Unmet Medical Needs and Therapeutic Landscape for Recurrent Follicular and Marginal Zone Lymphoma

Pier Luigi Zinzani Institute of Hematology «L. e A. Seràgnoli» University of Bologna RECURRENT remains the backbone therapy in 1L and 2L FL

Stage I/II: Watch and Wait Until debilitating symptoms RT to debulk

Induction • BR (most common approach in US) • RCHOP (most common approach in EU) Follow up

Line Symptomatic • Obinutuzumab + / CHOP/ CVP

st • RCVP 1 Stage III/IV • Rituximab as monotherapy CR/ PR Consolidation/ Maintenance • Single-agent alkylators (e.g. or cyclophosphamide) ± Rituximab {in elderly patients} • Rituximab maintenance • + Rituximab (category 2B) • Obinutuzumab maintenance • {in elderly patients} (Category 2B) • Ibritumomab tiuxetan (Category 2B)

Induction Follow up • Chemo-immunotherapy Same as 1L (different chemo chosen) • Bendamustine + Obinutuzumab/ Rituximab

Line Re-biopsy • Ibritumomab tiuxetan Consolidation/ Maintenance nd CR/ PR 2 (Relapse)/ • Lenalidomide + rituximab (US Approved – May 2019) • Rituximab maintenance Refractory • Fludarabine + rituximab • HDT + ASCT / Allogenic SCT (highly selected pts) • Obinutuzumab maintenance

• Copanlisib as monotherapy • Duvelisib as monotherapy • Idelalisib as monotherapy • Rituximab as monotherapy

Line Double Relapse/ • Ibritumomab tiuxetan

rd Refractory

3 • Lenalidomide + rituximab • as monotherapy • Clinical Trials with novel drugs • BSC/other palliative therapy 3 AA: Accelerated Approval Rituximab-based combination therapies continue to show a better efficacy profile in 2L FL

Treatment Phase/ Type of Previous Segment Source N ORR CR PR mDOR PFS OS Adverse Events (Grade ≥3) Arm study/ Sponsor Therapy

• Neutropenia – 1% Relapsed/ PII/ Non McLaughlin et / • – 1% Refractory Rituximab randomized/ 166 48% 6% 42% -- ~13m -- al, 1998 RIT • Lymphopenia – 1% (P) Roche • Anemia – 1%

PII/ Non • Neutropenia – 37% Relapsed Bendamustine randomized/ ISS Robinson et al, Rituximab 54 93% 54% 39% ~21m ~23m -- • Leukopenia – 30% (P) + Rituximab (Supported by 2008 based • Thrombocytopenia – 10% Cephalon)

Obinutuzumab + PIII/ • Neutropenia – 33% Relapsed/ Bendamustine Randomized/ Rituximab 1yr - 90% • Thrombocytopenia – 11% Refractory Sehn et al, 2016 396 79% 16% 63% >25m ~29m + Roche based 2yr – 81% • Infusion related Reactions – 11% (P) Obinutuzumab (GADOLIN) • Anemia – 8% maint.

• Neutropenia – 61% PIII/ Non • Thrombocytopenia – 25% Refractory Rituximab Bendamustine randomized/ Kahl et al, 2010 100 75% 17% 58% ~9.2m ~9.3m -- • Infection – 21% (P) based Cephalon • Fatigue – 14% • Anemia – 10%

Relapsed/ PII/ Non Bartlett et al, Rituximab • Neutropenia – 8% Ibrutinib 40 30% 3% 27% -- ~10m -- Refractory randomized/ ISS 2014 based • Anemia – 5%

4 The lenalidomide-rituximab combo is now approved by the FDA, it achieved the longest mPFS (39.4 m)

Treatment Phase/ Type of Previous Segment Source N ORR CR PR mDOR PFS OS Adverse Events (Grade ≥3) Arm study/ Sponsor Therapy

Chemotherapy/ • Neutropenia – 50% Relapsed/ PIII/ Lenalidomide + Leonard et al, Immunotherapy/ • Fatigue– 2% Refractory Randomized/ 178 80% 35% 44% 36.6m 39.4m 2yr – 93% Rituximab 2018 Not refractory to • Thrombocytopenia – 3% (P) Celgene Rituximab • Infections – 15%

Relapsed/ PIII/ • Thrombocytopenia – 60% Ibritumomab Refractory Randomized/ Witzig et al,2002 Chemotherapy 143 80% 30% 50% 17m ~12.6m -- • Neutropenia –57% tiuxetan (P) Bayer (Spectrum) • Anemia – 2%

PII/ Non • Thrombocytopenia – 63% Refractory Ibritumomab Rituximab randomized/ Witzig et al,2002 57 74% 15% 59% 6.4m 6.8m -- • Neutropenia – 60% (P) tiuxetan based Spectrum • Anemia – 17%

• Leukopenia – 54% Relapsed/ PIII/ Forstpointner et • Lymphopenia – 51% RFCM Chemotherapy 93 94% 40% 54% -- >3yrs 2yr – 90% Refractory Randomized/ ISS al, 2004 • Neutropenia – 40% • Thrombocytopenia – 12%

5 New products could receive accelerated approval in 3L FL in the next 2-3 yrs. based on Phase II pivotal trials

IV Ibrutinib + O Hu5F9-G4 + EHA 2019: ORR: 61%, CR: 24% Rituximab J&J/Abbvie/BMS Forty Seven, Inc. N=138; Jul’19 N= 72; Mar’20

IV REGN1979 Zanubrutinib O ± REGN2810* + Obinutuzumab Combination Regeneron BeiGene # N=172; Nov’20 N=210; Jan’20 P

IV O O ALLO-501 Umbralisib O Planned NDA Allogene TG Therapeutics Tazemetostat submission in Q4 2019 Zydelig Therapeutics UNITY-NHL Epizyme Gilead N=420; Nov’19 # ICML 2019 N=24; Oct’21 # N=~100; May’21 P P EZH2 MT: ORR: 77%; CR: 7% EZH2 WT: ORR: 34%; CR: 6% O IV O O O Tenalisib Kymriah Parsaclisib ME-401 (INCB050465) MEI Pharma Copkitra Rhizen Novartis Verastem N=20; Feb’20 N=63; Oct’19 Incyte (TIDAL)

Monotherapy N=100; Oct’ 20 N=165, Dec’20 P P

IV IV IV Initial data IV IV IV MB CART2019.1 Yescarta REGN1979 Copanlisib JCAR018* expected in 2020 Aliqopa Miltenyi Biotec GmbH Gilead Pharma Regeneron Bayer Juno/Celgene Bayer N=110; Jun’20 N=12; Sept’19 N=160; Mar’20 N=112; Jul’24 N=25; Dec’19 P P

Phase I/II Phase II Phase III Marketed

6 Monotherapy options continue to show more favourable efficacy and safety profile in 3L FL

EFFICACY SAFETY (Grade ≥3)

Hypotension CRS mDOR mPFS mOS Diarrhea Thrombocytopenia Anemia Neutropenia

Umbralisib (Phase I/II) 53% ORR – 53% ------

4% Parsaclisib 11% ------28% 46% (INCB050465) 21% 50% ORR – 71% 44% (Phase I/II)

Kymriah 13% (Phase II) 50% 29% ORR – 79% 15m – 83% 15m – 65% -- 13%

Tazemetostat 3% ORR – 77% m+: 8.3m m+: 11.1m m+: NR EZH2 m+ 7% 70% 2% Pipeline Monotherapy Pipeline (Phase II)* WT: 13m WT: 5.7m WT: 38.4m 14% REGN1979 23% ------21% ORR – 93% 17% (Phase I) 71% 22%

17% ME-401 ------75% ORR – 75% (Phase Ib)

*The results are in mutated type (15% of all FL). In the WT ORR 34% with 7% of CR 7 Competition increased in 3L FL (in the US market) with the approval of the 3rd Pi3k inhibitor Duvelisib

EFFICACY SAFETY (Grade ≥3)

Hypotension CRS CR PR SD PD Diarrhea Thrombocytopenia mDOR mPFS mOS Anemia Neutropenia

6% 12% 5% Idelalisib 34% 11m 12.5m 20.3m 5% ORR – 54% 23% (Marketed) 8% 46%

2% 15% Copanlisib 12.2 m 11.2m 38.4m (Marketed) 33% 28%

Marketed 20% 39% ORR – 59%

Duvelisib 1% 41% ORR – 42% 10m ~8.3m ~11.1m 13% 2% (Marketed) 27%

8 A few combo options tested in this monotherapy-dominated segment (3L FL), with early stage results

EFFICACY SAFETY (Grade ≥3)

Hypokalemia Hyponatremia Thrombocytopenia mDOR mPFS mOS Febrile Netropenia Neutropenia

Hu5F9-G4 + 16% ORR – 61% Rituximab 24% ------(Phase Ib/II) 24% 37%

Zanubrutinib + ORR – 72% Obinutuzumab 6% (Phase Ib) 39% 33% -- 24.9m -- 14%

6% 5% Ibrutinib + 28% 8% 32% -- 11.1m -- 4% Nivolumab ORR – 32% (Phase I/II) 10% 22% 28% Pipeline Combination Pipeline

G100 + ------ 46% ORR – 46% (Phase I/II)

9 RECURRENT MARGINAL ZONE LYMPHOMA Rituximab remains the backbone therapy in 1L and 2L MZL

Wait and Watch or Antibiotic/Antiviral Until debilitating Stage I/II therapy/splenectomy* symptoms

Induction • ISRT Symptomatic Follow up

Line • Rituximab (Preferred for SMZL)

st • Bendamustine + Rituximab (BR) 1 Stage III/IV • R-CHOP/CVP CR/ PR Consolidation/ Maintenance • Ibritumomab tiuxetan (Category 2B) • Lenalidomide + Rituximab (Category 2B) • Rituximab Consolidation (if initially • Chlorambucil/ Cyclophosphamide ± Rituximab (Elderly) treated with rituximab monotherapy)

Induction Follow up • Imbruvica - Approved • Revlimid + Rituxan (R2) - Approved Consolidation/ Maintenance

Line • Bendamustine + Rituximab/Obinutuzumab Re-biopsy CR/ PR • Obinutuzumab maintenance (if initially nd (Relapse)/ • R-CHOP/CVP 2 treated with Bendamustine + • Rituximab Refractory Obinutuzumab) for Rituximab refractory • Chlorambucil/ Cyclophosphamide ± Rituximab (Elderly or patients Infirm) • HDT+ ASCT/Allogenic SCT

• Copanlisib as monotherapy Double Relapse/ • Duvelisib as monotherapy Line Refractory • Idelalisib as monotherapy rd

3 • Ibritumomab tiuxetan (Category 2B)

All regimens are Category 1 or 2A/2B as per NCCN guidelines *For H.Pylori infections in gastric MZL; HCV infections/splenectomy for splenic MZL

Sources: NCCN Version 4.2019, FDA Labels 11 Imbruvica monotherapy and Revlimid in combination with Rituximab are approved for 2L MZL patients

Phase/ Type of study Segment Treatment Arm Source N ORR CR PR mDOR PFS OS Adverse Events (Grade ≥3) / Sponsor

Bendamustine + Relapsed/ PIII/ Randomized/ Cheson et obinutuzumab followed by 28 66.7% ------26m -- • Neutropenia: 27.5% Refractory (Roche) al, 2018 obinutuzumab

• Neutropenia: 50% Relapsed/ PIII/ Randomized/ USFDA 31 65% 29% -- -- 20.2m 2yr – 82% • Thrombocytopenia: 2% Refractory Celgene (AUGMENT) Label • Leukopenia: 7% Revlimid + Rituxan (Approved) • Neutropenia: 34% Relapsed/ PII/ Randomized/ ASCO 2019 45 65% 38% ------• Thrombocytopenia: 6% Refractory Celgene (MAGNIFY) • Leukopenia: 5%

USFDA Label; • Anemia: 13% Relapsed/ PII/ Non-Randomized Imbruvica (Approved) Noy et al 63 46% 3.2% 42.9% -- 14m 18m – 81% • Neutropenia: 13% Refractory (JNJ) 2017 • Thrombocytopenia: 6%

12 PI3K inhibitors are included in NCCN guidelines after presenting promising results in 3L MZL patients

Phase/ Type of Segment Treatment Arm Source N ORR CR PR mDOR mPFS mOS Adverse Events (Grade ≥3) study/ Sponsor

• Hyperglycaemia – 41% PII/ Non- Relapsed/ Dreyling et • Hypertension – 23.9% Copanlisib randomized/ 23 78% 13% 65% 9m -- -- Refractory al, 2017 • Neutropenia – 25.4% Bayer • Diarrhoea – 5.6%

PII/Non- Relapsed/ Flinn et al, • Neutropenia – 28% Duvelisib randomized/Vera 18 39% 6% 33% NR 15.5m -- Refractory 2019 • Diarrhoea – 17% stem

PII/ Non Relapsed/ Martin et al, Idelalisib randomized/ 15 47% 7% 40% 18.4 6.6m -- • Neutropenia – 12% Refractory 2015 Gilead

13 PI3K inhibitors demonstrated a favorable efficacy and safety profile in double relapse/refractory patients (3L)

EFFICACY SAFETY (Grade ≥3)

Fattigue Hyperglycemia mDOR mPFS mOS Diarrhea Thrombocytopenia Anemia Neutropenia

Hu5F9-G4 + 16% ORR – 61%; MZL 15% Rituximab 24% (N=3), results mixed ------(Phase I/II) 24% 37% With FL patients Combination 17% Duvelisib ------28% (Phase II) 6% 33% ORR – 39%

13% ORR – 78% 44% Copanlisib 17.4m 24.2m NR 13% (Phase II) 13% 65%

Monotherapy 7% Idelalisib 47% ORR – 47% 20% (Phase II) ------7% 40% 20%

14 Revlimid plus Rituximab (R2), only combination, was recently approved by the FDA in May 2019 in ≥2L MZL

EFFICACY SAFETY (Grade ≥3)

Anemia Nausea CR PR SD PD mDOR mPFS mOS Fatigue Thrombocytopenia Neutropenia

Lenalidomide MAGNIFY: ORR – 65% 35 29 MAGNIFY: MAGNIFY: 38.4m SoC + Rituximab* AUGMENT: ORR: 65% -- 5% 35.8m AUGMENT: 20.2m 6% (Approved) 34%

15 Monotherapies have shown promising results, with Imbruvica already approved by the FDA in ≥2L MZL

EFFICACY SAFETY (Grade ≥3)

mDOR mPFS mOS Diarrhea Thrombocytopenia Anemia Neutropenia

10% 7% Umbralisib* 36% NR -- -- 7% (Phase IIb) 19% 33% ORR – 52%

14% REGN1979 21% ORR – 60% (Phase I) 40% 20% ------17%

Pipeline 9% 10% Parsaclisib 8% 33% 44% ORR – 78% 20% (Phase I/II) ------

Zanubrutinib 78% ORR – 78% 9% (Phase II) ------9%

5% Imbruvica 6% 3% 43% ------13% (Approved) ORR – 46% 13%

16 THE ROLE OF BETALUTIN ® Betalutin®: promising safety and efficacy in R/R FL*

• In a phase I/IIa study (LYMRIT 37-01) Betalutin® was administered to 74 elderly, heavily pre- treated recurrent iNHL patients with advanced stage disease at baseline • Betalutin® was well tolerated, with most common grade 3-4 adverse events being transient and reversible cytopenias • A promising response rate from a single administration Betalutin® was observed in all patients (ORR = 61%, CR rate = 28%) • When administered to Follicular Lymphoma patients with more than 2 prior lines of therapy, the ORR was 70% and the CR rate 32% • Betalutin was also effective in a subset (n=9) of Marginal Lymphoma patients (ORR = 78%, CR rate = 44%) • Responses were durable, in particular in complete responders

*Kolstad A, et al. Abstract 2879, ASH 2018 ** MZL – Marginal Zone Lymphoma 18 Betalutin® continues to be a novel and effective therapy amongst single- agent 3L FL competitors

Pts.’ mDOR Mechanism of Median Route of Administration Source CR ORR (months) Action Age Kolstad et al, ASH 2018 ® 32% IV infusion (one-time administration), preceded by 1 CD37-targeting Betalutin 13.6** 68 (37 3L FL pts.); **Latest 70% RTX and 1 RIT (Phase I-2) company update (all pts.)

Idelalisib* Prescribing info 8% >12.5 62 Oral, twice daily Pi3k inhibitor (Marketed) (72 patients) 54% Copanlisib* 14% IV infusion (weekly – 3 weeks on and 1 week off) until Prescribing info (Marketed) 14.1 62 Pi3k inhibitor 59% progression (104 patients) Duvelisib* Prescribing info 1% 10 64 Oral, twice daily, until disease progression Pi3k inhibitor (Marketed) 42% (83 patients) Parsaclisib 59 (part A Forero-Torres et al, 21% N/A Oral, once daily Pi3k inhibitor (Phase I/II) 71% 66 (part B) ASH 2017 (4 patients) Line Tazemetostat rd 7% Epizyme, ICML 2019 3 EZH2m+ 8.3 61 Oral, twice daily EZH2 inhibitor (Phase II) 77% (43 patients) ASCO 2019 ME401 N/A 64.5 Oral, once daily Pi3k inhibitor (Phase 1b) 75% (30 patients)

IV infusion of re-engineered autologous T-cells, CAR- Novartis, ASH 2016 Kymriah 50% 15 (83%) 59 (Phase II) 79% preceded by leukapheresis and CT therapy (14 patients) Anti-CD20 X Anti- # 71% Regeneron Pharma, EHA REGN1979 NR 67 Multiple dose levels of REGN1979;IV CD3 bispecific 93% 2019 (21 pts.) (Phase I)

Umbralisib Oral; daily dose; until disease progression or off Matthews et al, ASH 2017 NR 66 Pi3k inhibitor (Phase I) 53% study (146 pts.)

• All agents are approved based on different phase results as mentioned along with asset • * Accelerated Approval basis on Phase II studies 19 • Results from different trials for comparison purpose only and NOT head to head studies • # at doses ≥5 mg Betalutin® is a novel, promising alternative in 2L MZL patients

CR ORR mDOR Mechanism of Source Route of Administration Additional care required (months) Action

® IV infusion (one time Betalutin 44% CD37-targeting No - convenient one-time -- Kolstad et al, ASH 2018 administration), preceded by 1 RTX (Phase I-2) RIT administration 78% (9 patients) and 1 lilotomab

Line Copanlisib 13% Panayiotidis et al, IV infusion (weekly – 3 weeks on rd (Phase I/II) 17.4 (23 patients) Pi3k inhibitor No

3 78% and 1 week off) until progression Duvelisib 6% ICML 2019 Oral, twice daily, until disease (Phase II) NA Pi3k inhibitor No 39% (18 patients) progression

Idelalisib 7% Blood 2015 18.4 Pi3k inhibitor Oral, twice daily Combination with other treatments may (Phase II) 47% (15 patients) increase toxicity

20 Betalutin® is a novel, promising alternative in 2L MZL patients

CR ORR mDOR Mechanism of Source Route of Administration Additional care required (months) Action ® Betalutin 44% IV infusion (one time Kolstad et al, ASH 2018 CD37-targeting No - convenient one-time (Phase I) -- administration), preceded by 1 RTX 78% (9 patients) RIT administration and 1 lilotomab

Umbralisib 19% ICML 2019 800 mg oral; QD; until progression

Line NR Pi3k inhibitor No (Phase IIb) (42 patients) or unacceptable toxicity

nd 52% 2 Zanubrutinib ASCO 2017 (Phase II) -- BTK inhibitor 160 mg oral; BID No 78% (9 patients) Parsaclisib 33% Andres et.al (Phase II) 4.4 months Pi3k inhibitor 10 to 45 mg; QD No 78% (9 patients)

REGN1979 40% EHA 2019 Anti-CD20 x anti- REGN1979 multiple dose levels; IV No (Phase I) (6 patients) CD3 bispecific IgG4 60% NR antibody

3% Imbruvica Not Prescribing Info 560 mg ; Oral; QD No evaluable BTK inhibitor (Approved) 46% (63 Patients)

21 FL: Comparison with Competitors

• BETALUTIN® vs «old» PI3Ki (idelalisib, • BETALUTIN® vs TAZEMETOSTAT: copanlisib, duvelisib): • Better: • Better: • ONE SHOT • ORR • No extra-hematological toxicities • CR • Only in 15% of FL patients • mDOR (=with COPA) • mDOR • ONE SHOT • BETALUTIN® vs BISPECIFIC MoAb: • No extra-hematological toxicities • Better: ® • BETALUTIN vs «new» PI3Ki (parsaclisib, • No extra-hematological toxicities umbralisib, ME-401): • No CRS or NT • Better: • More consolidated data • ONE SHOT • More consolidated data with same ORR and CR • No extra-hematological toxicities

22 MZL: Comparison with Competitors

• The game is absolutely open with: • Copanlisib (until the progression) • Duvelisib ( ORR/CR) • Idelalisib ( ORR/CR) • Zanubrutinib («MAGNOLIA» study is ongoing) • Parsaclisib («CITADEL-204» study is ongoing)

• At this point it is really quite close to the possibility of FDA/EMA official indication for umbralisib (comparing with ibrutinib its results are better in term of CR)

• REGN1979: too toxic regimen for MZL!!!

23