Session V: Follicular Lymphoma New possibilities for relapsing follicular lymphoma Massimo Federico, MD

Improving Survival of Follicular NHL: OS by Treatment 100 1990s-2000s 80 60 1990s Overall Survival (%) 40 1980s 4-Year N Death Estimate CHOP + Mab 179 18 91% ProMace 425 189 79% CHOP 356 226 69% 20 2 4 6 8 10 Years After Registration Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Fisher RI, et al. J Clin Oncol. 2005; 23:8447-8452.

TTF by arm (N=504) Events = 213 P R-CHOP vs R-CVP 0.003 R-FM vs R-CVP 0.006 R-CHOP vs R-FM 0.763 Federico M, et al. J Clin Oncol. 2013 Apr 20;31(12):1506-13

Response Duration Progressively Shortens with Each Relapse Johnson WM, et al. J Clin Oncol. 1995;13(1):140-147

So, a significant proportion of patients need a second chance

First relapse Observation for asyntomatic FL High dose CHT followed by ASCT or alloSCT CHT with monoclonal antibody-based therapy depending on initial therapy (R-CVP, R-CHOP, BR) RIT Monoclonal antibody-based therapy (R) Clinical trial, if available

Recommended treatment strategies in follicular lymphoma

Recommended treatment strategies in follicular lymphoma

Warm (and not Hot) Topics: Relapsed FL To transplant or not to transplant?

Modena Cancer Registry Diagnosis of FL from 1997 to 2012 124 relapsed 13/342 (4%) PBSC first line 9/124 (7%) PBSC second line 22 patient received transplant Median Follow up 134 months one pt who received second line PBSC died 54 mo after diagnosis

Progression-free survival High-dose therapy improves PFS and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. Progression-free survival Schouten H C et al. JCO 2003;21:3918-3927 ©2003 by American Society of Clinical Oncology

Consensus was reached that: Indications for HSCT in patients with FL: a consensus project of the EBMT-Lymphoma Working Party Consensus was reached that: high-dose therapy with ASCT is also appropriate in second/subsequent chemo-sensitive relapses; allotransplant (preferably a reduced intensity conditioning-allotransplant) should be considered at relapse after HDT with ASCT. Montoto S. et al Haematologica 2013; vol. 98, n.7, 1014-1021

2015 Jan;90(1):56-61

Aim of the study Primary Endpoint Secondary endpoints To analyse any effect of the type of first-line treatment (alkylating agents vs anthracyclines vs nucleoside analogues +/- rituximab) on the outcome of second-line treatments received by patients with relapsed follicular lymphoma To potentially identify an optimal sequence of first-line and salvage treatments in follicular lymphoma Primary Endpoint Time to next treatment after first relapse (Time to next treatment – TTNT) Secondary endpoints Progression free survival after relapse Overall survival

Inclusion criteria First-line treatment with one of the following regimens: AA: alkylating agents both as monotherapy or in combination (e.g. CVP) +/- rituximab AC: anthracyclin containing CHOP or CHOP-like regimens +/- rituximab NA: nucleoside analogues containing regimens (e.g. fludarabine)+/- rituximab Second-line treatment after relapse occurred during the period from 2000 and 2008

Rossi G. et al AJH 2015 Jan;90(1):56-61

TTNT after relapse by sequence of first- and second-line treatments HR = 2.10 (95CI 1.50-2.93), P<0.001 AC → HSCT Other sequences CI95% Rossi G. et al adapted

Conclusions First-line AC-containing chemotherapy obtained a better TTNT after relapse compared to AA- or NA-containing therapies. Second-line treatment programs including HSCT obtained the best TTNT compared to any other regimen. the efficacy of salvage auto-HSCT was highest when patients had received AC-containing CHT at first-line First-line AC-CHT followed by autologous HSCT at relapse was the most effective treatment sequence in patients with follicular lymphoma Rossi G. et al AJH 2015 Jan;90(1):56-61

FOLL05 Salvage treatment % Chemotherapy 98 55 PBSCT 33 19 RT 9 5 W&W 12 7 Palliative 3 2 Death before therapy 1 Loss to FU NA 11

FOLL05 PFS after relapse (# events 35/131) N (%) SAR % 3-yrs CHT 98 (75) 86 (77-92) PBSCT 33 (25) 87 (69-95) Log-rank, p =0.966 Renyi, p=0.833

FOLL05 Survival after relapse (SAR, n=131) N (%) SAR % 3-yrs CHT 98 (75) 86 (77-92) PBSCT 33 (25) 87 (69-95) Log-rank, p =0.327 Renyi, p=0.647

The Follicular Lymphoma Chronicle Journal Transplant or RIT??

Kaplan-Meier plots for progression-free survival (PFS) Morschhauser, F. et al. J Clin Oncol; 26:5156-5164 2008

ARA-C with R in vivo purging ARA-C with R in vivo purging A PHASE III MULTICENTER, RANDOMIZED STUDY COMPARING CONSOLIDATION WITH 90YTTRIUM-LABELED IBRITUMOMAB TIUXETAN (ZEVALIN®) RADIOIMMUNOTHERAPY VS AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) IN PATIENTS WITH RELAPSED FOLLICULAR LYMPHOMA (FL) AGED 18-65 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

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

Active Drugs in R/R follicular lymphoma Bendamustine Lenalidomide ………. ………..

Bendamustine Phase N ORR CR PFS BR II 63 90% NR 24 Rummel et al. JCO 2005 66 92% 55% 32 Robinson et al. JCO 2008 BR vs FR III 219 82% vs 49% 39% vs 16% 30 vs 12 Rummel et al., ASH 2010 B mono 100 75% 17% 9 Kahl et al. 74 77% 34% 8.3 Friedberg et al., JCO 2008 Overall response rate (ORR) between 82% and 92% with a median PFS of 23 to 30 months in combination with rituximab Most important side effects of single-agent bendamustine or the BR combination were grade 3 or 4 neutropenia, neutropenic fever, and infections , largely manageable

Bendamustine: Italian experience Relapsed/refractory First line elderly FL Retrospective analysis 1/07-12/09 175 NHL in 24 Italian centers 48 FL, 60 indolent, 34 DLBCL 79 relapse, 35 refractory, 61 PD Median age 69 years ORR 71% CR 29% ORR 23% Benda, 77% BR FL 17% Benda, 72% BR FLE09 study Elderly patients with FL at diagnosis Rituximab-BM 4 months+ 4 Rituximab ORR 83% after R-BM 93% end of treatment Rigacci et al Ann Hematol 91;1013, 2012 Boccomini et al 12 ICML Lugano 2013

Lenalidomide Lenalidomide single agent in FL Relapsed refractory grade 1-2 FL Lenalidomide 25 mg days 1-21 q 28 N° pts ORR % CR % PFS OS FU Witzig NHL 001 22 27 9 4.0 N/A 4.4 Grade 3 FL N° pts ORR % CR % PFS OS FU Wiernick NHL 002 6 60 20 4.0 N/A 3.7 Witzig NHL 003 19 42 11 8.9 9.2

Lenalidomide and rituximab Phase II study of Rituximab-Lena Frontline treatment. Phase II study of Rituximab-Lena R/R indolent NHL Pts ORR% CR (%) FL 17 94% 16 (34%) SLL 3 100% 1 (33%) MZL 8 63% 4 (50%) Pts ORR% CR (%) FL 22 77% 9 (41%) SLL 2 50% 1 (50%) MZL 3 67% 2 (67%) Fowler, ASH 2009. Tuscano , BJH, 2014, 165, 375–381 CALGB 50401 phase II randomized study in recurrent FL Rituximab and Lenalidomide vs Lenalidomide alone Pts ORR% EFS neutropenia Lena only 45 49% 1.2 yrs 16% R2 44 75% 2.0 yrs 19% Leonard, ASCO 2012

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

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

Renoir Study Participants: 50 Enrollement period: 36 months

Single agent or combination CHT Second or greater relapse Single agent or combination CHT Monoclonal antibody-based therapy Immunomodulatory Agents High dose CHT followed by ASCT or alloSCT

Promising novel agents in the clinic Monoclonal antibodies Unlabeled Radiolabeled Immunoconjugates Novel constructs and bispecifics Proteosome inhibitors BTK, PI3K inhibitors

Potential Antibody Targets for B-Cell Lymphomas Evolving Standards of Care in Non-Hodgkins Lymphoma VA Indolent Lymphoma v4 12/7/2018 11:59 PM 12/7/2018 11:59 PM Potential Antibody Targets for B-Cell Lymphomas CD40 CD52 CD37 CD74 CD80 CD23 Death receptors CD22 HLA-DR CD20 CD19 Surface immunoglobulin CD5 B cell Cheson BD, et al. N Engl J Med. 2008;359;613-626. Copyright © [year of publication] Massachusetts Medical Society. All rights reserved. Philip J. Bierman, M.D. 36

Antibodies in Follicular Lymphoma GA101: Anti-CD20 antibody Obinutuzumab (GA101) in Patients With R/R Indolent NHL: Results From the Phase II GAUGUIN Study Salles GA, et al. J Clin Oncol. 2013, 31 (23) pp. 2920-2926

The 1,600/800-mg dose schedule of obinutuzumab (GA101) has encouraging activity with an acceptable safety profile in relapsed/refractory iNHL. Salles GA, et al. J Clin Oncol. 2013, 31 (23) pp. 2920-2926

Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000) At induction end, 96% (27/28) of patients receiving G-CHOP (CR, 39% [11/28]) and 93% (26/28) receiving G-FC (CR, 50% [14 of 28]) achieved responses. G-CHOP and G-FC had an acceptable safety profile with no new or unexpected AEs, but G-FC was associated with more AEs than G-CHOP. Radford J, et al. Blood 2013 Aug 15;122(7):1137-43

MEDI-551, a Humanized Monoclonal Antibody directed against CD19, in subjects with Relapsed or Refractory Advanced B-cell Malignancies Hamadani M et al. Blood 2013;122:1810 ©2013 by American Society of Hematology

Complete remissions (CRs) of chemotherapy-refractory large-cell lymphomas in patients receiving anti-CD19 chimeric antigen receptor T cells. James N. Kochenderfer et al. JCO 2015;33:540-549 ©2015 by American Society of Clinical Oncology

Betalutin— Mechanism of action

Treatment schedule

Best tumour response by dose level

Small-Molecule Inhibitors in Follicular Lymphoma Ibrutinib (PCI-32765): BTK inhibitor Idelalisib (GS-1101): PI3K delta inhibitor IPI-145: PI3K delta and gamma inhibitor Ibrutinib (PCI-32765) Idelalisib (CAL-101, GS-1101) IPI-145

Antitumor response in all evaluable patients. (A) Best responses in the 48 patients evaluated by computed tomography scan for change from baseline in the sum of the largest diameter of each target lesion; negative values indicate tumor shrinkage. (B) Time on study for all 56 patients grouped by histology; bars describe the reason for patient discontinuation.

Idelalisib EMA Indication: in combination with R for the treatment of adult patients with CLL: - who have received at least one prior therapy, or - as first line treatment in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy.   as monotherapy for the treatment of adult patients with FL that is refractory to two prior lines of treatment.

Idelalisib PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. Figure 1. Best Overall Response Gopal AK et al. N Engl J Med 2014 Mar 13;370(11):1008-18.

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

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