

53 MEDI-551, a Humanized Monoclonal Antibody directed against CD19, in subjects with Relapsed or Refractory Advanced B-cell Malignancies Of 91 patients who received 1 dose of MEDI-551, 25 patients (CLL [3], DLBCL [6], FL [12], MM [4]) were enrolled in the phase 1 escalation portion (Jun 2010 Aug 2011). The phase 2 expansion phase included 66 patients (CLL [23], DLBCL [20], FL [22], MM [1]) as of 14Jul2013. MEDI-551 has an acceptable safety profile warranting further study. Anti-tumor activity was achieved in a heavily pre-treated population of DLBCL, CLL, and FL patients respectively in this single-agent study. Phase 2 studies of MEDI-551 in combination with chemotherapy in DLBCL and CLL are ongoing. Forero-Torres A. et al. Blood October 21, 2013 vol. 122 no

54 2013 by American Society of Hematology Hamadani M et al. Blood 2013;122:1810

55 BCR SIGNALING PATHWAY AS THERAPEUTIC TARGET IN INDOLENT LYMPHOMAS

56 Role of BCR in B-cell malignancies BCR pathway is markedly upregulated in B-cell malignancies¹ NB : BCR not expressed in chl, PEL, PMBCL and post-transplant lymphomas² Signaling from BCR led to proliferative and survival advantage Lymphomatous transformation is believed to be an antigenindipendent process in which downstream pathways from BCR are constitutively active or amplified³ ¹ Choi MY et al., Cancer J ² Kuppers R et al., Nature ³ Dühren-von Minden M et al., Nature. 2012

57 The B Cell Receptor (BCR) Transmembrane receptor protein Molecular structure: 1. Ligand binding moiety (Ig) 2. Signal transduction moiety (CD79) Biological functions: a) B-cell activation by antigen b) To mediate internalization of antigen

58 Critical Signaling Pathways and New Targeted Agents BCR Therapeutic potential in inhibiting BCR or the downstream kinase Ibrutinib AVL-292 PKC PLCγ2 BTK LYN SYK GSK-3 PI3K Delta p70s6k Fostamatinib GS-9973 AKT mtor Idelalisib IPI-145 TGR-1202 NF-kβ Pathway elf4e New inhibitors are targeting multiple components of BCR signaling including: - PI3K delta - BTK - Syk

59 PI3K-delta inhibitors currently in development TGR-1202 TG Therapeutics Idelalisib (CAL-101, GS-1101) Gilead IPI-145 Infinity Pharmaceuticals Selectivity, Fold Change Isoform α β γ δ TGR-1202 [1] > > 50 > 48 1 Idelalisib [2] > 300 > 200 > 35 1 IPI-145 [3] > 1000 > 60 > Vakkalanka S, et al. ASH Abstract Lannutti BJ, et al. Blood. 2011;117: DiNitto J, et al. Keystone Symposium Abstract 1032.

60 Three PI3K Inhibitors in Clinical Development Idelalisib is a first-in-class PI3K inhibitor, and has shown promising activity in indolent lymphoma. IPI-145 is a PI3K inhibitor that has demonstrated promising activity in both B-and T-cell lymphoma. Idelalisib and IPI-145 share high structural similarity and contain nitrogen based heterocyclic backbones that are associated with hepatotoxicity. TGR-1202 has a different backbone designed to potentially minimize liver toxicity while preserving delta specificity.

61 % Change in Tumor Size Idelalisib Idelalisib Active as Mono- or Combination Therapy in Indolent NHL Best On-Treatment Change in Tumor Size (ITT Analysis) Single Agent (n = 59) Combination with rituximab and/or bendamustine (n = 52) Unevaluable (patients without a follow-up tumor assessment) a 2007 criteria for lymphoma response de Vos S, et al. ASH Abstract Cheson BD, et al. J Clin Oncol. 2007;25:

62 Idelalisib ASH 2013 Mature Response Data From a Phase 2 Study Of PI3K-Delta Inhibitor Idelalisib In Patients With Double (Rituximab and Alkylating Agent)- Refractory Indolent B-Cell Non-Hodgkin Lymphoma (inhl) 125 enrolled patients : 58% FL, 22% SLL, 12%MZL, 8% LPL/WM Median Fup 9.4 months ORR 57% : FL 54% SLL 61% LPL/WM 80% MZL 47% Median PFS 11 months, Median OS 20.4 months Most common adverse events were (total%/ grade 3%) diarrhea (43/13), fatigue (30/2), nausea (30/2), cough (29/0), pyrexia (28/2), dyspnea (18/3), rash (13/2), and pneumonia (11/7). Grade 3 ALT/AST elevations in 16 pts (13%). Grade 3 neutropenia in 27%, thrombocytopenia in 6%, and anemia in 2%. Ajay Gopal et al.

63 Bruton s Tirosine Kinase (BTK): Signal and Inhibition BTK is an essential element of the BCR signaling and critical for lymphoma growth and survival ¹ Inhibitors of BTK block BCR signaling and induce apoptosis ² Targeting BTK is a novel approach for the treatment of B-cell malignancies ¹ Herman SEM, et al. Blood ² Davis RE, et al. Nature

64 IBRUTINIB and INDOLENT LYMPHOMA Akinleye A et al. Clin Lymphoma Myeloma Leuk Nov 15. [Epub ahead of print]

65 Ibrutinib in Treating Patients With Relapsed or Refractory Follicular Lymphoma

66 The Lymphoma Hub An online network for healthcare professionals treating lymphoma and chronic lymphocytic leukemia

67 What we cover (1) News The news feeds delivers the most upto-date information for lymphoma and CLL Regular breaking news direct from Steering Committee endorsed sources Original stories from Lymphoma Hub writers Drugs Profiles of emerging new molecules for the treatment of lymphoma and CLL An easy-to-use menu displaying drugs by their development stage This section provides profiles of molecules, their mechanisms of action, and currently available date 67

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69 The Changing Face of FL in Recent Years 1. Indolent B-cell lymphoma 2. Excellent reponse to R-Chemo 3. Duration of remissions may be prolonged by maintenance or adequate salvage therapies 4. Death for lymphoma is becoming a later event 5. Potentially curable disease