Differentiating Decisions in Transplant-Ineligible Relapsed/Refractory DLBCL: What Are Our Options, and How Do We Choose Between Them?

An expert discusses DLBCL in this IME activity titled "Differentiating Decisions in Transplant-Ineligible Relapsed/Refractory DLBCL: What Are Our Options, and How Do We Choose Between Them?" For the full presentation, please visit us at www.peervoice.com/DDU870.

1. PeerVoice

Differentiating Decisions in Transplant-Ineligible Relapsed/Refractory DLBC
What Are Our Options, and How Do We Choose Between Them?

Learning Objectives

Assess clinical trial data evaluating approved therapies in the management of
relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), including chemotherapy,
immunotherapy, and CAR T-cell therapy

Formulate individualised treatment plans for patients with DLBCL upon progression to
relapsed/refractory disease who are ineligible for stem-cell transplantation

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Part lof 2
Current Challenges in Managing R/R DLBCL: What Are Our Options for SCT-Ineligible Patients?

Gilles Salles, MD, PhD

Weill Cornell Medical College

Memorial Sloan Kettering Cancer Center
New York, New York, USA

Copyright © 2010-202.

3. PeerVoice

Gilles Salles, MD, PhD, has a financial interest/relationship or affiliation in
the form of:

Consultant for AbbVie Inc.; ATB Therapeutics; Bayer AG; BeiGene; Bristol
Myers Squibb Company; Celgene Corporation; Debiopharm Group; Eli Lilly
and Company; F. Hoffmann-La Roche Ltd; Genentech, Inc; Genmab A/S;
Gilead Sciences, Inc.; Incyte; Ipsen Biopharmaceuticals, Inc.; Janssen Inc.;
Kite Pharma, Inc.; Loxo Oncology, Inc.; Merck KGaA; Molecular Partners AG;
MorphoSys AG; Nordic Nanovector ASA; Novartis AG; Nurix Therapeutics,
Inc; Orna Therapeutics; Regeneron Pharmaceuticals, Inc.; and Takeda
Pharmaceutical Company Limited.

Grant/Research Support from institutional relationships with Genentech,
Inc.; Ipsen Biopharmaceuticals, Inc.; and Janssen Inc.

Stock Shareholder in Owkin, Inc.

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4. PeerVoice

GOYA: Early Relapse Associated With Poor Survival in DLBCL

Refractory Status POD12 Status
1 1
se es
Bos 2 os
Ê 2
& os & 04
8
| à Sal Lo.
LES Lee
0 6 2 @ de 30 36 42 a8 64 60 66 72 79 8% © 6 2 W 2 30 36 42 a8 54 60 66 72 78 84
Time, mo Time, mo
Chemorefractory Medianos, mo _2-¥ Survival, % PB PODIZ Population Median OS, mo
opulation
Primary 144 286 149
Non-primary NR 941 Without NR

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OR 24 36 40 Go 7 04 96 109 20 102 ua HE MB HO

Time From Start of Salvage Therapy, mo
Population Median OS, mo
All

Survi

20

© 20 4 6 m m

mo wo mo no

Time From Start of Salvage Therapy, mo

Population

Primary refractory

Refractory 10 22 lines of therapy.

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Relapse 112 mo post-ASCT

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Emerging Algorithm for the Second-Line Management of LBCLs

Eligible for CAR T-coll?

(axi-cel or liso-cel)

-30% to 40%,

Projected Cure

(20% of All Second-Line
LBCL)

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Therapeutic Options

Investigational agent or regimen

Immunochemotherapy
CAR T-cell therapy

(if not given in second-line)
Polatuzumab vedotin + BR

Selinexor
Tofasitamab-lenalidomide
Loncastuximab tesirine
BSC or XRT

Ay: -25%

Eligible for ASCT?

-40% to 50%

Cure
(-5% of All Second-Line

LBCL)

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7. PeerVoice

Polatuzumab Vedotin + BR for R/R DLBCL

Polatuzumab vedotin: ADC targeting CD79b

1 — Pola-BR (n = 40)
— ER (n= 40)

+ Censored

o
©

HR, 0.36
95% CI, 0.21-0.63
Log-rank P< OO!

PFS Probability
o e
>» ©

o
iS

o

LS yon mu vum ya zum r
0246 8 10 12 14 16 18 20 22 24 26

Time, mo

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Tafasitamab + Lenalidomide for R/R DLBCL

Tafasitamab: Humanised anti-CD19 Ab

+ Overall (N = 46)
+ One prior line of therapy (n = 27)
Two prior lines of therapy (n = 19)

3
3

75

Overall median DOR
has not been reached
(median follow-up, 44.0 mo)

25

Probability of DOR, %
3

o 6 12 1 24 30 36 42 48 54 60 66 72

Time, mo

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Loncastuximab Tesi

Loncastuximab tesirine: Anti-CD19 Ab

+Censored

1

PFS Probability
o

N =145
Median PFS, 4.93 mo

0123456 7890118 W116 7 B 19 202122232425262728

Time, mo

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Anti-CD19 CAR T-Cell Therapies in Aggressive R/R NHL

Axicabtagene Ciloleucel Lisocabtagene Maraleucol

‚agenlecleucel

(Axi-cel)
Vector ma
Costimulatory domain CD28 4-188
Discos sate DIOL Tr PECL asoL TA. BOL PECL,
‘ORR, % 84 54 73
En se 20 5
Median follow-up, mo 27 32 12
Median PFS, mo 59 29 68
Median OS, mo 260 m 210
Grade 3-4 CRS, % " 23 2
RA 2 1 D
Approval stats EEE EM Aug 2018 EM Aug 2018

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erveice

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Abbreviations and References

GOYA: Early Relapse Associated With Poor Survival in DLBCL

Abbreviation(s): DLBCL: diffuse large B-cell lymphoma; NR: not reached; OS: overall survival;
PODI2: investigator-assessed disease progression within 12 months.
Reference(s): Ruiz IC et al. Clin Lymphoma Myeloma Leuk. 2022;22(8):e804-e814.

SCHOLAR-1: Unmet Need in R/R DLBCL

Abbreviation(s): ASCT: autologous stem cell transplantation; R/R: relapsed/refractory.
Reference(s): Crump M et al. Blood. 2017:130:1800-1808.

Emerging Algorithm for the Second-Line Management of LBCLs

Abbreviation(s): BR: bendamustine + rituximab; BSC: best supportive care; CAR: chimeric antigen
receptor; LBCL: large B-cell lymphoma; XRT: radiation therapy.
Reference(s): Westin J, Sehn LH. Blood. 2022:139:2737-2746,

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Abbreviations and References (Cont'd)

Polatuzumab Vedotin + BR for R/R DLBCL

Abbreviation(s): ADC: antibody-drug conjugate; PFS: progression-free survival; Pola: polatuzumab
vedotin.

Reference(s): Sehn LH et al. J Clin Oncol. 2020;38:155-165.
Tafasitamab + Lenalidomide for R/R DLBCL

Abbreviation(s): Ab: antibody; DOR: duration of response.
Reference(s): Duell J et al. American Association for Cancer Research AACR Annual Meeting 2023
(AACR 2023). Abstract 9810.

Loncastuximab Tesirine for R/R DLBCL
Reference(s): Caimi PF et al. Lancet Oncol. 2021;22:790-800.

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Abbreviations and References (Cont'd)

Anti-CD19 CAR T-Cell Therapies in Aggressive R/R NHL

Abbreviation(s): CR: complete response; CRS: cytokine release syndrome; EMA: European Medicines
Agency; FDA: US Food and Drug Administration; FL3B: follicular lymphoma grade 3B; NHL: non-Hodgkin
lymphoma; ORR: overall response rate; PMBCL: primary mediastinal large B-cell lymphoma;

T-iNHL: T-cell indolent NHL; TFL: transformed follicular lymphoma

Reference(s): Courtesy of Gilles Salles, MD, PhD; August 2023.

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Part 2 of 2
How Do We Choose Between Options? Navigating Treatment Decisions in Transplant-Ineligible R/R DLBCL

Gilles Salles, MD, PhD

Weill Cornell Medical College

Memorial Sloan Kettering Cancer Center
New York, New York, USA

Copyright © 2010-2024, PeerVoice

15. PeerVoice

Gilles Salles, MD, PhD, has a financial interest/relationship or affiliation in
the form of:

Consultant for AbbVie Inc.; ATB Therapeutics; Bayer AG; BeiGene; Bristol
Myers Squibb Company; Celgene Corporation; Debiopharm Group; Eli Lilly
and Company; F. Hoffmann-La Roche Ltd; Genentech, Inc; Genmab A/S;
Gilead Sciences, Inc.; Incyte; Ipsen Biopharmaceuticals, Inc.; Janssen Inc.;
Kite Pharma, Inc.; Loxo Oncology, Inc.; Merck KGaA; Molecular Partners AG;
MorphoSys AG; Nordic Nanovector ASA; Novartis AG; Nurix Therapeutics,
Inc; Orna Therapeutics; Regeneron Pharmaceuticals, Inc.; and Takeda
Pharmaceutical Company Limited.

Grant/Research Support from institutional relationships with Genentech,
Inc.; Ipsen Biopharmaceuticals, Inc.; and Janssen Inc.

Stock Shareholder in Owkin, Inc.

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Algorithm for the Management of LBCLs

Patients With R/R DLBCL

Who Are Not Candidates for ASCT (~50%)

Second-Line Therapy

Third-Line Therapy or More

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Immunochemotherapy

CAR T-celltherapy

Polatuzumab vedotin + BR
Tafasitamab-lenalidomide
Loncastuximab tesirine

Selinexor

CD3xCD20 (glofitamab, epcoritamab)
Investigational agent or regimen
Allogeneic SCT

BSC (including XRT)

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Phase 1b/2 Study: Efficacy of Polatuzumab Vedotin + BR for R/R

DLBCL
Pola+ BR BR
IRC Outcome (Phase 2, EOT) (n= 40) (n= 40)
ORR, % 45.0 7.5
CR, % 40.0 17.5
Median PFS, mo 9.5 37

PFS HR (95% CI)

0.36 (0.21-0.63)
P< .001

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Phase 1b/2 Study Follow-Up/Extension: Efficacy of Polatuzumab
Vedotin + BR for R/R DLBCL

Randomised Extension Cohort
Median Survival, mo
Pola + BR (n = 40) BR (n= 40) Pola + BR (N = 106)
PFS 9.2 37 6.6
OS 12.4 47 12.5

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Phase 1b/2 Study: Safety of Polatuzumab Vedotin + BR for R/R

DLBCL
AE 215% at Any
Grade
Anaeı 53.8 28.2 25.6 179
Neutropenia 538 462 385 333
Thrombocytopenia 487 41.0 28.2 231
Diarrhoea 385 26 282 26
Nausea 308 o 410 o
Constipation 79 o 205 26
Fatigue 35.9 26 35.9 26
Pyrexia 333 26 205 o
Decreased appetite 25.6 26 205 o
Peripheral
see) 436 o 77 o

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L-MIND and RE-MIND: Efficacy of Tafasitamab + Lenalidomide

for R/R DLBCL

Prospective L- Tafasitamab + Retrospective Tafasitamab

MIND: INV RE-MIND: +LEN

Outcome,'% Outcome,? % (n= 76)

ORR 60 ORR 671 34.2
PET-confirmed CR 43 CR 39.5 13.2
PR 18 PR 276 211
SD 14 SD 10.5 14.5

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L-MIND 3-Year Follow-Up: Efficacy of Tafasitamab +

Lenalidomide for R/R DLBCL

Retrospective Tafasitamab + LEN

Outcome From A Ml Patients With 1 Prior
Follow-Up Analysis All Patients (N = 80) Treatment (n = 40)

ORR, % 57.5

CR, % 40.0 >
Median DOR, mo 43.9 43.9
Median PFS, mo 11.6 235)
Median OS, mo 835 45.7

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-MIND: Safety of Tafasitamab + Lenalidomide for R/R DLBCL

Tafasitamab + LEN (N= 80) Up to 12 Cycles;

AE 210% at Any Grade, % Median Exposure, 6.5 mo
Gri Gr2 Gra Gra

Neutropenia 1 > 29 19
‘Anaemia 10 16 8 -
Thrombocytopenia n A 2 5
Diarrhoea 18 10 1 =
Asthenia 4 9 1 =
Peripheral oedema 0 10 = =
Pyrexia 15 4 1 =
Decreased appetite 15 5 E E
Cough 12 5 1 =
Nausea 10 5 = =
Constipation n 4 3 =

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Outcome (All Patients) nca (N = 145)

ORR, % 48.3
CR, % 241
Median DOR, mo 10.25
Median PFS, mo 4.93

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LOTIS-2: Safety of Loncastuximab Tesirine for R/R DLBCL

AE 220% at Any Grade, %
Increased GGT

Neutropenia

Thrombocytopenia

Fatigue

Anaemia

Nausea
Cough

Increased ALP

Peripheral oedema

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JULIET and ZUMA-1: Efficacy of CAR T-Cell Therapy for R/R

DLBCL

Phase 2 JULIET:
Long-Term Outcomes,! %

ORR 53
CR 39

Tisa-Cel (N = 115)

Phase 2 ZUMA-1:
5-Year Follow-Up Outcomes,? %

ORR 83
CR 58

Data are from separate trials and cannot be directly compared.

Axi-Cel (N = 101)

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Efficacy of Bispecific Antibodies for R/R DLBCL

Ocio S Mosunetuzumab Odronextamab Glofitamab Epcoritamab
a (N= 82) (N = 45) (N =155) (N =157)

ORR 33 40 52 63

CR 20 36 39 39

Data are from separate trials and cannot be directly compared.

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Abbreviations and References

Algorithm for the Management of LBCLs

Abbreviation(s): ASCT: autologous stem cell transplantation (SCT); BR: bendamustine + rituximab;
BSC: best supportive care; CAR: chimeric antigen receptor; DLBCL: diffuse large B-cell lymphoma
(LBCL); R/R: relapsed/refractory; XRT: radiation therapy.

Reference(s): Courtesy of Gilles Salles, MD, PhD; August 2023.

Sehn LH, Salles G. N Engl J Med. 2021;384:842-858.

Phase 1b/2 Study: Efficacy of Polatuzumab Vedotin + BR for R/R DLBCL

Abbreviation(s): CR: complete response; EOT: end of treatment; IRC: Independent Review Committee;
ORR: objective/overall response rate; PFS: progression-free survival; Pola: polatuzumab vedotin.
Reference(s): Sehn LH et al. J Clin Oncol. 2020;38:155-165.

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Abbreviations and References (Cont'd)

Phase 1b/2 Study Follow-Up/Extension: Efficacy of Polatuzumab Vedotin + BR for R/R
DLBCL

Abbreviation(s): OS: overall survival.
Reference(s): Sehn LH et al. 62nd American Society of Hematology Annual Meeting and Exposition (ASH
2020). Abstract 3020.

Phase 1b/2 Study: Safety of Polatuzumab Vedotin + BR for R/R DLBCL
Abbreviation(s): AE: adverse event.

Reference(s): Sehn LH et al. J Clin Oncol. 2020;38:155-165.

L-MIND and RE-MIND: Efficacy of Tafasitamab + Lenalidomide for R/R DLBCL

Abbreviation(s): INV: investigator; LEN: lenalidomide; PET: positron emission tomography; PR: partial
response; SD: stable disease.

Reference(s): 1. Salles G et al. Lancet Oncol. 2020;21:978-988.

2. Zinzani PL et al. Clin Cancer Res. 2021:27:6124-6134.

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Abbreviations and References (Cont'd)

L-MIND 3-Year Follow-Up: Efficacy of Tafasitamab + Lenalidomide for R/R DLBCL
Abbreviation(s): DOR: duration of response.

Reference(s): Duell J et al. Haematologica. 2021 Aug 19. doi: 10.3324/haematol.2021.279802. Online
ahead of print.

L-MIND: Safety of Tafasitamab + Lenalidomide for R/R DLBCL

Abbreviation(s): Gr: grade.

Reference(s): Salles G et al. Lancet Oncol. 2020;21:978-988.

Courtesy of Gilles Salles, MD, PhD; August 2023.

LOTIS-2: Efficacy of Loncastuximab Tesirine for R/R DLBCL

Abbreviation(s): Lonca: loncastuximab tesirine.
Reference(s): Caimi PF et al. Lancet Oncol. 2021;22:790-800.

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Abbreviations and References (Cont'd)

LOTIS-2: Safety of Loncastuximab Tesirine for R/R DLBCL
Abbreviation(s): ALP: alkaline phosphatase; GGT: gamma-glutamyltransferase.
Reference(s): Caimi PF et al. Lancet Oncol. 2021;22:790-800.

JULIET and ZUMA-1: Efficacy of CAR T-Cell Therapy for R/R DLBCL

Abbreviation(s): axi-cel: axicabtagene ciloleucel; tisa-cel: tisagenlecleucel.
Reference(s): 1. Schuster SJ et al. Lancet Oncol. 2021:22:1403-1415.
2. Neelapu SS et al. Blood. 2023;141:2307-2315.

Efficacy of Bispecific Antibodies for R/R DLBCL
Reference(s): Courtesy of Gilles Salles, MD, PhD; August 2023.

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