Traitement de première ligne du lymphome folliculaire. F Morschhauser DES, 17 novembre,2017 Centre Hospitalier Universitaire de Lille, France

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1 Traitement de première ligne du lymphome folliculaire F Morschhauser DES, 17 novembre,2017 Centre Hospitalier Universitaire de Lille, France

2 What do I say to a newly diagnosed FL patient?

3 Probability (%) Probability (%) Until the end of the 20th century: FL was considered as incurable Until the end of the 90 s, FL natural history was thought not to be influenced by any therapeutic strategy 1, 2, (195) (513) (314) (5,601) (4,714) (4,249) Log-rank P= Log-rank P= Years Months following diagnosis 1. Horning SJ. Semin Oncol 1993; 20 (Suppl. 5): Swenson WT et al., J Clin Oncol 2005; 23: Lister TA, J Clin Oncol, 2005; 25:

4 Overall survival % After 2000, a new hope for FL patients Improved overall survival with anti-cd20 antibodies: Multiple randomized trials and series 1, plus 1 meta-analysis 2 Epidemiological surveys: substantial OS improvement p < CHOP + antibody ProMACE CHOP Years Observation period 5-year survival Probability (SD) 10-year Survival Probability (SD) (1.3) 52.2 (1.6) (0.9) 71.5 (1.4) 1. Fisher RI et al, J Clin Oncol 2005;23: Schulz H et al., Cochrane Database of Systematic Reviews 2007; 4:CD Pulte D et al; Arch Intern Med. 2008;168:

5 Survival of FL patients in the rituximab era OS N = 1655 Cause of death French 10 year OS: 79.8% USA 10 year OS: 76.6% Lymphoma: 10 year estimate: 10.4% Sarkozy et al, ICML 2017, Abstr 016

6 Follicular Lymphoma a very heterogeneous lymphoma Patients focussed on I have Stage IV Dr Google Physician focussed on: multiple FLIPI & FLIPI2 prognostic factors: B 2 M, LDH, Stage, Hb, LODLIN, age, # nodal sites Treatment criteria (GELF / BNLI) patient age and comorbidities Emerging combined prognostic index ( m7 FLIPI, POD24 PI, PET MTV) which affect timing, choice and outcome of therapy.

7 When are we going to start a cytotoxic treatment? GELA criteria High tumor bulk defined by either: - a tumor > 7 cm - 3 nodes in 3 distinct areas each > 3 cm - symptomatic splenic enlargement - organ compression - ascites or pleural effusion Presence of systemic symptoms Serum LDH or β2-microglobulin above normal values BNLI criteria Rapid disease progression in the preceding 3 months Life threatening organ involvement Renal or liver infiltration Bone lesions Systemic symptoms or pruritus Hb<10 g/dl or WBC< /L or Plat.< /L ; related to marrow involvement

8 GELF Criteria GELF86 GELF 94 FL2000 PRIMA B symptoms PS > LDH > N β2-micro > N > 3 mg/l > 3 mg/l > N Compression, effusion, spleen Cytopenia + Tumor diameter > 7 cm lymph nodes > 3 cm + + +

9 GELF Criteria P= Tumor Burden Low High Years

10 Follicular Lymphoma Treatment First line 2017 Staging evaluation Localized Advanced indolent Advanced with symptoms W&W radiotherapy W&W Rituximab R-chemo G-chemo no-chemo?

11 PFS of rigorously staged patients with stage I follicular lymphoma by treatment modality. Compared with patients treated with radiation therapy, patients treated with rituximabcontaining chemotherapy (R-chemotherapy) or systemic therapy and radiation therapy had significantly better PFS. Friedberg et al J Clin Oncol Sep 20; 30(27):

12 Modern Standard of Care of Follicular lymphoma Low tumor burden or Advanced indolent or No need for therapy

13 Colombat P et al, Ann Oncol 2012; 23: Rituximab monotherapy: M39006 Co tro arm a o gside W&W?

14 RWW Study(Ardeshna et al) R A N D O M I S A T I O N ARM A Watch and Wait cc ARM B Rituximab Induction ARM C Rituximab Induction & maintenance Progressive disease requiring therapy stops protocol treatment Compulsory CT scan Clinic visits CT scan only if clinical CR Compulsory CT scan Continued follow up Bone marrow for histology and MRD only if CT shows ccr

15 RWW (NCRI) W&W versus RTX in asymptomatic FL No New Treatment (%) OS (%) No Histological Transformation (%) PFS (%) Time to Start of New Treatment PFS Pts at Risk, n Watch and wait Maintenance rituximab HR: 0.21 (95% CI: ; log-rank P <.0001) OS HR: 0.23 (95% CI: ; log-rank P <.0001) Time to Histological Transformation Pts at Risk, n Watch and wait Maintenance rituximab 25 HR: 0.73 (95% CI: ; log-rank P =.40) Yrs From Randomization Ardeshna KM, et al. Lancet Oncol. 2014;15: HR: 0.62 (95% CI: ; log-rank P =.19) Yrs From Randomization

16 E4402 (RESORT) Schema Rituximab 375 mg/m 2 qw 4 CR or PR R A N D O M I Z E Rituximab Maintenance* 375 mg/m 2 q 3 months Rituximab re-treatment at progression* 375 mg/m 2 qw 4 *Continue until treatment failure No response to retreatment or PD within 6 months of R Initiation of cytotoxic therapy or Inability to complete rx 16

17 RESORT trial Primary Endpoint: Time to Treatment Failure Treatment failure: no response to retreatment or PD within 6 months of R, Initiation of an alternative therapy or Inability to complete planned therapy Kahl BS, et al. J Clin Oncol. 2014;32:

18 RESORT Conclusions Both strategies appear to delay time to chemotherapy compared to historical controls How to interpret? Given the excellent outcomes with RR 86% chemotherapy free at 3 years Given the lack of QOL difference Given fewer AE failures Given fewer R doses required with RR Rituximab retreatment is our recommended strategy if opting for Rituximab monotherapy in LTB FL Kahl BS, et al. J Clin Oncol. 2014;32:

19 SC route improves exposure and may improve anti-lymphoma imunity Effector CD4 + T cell Cytotoxic CD8 + T cell Tumor peptide MHC class II Cross-presentation. TCR MHC class I Dendritic cell FcgRIIIa FcgRIIa CD11b Cartron G et al, Blood 2004; 104:

20 FLIRT Trial Control arm J1 J8 J15 J21 E E R Experimental arm J1 J8 J15 J21 E M3 M5 M7 M9 E Rituximab iv 375 mg/m 2 Rituximab sc 1400 mg E Evaluation Endpoint: PFS Hypothesis: Control arm: median 23.5 m vs median 45 month in experimental arm: Number of patients: 210 First patient: Q1-Q2 2014

21 Ancillary studies A ci ary studies FCGRT and FcRn Rituximab PK and variability Immunity against FL Ag Prognostic value of t(14;18)

22 Low tumor burden FL Conclusions W&W +++ Rituximab: 4 to 8 or retreatment Radiotherapy? Still given in stage 1 in many countries Recommendation: No RT alone: Low dose+rituximab? Kahl BS, et al. J Clin Oncol. 2014;32:

23 Modern Standard of Care of Follicular lymphoma High tumor burden Or Need for therapy

24 What are the relevant questions? What is the best induction regimen? What is the best treatment schedule following induction? What is the best anti-cd20? Does the choice of the anti-cd20 impact the choice of induction chemotherapy? Is chemo-free an option?

25 FOLL05 Study R-CVP vs R-CHOP vs R-FC Probability N = 500, median FU 7 years TTF OS 0.25 ITT HR *(95CI) P R-CHOP 0.73 ( ) R-FM 0.70 ( ) Years R-CVP R-CHOP R-FM Years R-CVP R-CHOP R-FM Luminari et al, ICML 2017, abstr 15

26 FOLL05 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 R-CHOP is associated with the best efficacy/toxicity ratio

27 Survival Distribution Function FL: StiL vs BRIGHT study (PFS) 1.0 inhl BR R-CHOP-CVP At Risk = BR = R-CHOP/R-CVP yr rate % (95% CI): 70.3 (62.8, 76.5) vs 62.0 (54.1, 68.9) HR = 0.70 ( ; P = ) Time (months) Rummel MJ, et al. Lancet Hawkins et al. ICML 2017; abstract 131.

28 Benda versus CHOP Stil-NHL PRIMA:PFS -R-CHOP arm Median for R-CHOP+ observation : 40.9 mo Median for R-CHOP+ observation : 54,7 mo

29 Bendamustine plus Rituximab versus CHOP plus Rituximab as First-Line Treatment in Patients with Indolent Lymphomas: 10-year updated results from the StiL NHL study on behalf of the StiL (Study Group indolent Lymphomas, Germany) Mathias Rummel, Georg Maschmeyer, Arnold Ganser, Andrea Heider, Ulrich v. Grünhagen, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz Albert Dürk, Harald Ballo, Martina Stauch, Wolfgang Blau, Alexander Burchardt, Jürgen Barth, Frank Kauff, Axel Hinke, and Wolfram Brugger on behalf of the StiL MJR

30 Probability Time to next treatment (117 months follow-up) 1 0,75 months (median) salvage (events) B-R n. y. r. 77 CHOP-R ,5 0,25 0 Hazard ratio, 0.55 (95% CI ) p < Time (months) MJR

31 Overall survival according to entities Follicular Waldenstroem 1 1 0,75 0,75 0,5 0,5 0,25 0 B-R CHOP-R ,25 0 B-R CHOP-R Small lymphocytic Marginal zone 1 1 0,75 0,75 0,5 0,5 0,25 0 B-R CHOP-R ,25 0 B-R CHOP-R MJR

32 Probability Overall survival: LDH elevated ( > 240 U/l ) median deaths 1 B-R 130 mo 37 (44%) CHOP-R 127 mo 31 (46%) 0,75 0,5 0,25 0 Hazard ratio, 1.01 (95% CI ) p = Time (months) MJR

33 Probability OS: follicular, FLIPI high (3-5) (n=127) 1 0,75 0,5 0,25 0 Hazard ratio, 1.04 (95% CI ) p = yrs deaths B-R 56.3% 26 (41%) CHOP-R 59.3% 27 (42%) Time (months) MJR

34 B-R vs CHOP-R - secondary malignancies (2nd-NPL) B-R (n=215) CHOP-R (n=205) Pat. with 2nd-NPL * nd-NPL Prostate Colon/gastric Bronchial Kidney / urothel Pancreatic Breast Other carcinoma MDS AML - 1 * Patients may have reported more than 1 new malignancy

35 Conclusion: B-R vs CHOP-R Prolonged TTNT for B-R No difference in Overall Survival Fewer salvage treatments needed after initial B-R No increased rate of 2nd NPL after B-R compared to CHOP-R Achieving a CR resulted in a longer overall survival Hint for a longer OS for B-R in the subgroup with initial low LDH OS rate at 10 years is 70% with 6 x B-R (without R-maintenance)

36 Symptomatic, high burden FL Top 5 Regimens for FL From 2012 to 2014 Follicular Lymphoma LOT1 Top 5 Regimens 11% 4% 19% 31% 35% Bendamustine + rituximab (n = 489, 35.0%) Rituximab (n = 431, 30.9%) R-CHOP (n = 266, 19.1%) R-CVP (n = 153, 11.0%) Other (n = 57, 4.1%) *1396 pts with FL met the inclusion/exclusion criteria and started LOT1 regimens between 6/2012-6/2014. Market Connect: McKesson Specialty Health

37 Treatment options following R-Chemo induction Consolidate with ASCT? 6 8 x R-Chemo Maintenance with rituximab? PRIMA study Consolidate with RIT? FIT, SWOG study

38 FIT Study Schema Patients with previously untreated follicular lymphoma First-line therapy with chlorambucil, CVP,CHOP, CHOP-like, fludarabine combination, or rituximab combination INDUCTION NR PD NOT ELIGIBLE Start of study 6-12 weeks after last dose of induction CR/CRu or PR R A N D O M I Z A T I O N 90 Y-ibritumomab (n = 207) Rituximab 250 mg/m 2 IV on day 7 and day Y-ibritumomab 14.8 MBq/kg (0.4 mci/kg) on day 0 CONSOLIDATION No further treatment (n = 202) CONTROL CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CVP = cyclophosphamide, vincristine, prednisone; NR = no response; PD = progressive disease. Morschhauser et al. J Clin Oncol. 2008;26:

39 Cumulative percentage Overall PFS for Treatment Groups 100 Hazard ratio, % CI, P < Y-Ibritumomab n = 207 Median PFS = 4.1 y 8-y PFS = 41% Control 90 Y-ibritumomab 25 0 N F Control Y-ibritumomab Years At risk: Control n = 202 Median PFS = 1.1 y 8-y PFS = 22%

40 Cumulative percentage Time to Next Treatment (TTNT) 100 HR = 0.47 (95% CI: ) P < Y-Ibritumomab n = 207 Median TTNT = 8.1 y Control n = 202 Median TTNT = 3.0 y Control 90 Y-ibritumomab N F Control Y-ibritumomab Years At risk:

41 Incidence of Secondary Malignancies Secondary Malignancies, n (%) Control (n=202) 90 Y-Ibritumomab (n=207) Total (N=409) Overall total (P = 0.086) 14 (7) 26 (13) 40 (10) AML/MDS 1* (0.5) 7 (3) 8 (2) Pancreas 3 (1) 3 (1) Prostate 3 (1) 3 (1) Other 13 (6) 13 (6) 26 (6) Median time from study registration to incidence of secondary AML/MDS was 4.6 y for Control vs 4.8 y for 90 Y-Ibritumomab No additional late toxicities or congenital malformations were detected *Patient received 90 Y-Ibritumomab during follow-up, followed by secondary AML/MDS 2.9 years later.

42 SWOG study Progression Free Survival 100% 80% 60% 40% 20% 0% Median FU 4.9 yr CHOP -RIT CHOP-R At Risk Relapse or Death sided, multivariate p =.11 2-Year Estimate 80% 76% CHOP-RIT CHOP-R Years from Registration S0016

43 High tumor burden FL PRIMA 6 years follow-up Progression free survival from randomization 6 years = 59.2% HR= 0.57 P< years = 42.7% Median follow-up since randomisation : 73 months

44 PRIMA 6 years follow-up Overall survival 6 years = 88.7% 6 years = 87.4% HR= P=.885 Median follow-up since randomisation : 73 months

45 ZAR study: Design Registration Induction Consolidation / Maintenance 90 Y-Ibritumomab tiuxetan 1 dose Untreated FL stages II IV R-CHOP x 6 R* CR/PR Follow-up 5 years Rituximab Maintenance 1 dose every 8 weeks for 24 months PDs/SDs off study *Stratification by response (CR / PR) ClinicalTrials.gov: NCT

46 Primary endpoint: Progression-free survival (PFS) 77% Rituximab (N=62; failed 14) 63% 90 Y Ibritumomab Tiuxetan (N=64; failed 25) HR=0.517 (95%CI: ) P=0.044

47 Time to next treatment (TTNT) by arm 90 Y Ibritumomab Tiuxetan Rituximab P=NS

48 Overall survival (OS) 90 Y Ibritumomab Tiuxetan Rituximab Causes of death: progression (6), GVHD (1)

49 Gallium: challenging rituximab in indolent lymphomas Bendamustine : 827, CHOP : 433, CVP : 141 ASH 2016 Marcus R, abstract 6

50 Probability INV-assessed PFS (FL; primary endpoint) R-chemo (N=601) G-chemo (N=601) Censored Pts with event, n (%) 3-yr PFS, % (95% CI) HR (95% CI), p-value* R-chemo, n= (24.0) 73.3 (68.8, 77.2) 0.66 (0.51, 0.85), p= G-chemo, n= (16.8) 80.0 (75.9, 83.6) 0 Median follow-up: 34.5 months No. of patients at risk R-chemo G-chemo Time (months) *Stratified analysis; stratification factors: chemotherapy regimen, FLIPI risk group, geographic region

51 Probability OS (FL) Pts with event, n (%) R-chemo, n= (7.7) G-chemo, n= (5.8) yr OS, % (95% CI) 92.1 (89.5, 94.1) 94.0 (91.6, 95.7) R-chemo (N=601) G-chemo (N=601) Censored HR (95% CI), p-value* 0.75 (0.49, 1.17), p= Median follow-up: 34.5 months Pts at risk, n R-chemo G-chemo Time (months) *Stratified analysis; stratification factors: chemotherapy regimen, FLIPI risk group, geographic region 53

52 Probability Probability INV-assessed PFS by chemo regimen (FL) 1.0 Post-hoc analysis: study not powered to detect differences between chemotherapy regimens in either treatment arm G-chemo arm 1.0 R-chemo arm HR* (95% CI) G-B vs R-B 0.61 (0.43, 0.86) No. of patients at risk G-B G-CHOP G-CVP G-B (N=345) G-CHOP (N=196) G-CVP (N=60) Time (months) No. of patients at risk R-B R-CHOP R-CVP R-B (N=341) R-CHOP (N=203) R-CVP (N=57) Time (months) G-CHOP vs R-CHOP G-CVP vs R-CVP 0.77 (0.50,1.20) 0.63 (0.32, 1.21) *Unstratified analysis 54

53 Gallium: MRD and PFS PFS according to MRD at the end of induction 25% relapse ASH 2016 Marcus R, abstract 6, and Pott C, abstract 613

54 Safety summary (FL) % (n) R-chemo (n=597) G-chemo (n=595) Any AE 98.3% (587) 99.5% (592) Grade 3 AEs ( 5% in either arm) 67.8% (405) 74.6% (444) Neutropenia 37.9% (226) 43.9% (261) Leucopenia 8.4% (50) 8.6% (51) Febrile neutropenia 4.9% (29) 6.9% (41) IRRs* 3.7% (22) 6.7% (40) Thrombocytopenia 2.7% (16) 6.1% (36) Grade 3 AEs of special interest by category (selected) Infections 15.6% (93) 20.0% (119) IRRs 6.7% (40) 12.4% (74) Second neoplasms 2.7% (16) 4.7% (28) SAEs 39.9% (238) 46.1% (274) AEs causing treatment discontinuation 14.2% (85) 16.3% (97) Grade 5 (fatal) AEs 3.4% (20) 4.0% (24)** Median (range) change from baseline in IgG levels at end of induction, g/l ( ) ( ) *As MedDRA preferred term; All events in MedDRA System Organ Class Infections and Infestations ; Any AE occurring during or within 24h of infusion of G or R and considered drug-related; Standardized MedDRA query for malignant or unspecified tumors starting 6 mo after treatment start; Ig levels were measured during screening, at EOI and end of maintenance and during follow-up; **Includes patient who died after clinical cut-off date from AE starting before cut-off date; n=472; n=462 56

55 Grade 5 (fatal) AEs by treatment (FL)* Number of days from Cycle 1, Day 1 Total Infections G-B N= (5.6%) 9 (2.7%) R-B N=338 G-CHOP N=191 R-CHOP N=201 G-CVP N=61 R-CVP N=56 15 (4.4%) 2 (0.6%) 3 (1.6%) 1 (0.5%) 4 (2.0%) 1 (1.6%) 1 (1.8%) Induction Maintenance Follow-up Infections and infestations Neoplasms benign, malignant, and unspecified General disorders and administration site conditions Nervous system disorders Cardiac disorders Respiratory, thoracic, and mediastinal disorders Gastrointestinal disorders Metabolism and nutrition disorders *Includes only pts who died before clinical cut-off date; this patient (G-B group) was initially assigned three causes of death (Clostridium difficile colitis, prostate cancer, and myelodysplastic syndrome); Clostridium difficile colitis was the most acute, so the patient has been assigned to the Infections and infestations category and the number of fatal AEs in G-B pts in neoplasms SOC reduced from 5 to 3 57

56 Does everyone need maintenance? Decision based on PET/MRD results?

57 Meta-analysis: toxicities of R-maintenance Event Pts RR (95% CI) Grade 3-4 AE ( ) AEs with D/C ( ) Infections ( ) Grade 3-4 Infections ( ) Vidal et al, JNCI 103:1799, 2011

58 Effect of MR after R-CHOP or BR STIL BR better than R-CHOP no maintenance BRIGHT BR a little better than R-CHOP half of patients with maintenance GALLIUM BR same as R-CHOP all had maintenance

59 Hypothesis Maintenance improves prognosis after CVP and CHOP, but not after Bendamustine Reasons could be: R needs an intact immune system to be active R is too toxic after immunosupressive chemo

60 R-bendamustine and lymphopenia 1160 pts with indolent lymphoma R-benda x 6 + R-maintenance WBC 6 600/ul 3 800/ul Lympho 1 500/ul 500/ul CD4 555/ul 118/ul IgM 0.76 g/l 0.42 g/l 124 infections (44 pneumonia, 3 pneumocystis) 17 toxic deaths (1.4 %) Burchardt, et al., abstr. 32, ICML-12, 2013

61 GALLIUM: Selected grade 3 5 AEs by chemo n (%) of pts reporting 1 event R-benda, n=338 G-benda, n=338 R-CHOP, n=203 G-CHOP, n=193 R-CVP, n=56 G-CVP, n=61 Cardiac events 12 (3.6) 13 (3.8) 5 (2.5) 6 (3.1) 0 (0.0) 4 (6.6) Neutropenia 107 (31.7) 107 (31.7) 115 (56.7) 142 (73.6) 14 (25.0) 29 (47.5) Febrile neutropenia 13 (3.8) 18 (5.3) 14 (6.9) 22 (11.4) 2 (3.6) 2 (3.3) Second malignancies 12 (3.6) 21 (6.2) 7 (3.4) 7 (3.6) 2 (3.6) 1 (1.6) Other solid tumours 9 (2.7) 11 (3.3) 7 (3.4) 4 (2.1) 2 (3.6) 0 Hematological tumours 0 3 (0.9) 0 3 (1.6) 0 0 Non-melanoma skin cancer 3 (0.9) 7 (2.1) (1.6) Infections 66 (19.5) 89 (26.3) 25 (12.3) 23 (11.9) 7 (12.5) 8 (13.1) Opportunistic infections 6 (1.8) 10 (3.0) 2 (1.0) 5 (2.6) 0 0 Hiddemann et al, ICML 2017, abstr 107

62 Grade 3 5 infections by chemo and by phase n (%) of pts reporting 1 event R-benda, n=338 G-benda, n=338 R-CHOP, n=203 G-CHOP, n=193 R-CVP, n=56 G-CVP, n=61 All study periods 66 (19.5) 89 (26.3) 25 (12.3) 23 (11.9) 7 (12.5) 8 (13.1) Induction 26 (7.7) 27 (8.0) 13 (6.4) 14 (7.3) 4 (7.1) 3 (4.9) Maintenance 39 (13.0) 51 (16.7) 11 (5.9) 7 (3.9) 1 (2.5) 5 (8.8) Observation 12 (3.8) 28 (8.8) 6 (3.1) 3 (1.6) 3 (5.7) 1 (1.7) N (%) of pts receiving G-CSF prophylaxis 48 (14.2) 54 (16.0) 108 (53.2) 112 (58.0) 13 (23.2) 10 (16.4) Hiddemann et al, ICML 2017, abstr 107 *Safety population

63 EOI Mo Mo Mo EOI Mo 18 Mo 30 Mo 36 EOI Mo 18 Mo 30 Mo 36 BL C1/C2 C4/C5 BL C1/C2 C4/C5 BL C1/C2 C4/C5 CD3+ CD4+ (cells/µl) CD4 T-cell counts over time BENDAMUSTINE CHOP CVP Hiddemann et al, ICML 2017, abstr

64 Postinduction PET status (cut-off 4) and Outcome PFS Score 4 OS Score 4 97% 63% 87% 23% HR 3.9 (95% CI , p<.0001) Median PFS:16.9 ( ) vs mo (54.7-NR) HR 6.7, 95% CI , p= Median OS: 79 months vs. NR

65 FOLL12 TRIAL DESIGN Maintenance 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

66 Towards a chemo-free first-line treatment in FL?

67 SAKK 35/98 Long term outcome R-maintenance after single agent rituximab 45% of chemo-naïve responders still in first remission at 8 years EFS in previously untreated patients responding to the induction treatment Martinelli et al. JCO 2010; 28:4480-4

68 The ugly guys CXCR4 antagonists Btk/Syk inhibitors Anti-VLA4 mab Stromal cells Anti-CTLA4 mab Anti-PD-1 mab Pro-tumoral microenvironment The bad guys Anti-PD-1 mab T FH Blood vessels Treg/ T FR IMIDs Anti-CD47 mab Btk/Syk inhibitors ITKs TAM FL cells NK IMiDs Anti-CD137 mab Th CD8 Tgd BrHPP/IL-2 Amé-Thomas Semin Cancer Biol 2014;24: 23 IMiDs Anti-CD137 mab Anti-PD-1 mab Anti-tumoral microenvironment The good guys

69 Pre-clinical rationale for lenalidomide in FL Lenalidomide is able to repair FL T-cell immunologic synapse dysfunction with autologous tumor cells in vitro (Ramsay et al., Blood 2009) Untreated (UT) Lenalidomide (Len.) CD 3 - sag P <.01 CD 3 +sa g P <.05 CD 3 - sag CD3 +sa g

70 R 2 as Frontline Combination for Follicular Lymphoma: Clinical Response BY GELF CRITERIA N=45 GELF (+) N=22 (49%) GELF (-) 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% 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% Fowler, N. et al. ICML Abst#137.

71 Percent survival R 2 as Frontline therapy in FL: PFS N=46 36 mo PFS: 81% N=46 36 mo PFS: 81% PFS (months) Fowler, N. et al. ASH 2012.

72 SAKK-Nordic 35/10 Trial design Wks. No CR/PR/MR MR >25% decrease in SPD Therapy off-protocol Ritux i.v. 375 mg/m 2 1:1 Randomization Stratification: FL grade 1-2 vs 3A Bulky vs no bulk FLIPI score 1+2 vs >3 Center First restaging Second restaging Follow-up Lenalidomide 15 mg daily Ritux i.v. 375 mg/m 2 2 wks pre-phase 2 wks post-phase NLG 79 Eva Kimby - December 9, 2014

73 Results Assessment of primary endpoint [CR/CRu] at week 23 Addition of lenalidomide to rituximab results in a significantly higher CR/CRu rate (IRR: 61% vs 36%) with increased but manageable toxicity Kimby et al. Blood (21):799, Zucca et al. Hematol Oncol (s1):105 Now the analysis of secondary endpoints at a median follow-up of 3.5 years Progression-free survival (PFS) Time to next anti-lymphoma treatment (TTNT) CR/CRu duration CR/CRu rate at 30 months (CR30) Overall survival (OS) NLG 80 Eva Kimby - December 9, 2014

74 Progression-free survival Rituximab + Lenalidomide Median PFS not reached vs 2.3 years Rituximab HR (95% CI) = 0.58 ( ) Log-Rank test p-value = 0.03 NLG 81 Eva Kimby - December 9, 2014

75 Time to new therapy Rituximab + Lenalidomide Median TTNT not reached vs 2.1 years Rituximab HR (95% CI) = 0.56 ( ) Log-Rank test p-value = 0.01 NLG 82 Eva Kimby - December 9, 2014

76 FLASH: Follicular Lymphoma Analysis of Surrogate Hypotheses Group Study Conclusions Principal candidate CR30 met the surrogacy qualification criteria for PFS overall and within trial types Correlation of treatment effects on PFS and CR30 was more marked in patients with advanced disease or high FLIPI score CR30 may be considered an appropriate primary endpoint in future first-line FL studies Sargent et a, ICML

77 CR30 and OS A significantly improved CR30 in RL RL: 42% (95% CI 30-53%) R: 19% (95% CI 11-30%) (p=0.001) OS rates at 3 years similar between the arms RL: 93% (95% CI 85-97%) R: 92% (95% CI 82-96%) NLG 84 Eva Kimby - December 9, 2014

78 The RELEVANCE Trial 1st line FL N=1000 R R 2 R-Chemo CR, CRu, PR CR, CRu, PR R 2 maintenance (lenalidomide 1 yr + rituximab 2 yrs) Rituximab maintenance (2 yrs) 6 mos. 24 mos. R-Chemo: Investigator choice of R-CHOP, R-CVP, or R-B Eligibility: Patients who need treatment (GELF criteria) Stratification: FLIPI (0-1 v 2 v 3-5), Age (>60 v 60), diameter of largest node (> 6 v 6 cm) Endpoints: PFS, CR/CRu? At 30 months R 2 Regimen: Rituximab weekly x 4, then day 1 of each cycle 2 to cycle 6, 8 weeks later responding patients continue every 8 weeks for 12 cycles Lenalidomide 20 mg x 6 cycles - CR-10 mg lenalidomide 10 mg for 12 cycles - PR- 20 mg lenalidomide 3-6 months then, 10 mg 18 cycle

79 Conclusions R-Benda is equivalent to R-CHOP G-chemo + maintenance superior to R-chemo + maintenance in untreated advanced FL Clinically meaningful improvement in PFS: 34% reduction in risk; HR=0.66 Non-fatal AEs were higher in the G arm Fatal AEs more common in patients on bendamustine in both arms PET and MRD? to decide upon maintenance duration R2 has made chemo-free therapy a near future reality but is it appropriate for all first-line FL in need of treatment? Elaborate on better frontline molecular markers to select patients Surrogate endpoint (for median PFS) adapted to chemo-free approaches needed