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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