Unmet Medical Needs and Therapeutic Landscape for Recurrent Follicular and

Marginal Zone Lymphoma

Pier Luigi ZinzaniInstitute of Hematology «L. e A. Seràgnoli»

University of Bologna

RECURRENT FOLLICULAR LYMPHOMA

Rituximab remains the backbone therapy in 1L and 2L FL3rd

Line

2ndLi

ne1st

Line

Stage I/II:RT to debulk

Watch and Wait Until debilitating symptoms

Re-biopsy (Relapse)/Refractory

• Copanlisib as monotherapy• Duvelisib as monotherapy• Idelalisib as monotherapy • Rituximab as monotherapy• Ibritumomab tiuxetan • Lenalidomide + rituximab• Ibrutinib as monotherapy• Clinical Trials with novel drugs• BSC/other palliative therapy

Stage III/IV CR/ PR

Follow up

• Rituximab maintenance• Obinutuzumab maintenance• Ibritumomab tiuxetan (Category 2B)

Consolidation/ Maintenance

• Chemo-immunotherapy Same as 1L (different chemo chosen) • Bendamustine + Obinutuzumab/ Rituximab• Ibritumomab tiuxetan • Lenalidomide + rituximab (US Approved – May 2019)• Fludarabine + rituximab

Induction

CR/ PR

Follow up

• Rituximab maintenance• HDT + ASCT / Allogenic SCT (highly selected

pts)• Obinutuzumab maintenance

Consolidation/ Maintenance

Double Relapse/ Refractory

Symptomatic

• BR (most common approach in US)• RCHOP (most common approach in EU)• Obinutuzumab + Bendamustine/ CHOP/ CVP• RCVP• Rituximab as monotherapy• Single-agent alkylators (e.g. Chlorambucil or cyclophosphamide) ±

Rituximab {in elderly patients}• Lenalidomide + Rituximab (category 2B)• Ibritumomab tiuxetan {in elderly patients} (Category 2B)

Induction

AA: Accelerated Approval3

Rituximab-based combination therapies continue to show a better efficacy profile in 2L FL

Segment TreatmentArm

Phase/ Type of study/ Sponsor Source Previous

Therapy N ORR CR PR mDOR PFS OS Adverse Events (Grade ≥3)

Relapsed/ Refractory

(P)Rituximab

PII/ Non randomized/

Roche

McLaughlin et al, 1998

Chemotherapy/ RIT 166 48% 6% 42% -- ~13m --

• Neutropenia – 1%• Thrombocytopenia – 1%• Lymphopenia – 1%• Anemia – 1%

Relapsed (P)

Bendamustine + Rituximab

PII/ Non randomized/ ISS

(Supported by Cephalon)

Robinson et al, 2008

Rituximab based 54 93% 54% 39% ~21m ~23m --

• Neutropenia – 37%• Leukopenia – 30%• Thrombocytopenia – 10%

Relapsed/ Refractory

(P)

Obinutuzumab +

Bendamustine +

Obinutuzumab maint.

PIII/ Randomized/

Roche(GADOLIN)

Sehn et al, 2016 Rituximabbased 396 79% 16% 63% >25m ~29m 1yr - 90%

2yr – 81%

• Neutropenia – 33%• Thrombocytopenia – 11%• Infusion related Reactions – 11%• Anemia – 8%

Refractory (P) Bendamustine

PIII/ Non randomized/

CephalonKahl et al, 2010 Rituximab

based 100 75% 17% 58% ~9.2m ~9.3m --

• Neutropenia – 61%• Thrombocytopenia – 25%• Infection – 21%• Fatigue – 14%• Anemia – 10%

Relapsed/ Refractory Ibrutinib PII/ Non

randomized/ ISSBartlett et al,

2014Rituximab

based 40 30% 3% 27% -- ~10m -- • Neutropenia – 8%• Anemia – 5%

4

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

Segment TreatmentArm

Phase/ Type of study/ Sponsor Source Previous

Therapy N ORR CR PR mDOR PFS OS Adverse Events (Grade ≥3)

Relapsed/Refractory

(P)

Lenalidomide + Rituximab

PIII/ Randomized/

Celgene

Leonard et al, 2018

Chemotherapy/Immunotherapy/ Not refractory to

Rituximab

178 80% 35% 44% 36.6m 39.4m 2yr – 93%

• Neutropenia – 50%• Fatigue– 2%• Thrombocytopenia – 3%• Infections – 15%

Relapsed/ Refractory

(P)

Ibritumomab tiuxetan

PIII/ Randomized/

Bayer (Spectrum)Witzig et al,2002 Chemotherapy 143 80% 30% 50% 17m ~12.6m --

• Thrombocytopenia – 60%• Neutropenia –57%• Anemia – 2%

Refractory (P)

Ibritumomab tiuxetan

PII/ Non randomized/

SpectrumWitzig et al,2002 Rituximab

based 57 74% 15% 59% 6.4m 6.8m --• Thrombocytopenia – 63%• Neutropenia – 60%• Anemia – 17%

Relapsed/ Refractory RFCM PIII/

Randomized/ ISSForstpointner et

al, 2004 Chemotherapy 93 94% 40% 54% -- >3yrs 2yr – 90%

• Leukopenia – 54%• Lymphopenia – 51%• 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

Com

bina

tion

Mon

othe

rapy

Phase I/II Phase II Phase III Marketed

CopanlisibBayer

N=25; Dec’19

IV

Ibrutinib + Nivolumab

J&J/Abbvie/BMSN=138; Jul’19

O

KymriahNovartis

N=63; Oct’19

IV

JCAR018*Juno/CelgeneN=110; Jun’20

IVAliqopaBayer

IV

#

YescartaGilead PharmaN=160; Mar’20

IV

CopkitraVerastem

OTenalisib

RhizenN=20; Feb’20

O

P

Zanubrutinib+ Obinutuzumab

BeiGeneN=210; Jan’20

O

P#

Parsaclisib(INCB050465)

IncyteN=100; Oct’ 20

O

P

REGN1979Regeneron

N=112; Jul’24

IV

REGN1979 ±REGN2810*

RegeneronN=172; Nov’20

IV

ME-401MEI Pharma

(TIDAL)N=165, Dec’20

O

MB CART2019.1Miltenyi Biotec GmbH

N=12; Sept’19P

TazemetostatEpizyme

N=420; Nov’19

O

#P

ZydeligGilead

O

P

Initial dataexpected in 2020

IV

ALLO-501Allogene

TherapeuticsN=24; Oct’21

IV Planned NDA submission in Q4 2019

UmbralisibTG Therapeutics

UNITY-NHLN=~100; May’21

O

P ICML 2019EZH2 MT: ORR: 77%; CR: 7%EZH2 WT: ORR: 34%; CR: 6%

Hu5F9-G4 + Rituximab

Forty Seven, Inc.N= 72; Mar’20

IVEHA 2019: ORR: 61%, CR: 24%

6

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

*The results are in mutated type (15% of all FL). In the WT ORR 34% with 7% of CR

TazemetostatEZH2 m+(Phase II)*

ORR – 75%

EFFICACY

17%

44%

21%

2%

28%

14%

3%

46%

17%

11%

13%13%

4%

Hypotension CRSDiarrhea ThrombocytopeniaAnemia Neutropenia

SAFETY (Grade ≥3)

mDOR mPFS mOS

-- -- --

-- -- --

15m – 83% 15m – 65% --

m+: 8.3mWT: 13m

m+: 11.1mWT: 5.7m

m+: NRWT: 38.4m

-- -- --

-- -- --

ORR – 79%

ORR – 77%

Kymriah(Phase II)

Pip

elin

e M

onot

hera

py

REGN1979(Phase I) ORR – 93%

ME-401(Phase Ib)

Parsaclisib(INCB050465)(Phase I/II)

ORR – 71%

75%

Umbralisib(Phase I/II) 53%

21% 50%

50% 29%

7% 70%

71% 22%23%

ORR – 53%

7

Competition increased in 3L FL (in the US market) with the approval of the 3rd

Pi3k inhibitor Duvelisib

Idelalisib(Marketed)

1%

20%

8%

41%

39%

46%

33%

34%

2%

12%

CR PR SD PD

Duvelisib(Marketed)

ORR – 42%

ORR – 59%

EFFICACY

27%

28%

23%

2%

5%5%

13%

15%

6%

Hypotension CRSDiarrhea ThrombocytopeniaAnemia Neutropenia

SAFETY (Grade ≥3)

mDOR mPFS mOS

11m 12.5m 20.3m

12.2 m 11.2m 38.4m

10m ~8.3m ~11.1m

Copanlisib(Marketed)

Mar

kete

d

ORR – 54%

8

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

Zanubrutinib + Obinutuzumab(Phase Ib)

Ibrutinib + Nivolumab(Phase I/II) 10% 22%

32%28%

ORR – 61%

EFFICACY SAFETY (Grade ≥3)

mDOR mPFS mOS

-- -- --

-- 24.9m --

-- 11.1m --

-- -- --

ORR – 32%

Pip

elin

e C

ombi

natio

n

G100 +Pembrolizumab(Phase I/II)

ORR – 46%

39% 33%

46%

Hu5F9-G4 + Rituximab(Phase Ib/II) 24% 37%

24%16%

ORR – 72%

28%

14%

4%8%

6%

5%6%

Hypokalemia Hyponatremia Thrombocytopenia

Febrile Netropenia Neutropenia

9

RECURRENT MARGINAL ZONE LYMPHOMA

Rituximab remains the backbone therapy in 1L and 2L MZL

Sources: NCCN Version 4.2019, FDA Labels

3rd

Line

2nd

Line

1stLi

ne

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

Until debilitating symptoms

Re-biopsy (Relapse)/Refractory

• Copanlisib as monotherapy• Duvelisib as monotherapy• Idelalisib as monotherapy• Ibritumomab tiuxetan (Category 2B)

Stage III/IV CR/ PR

Follow up

• Rituximab Consolidation (if initially treated with rituximab monotherapy)

Consolidation/ Maintenance

• Imbruvica - Approved• Revlimid + Rituxan (R2) - Approved• Bendamustine + Rituximab/Obinutuzumab• R-CHOP/CVP• Rituximab• Chlorambucil/ Cyclophosphamide ± Rituximab (Elderly or

Infirm)

Induction

CR/ PR

Follow up

• Obinutuzumab maintenance (if initially treated with Bendamustine + Obinutuzumab) for Rituximab refractory patients

• HDT+ ASCT/Allogenic SCT

Consolidation/ Maintenance

Double Relapse/ Refractory

Symptomatic • ISRT• Rituximab (Preferred for SMZL)• Bendamustine + Rituximab (BR)• R-CHOP/CVP• Ibritumomab tiuxetan (Category 2B)• Lenalidomide + Rituximab (Category 2B)• Chlorambucil/ Cyclophosphamide ± Rituximab (Elderly)

Induction

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

11

Imbruvica monotherapy and Revlimid in combination with Rituximab are approved for 2L MZL patients

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

Relapsed/ Refractory

Bendamustine + obinutuzumab followed by

obinutuzumabPIII/ Randomized/

(Roche)Cheson et al, 2018 28 66.7% -- -- -- 26m -- • Neutropenia: 27.5%

Relapsed/ Refractory

Revlimid + Rituxan (Approved)

PIII/ Randomized/ Celgene (AUGMENT)

USFDA Label 31 65% 29% -- -- 20.2m 2yr – 82%

• Neutropenia: 50%• Thrombocytopenia: 2%• Leukopenia: 7%

Relapsed/ Refractory

PII/ Randomized/ Celgene (MAGNIFY) ASCO 2019 45 65% 38% -- -- -- --

• Neutropenia: 34%• Thrombocytopenia: 6%• Leukopenia: 5%

Relapsed/ Refractory Imbruvica (Approved) PII/ Non-Randomized

(JNJ)USFDA Label;

Noy et al 2017

63 46% 3.2% 42.9% -- 14m 18m – 81%• Anemia: 13%• Neutropenia: 13%• Thrombocytopenia: 6%

12

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

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

Relapsed/ Refractory Copanlisib

PII/ Non-randomized/

Bayer

Dreyling et al, 2017 23 78% 13% 65% 9m -- --

• Hyperglycaemia – 41%• Hypertension – 23.9%• Neutropenia – 25.4%• Diarrhoea – 5.6%

Relapsed/ Refractory Duvelisib

PII/Non-randomized/Vera

stem

Flinn et al,2019 18 39% 6% 33% NR 15.5m -- • Neutropenia – 28%

• Diarrhoea – 17%

Relapsed/ Refractory Idelalisib

PII/ Non randomized/

Gilead

Martin et al, 2015 15 47% 7% 40% 18.4 6.6m -- • Neutropenia – 12%

13

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

EFFICACY SAFETY (Grade ≥3)

mDOR mPFS mOS

-- -- --

-- -- --

17.4m 24.2m NR

-- -- --

Mon

othe

rapy

Duvelisib(Phase II) ORR – 39%

Hu5F9-G4 + Rituximab(Phase I/II)

ORR – 61%; MZL (N=3), results mixed With FL patients

Copanlisib(Phase II)

ORR – 78%

Idelalisib(Phase II) ORR – 47%

24% 37%24%

16%

6% 33%

13% 65%

7% 40%47%

7%

Com

bina

tion

20%

28%

15%

20%

13%

17%

44%13%

Fattigue HyperglycemiaDiarrhea ThrombocytopeniaAnemia Neutropenia

14

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

EFFICACY SAFETY (Grade ≥3)

mDOR mPFS mOS

MAGNIFY: 35.8m

MAGNIFY: 38.4mAUGMENT: 20.2m --S

oC 35 29

CR PR SD PD

Lenalidomide + Rituximab*(Approved)

MAGNIFY: ORR – 65%AUGMENT: ORR: 65%

34%6%5%

Anemia NauseaFatigue ThrombocytopeniaNeutropenia

15

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

13%

9%

20%

17%

7%

13%

9%

8%

21%

6%

10%

14%

5%

9%

10%

Diarrhea Thrombocytopenia Anemia Neutropenia

19% 33%36%

7%

EFFICACY SAFETY (Grade ≥3)

mDOR mPFS mOS

NR -- --

-- -- --

-- -- --

-- -- --

-- -- --

Pip

elin

e

REGN1979(Phase I)

Umbralisib* (Phase IIb)

ORR – 52%

Parsaclisib(Phase I/II)

ORR – 78%

Imbruvica(Approved) 3% 43% ORR – 46%

Zanubrutinib(Phase II)

ORR – 78%78%

33% 44%

40% 20% ORR – 60%

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

18*Kolstad A, et al. Abstract 2879, ASH 2018** MZL – Marginal Zone Lymphoma

Betalutin® continues to be a novel and effective therapy amongst single-agent 3L FL competitors

Betalutin ®

(Phase I-2)

3rd

Line

53%

93%

79%

75%

77%

71%

42%

59%

54%

70%

71%

50%

7%

21%

1%

14%

8%

32%

CR ORR

• All agents are approved based on different phase results as mentioned along with asset• Results from different trials for comparison purpose only and NOT head to head studies

• * Accelerated Approval basis on Phase II studies• # at doses ≥5 mg

Copanlisib*(Marketed)

Idelalisib*(Marketed)

ME401(Phase 1b)

Duvelisib*(Marketed)

Kymriah(Phase II)

TazemetostatEZH2m+(Phase II)

REGN1979#

(Phase I)

Parsaclisib(Phase I/II)

Umbralisib(Phase I)

mDOR (months)

Pts.’ Median Age

Route of Administration Mechanism of Action Source

13.6** 68 IV infusion (one-time administration), preceded by 1 RTX and 1 lilotomab

CD37-targeting RIT

Kolstad et al, ASH 2018 (37 3L FL pts.); **Latest company update (all pts.)

>12.5 62 Oral, twice daily Pi3k inhibitor Prescribing info(72 patients)

14.1 62 IV infusion (weekly – 3 weeks on and 1 week off) until progression Pi3k inhibitor Prescribing info

(104 patients)

10 64 Oral, twice daily, until disease progression Pi3k inhibitor Prescribing info(83 patients)

N/A 59 (part A66 (part B) Oral, once daily Pi3k inhibitor Forero-Torres et al,

ASH 2017 (4 patients)

8.3 61 Oral, twice daily EZH2 inhibitor Epizyme, ICML 2019(43 patients)

N/A 64.5 Oral, once daily Pi3k inhibitor ASCO 2019(30 patients)

15 (83%) 59 IV infusion of re-engineered autologous T-cells, preceded by leukapheresis and CT

CAR-T cell therapy

Novartis, ASH 2016(14 patients)

NR 67 Multiple dose levels of REGN1979;IVAnti-CD20 X Anti-CD3 bispecific antibody

Regeneron Pharma, EHA 2019 (21 pts.)

NR 66 Oral; daily dose; until disease progression or off study Pi3k inhibitor Matthews et al, ASH 2017

(146 pts.)

19

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

Betalutin®

(Phase I-2)

3rd

Line

47%

39%

78%

78%

7%

6%

13%

44%

CR ORR mDOR (months) Source Mechanism of

Action Route of Administration Additional care required

-- CD37-targeting RIT

IV infusion (one timeadministration), preceded by 1 RTXand 1 lilotomab

No - convenient one-time administration

17.4 Pi3k inhibitor IV infusion (weekly – 3 weeks onand 1 week off) until progression No

NA Pi3k inhibitor Oral, twice daily, until diseaseprogression No

18.4 Pi3k inhibitor Oral, twice daily Combination with other treatments mayincrease toxicity

Copanlisib(Phase I/II)

Duvelisib(Phase II)

Panayiotidis et al,(23 patients)

Kolstad et al, ASH 2018(9 patients)

ICML 2019(18 patients)

Idelalisib(Phase II) Blood 2015

(15 patients)

20

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

Betalutin®

(Phase I)

2nd

Line

46%

60%

78%

78%

52%

78%

3%

40%

33%

19%

44%

CR ORR mDOR (months) Source Mechanism of

Action Route of Administration Additional care required

-- CD37-targeting RIT

IV infusion (one timeadministration), preceded by 1 RTXand 1 lilotomab

No - convenient one-time administration

NR Pi3k inhibitor 800 mg oral; QD; until progression or unacceptable toxicity No

-- BTK inhibitor 160 mg oral; BID No

4.4 months Pi3k inhibitor 10 to 45 mg; QD No

NR

Anti-CD20 x anti-CD3 bispecific IgG4

antibody

REGN1979 multiple dose levels; IV No

Not evaluable BTK inhibitor

560 mg ; Oral; QD No

Umbralisib(Phase IIb)

Zanubrutinib(Phase II)

ICML 2019(42 patients)

Kolstad et al, ASH 2018(9 patients)

ASCO 2017 (9 patients)

Parsaclisib(Phase II) Andres et.al

(9 patients)

REGN1979(Phase I)

EHA 2019(6 patients)

Imbruvica(Approved)

Prescribing Info(63 Patients)

21

FL: Comparison with Competitors

• BETALUTIN® vs «old» PI3Ki (idelalisib, copanlisib, duvelisib):

• Better: • ORR• CR• mDOR (=with COPA)• ONE SHOT• No extra-hematological toxicities

• BETALUTIN® vs «new» PI3Ki (parsaclisib, umbralisib, ME-401):

• Better: • ONE SHOT• More consolidated data with same ORR

and CR• No extra-hematological toxicities

• BETALUTIN® vs TAZEMETOSTAT: • Better:

• ONE SHOT• No extra-hematological toxicities• Only in 15% of FL patients• mDOR

• BETALUTIN® vs BISPECIFIC MoAb: • Better:

• No extra-hematological toxicities• No CRS or NT• More consolidated data

22

• 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!!!

MZL: Comparison with Competitors

23