Addressing Unmet Needs for Better Outcomes in DLBCL: Leveraging Prognostic Assessment and Off-the-Shelf Immunotherapy Strategies

Chair, Grzegorz (Greg) S. Nowakowski, MD, FASCO, discusses diffuse large B-cell lymphoma in this CME activity titled “Addressing Unmet Needs for Better Outcomes in DLBCL: Leveraging Prognostic Assessment and Off-the-Shelf Immunotherapy Strategies.” For the full presentation, downloadable Practice Aid, and complete CME information, and to apply for credit, please visit us at https://bit.ly/49JdxV4. CME credit will be available until February 27, 2026.

1. Addressing Unmet Needs
for Better Outcomes in DLBCL

Leveraging Prognostic Assessment
and Off-the-Shelf Immunotherapy Strategies

Grzegorz (Greg) S. Nowakowski, MD, FASCO
Professor of Medicine and Oncology

Chair, Lymphoid Malignancy Group

Enterprise Deputy Director, Clinical Research
Mayo Clinic Comprehensive Cancer Center
Vice-Chair, Division of Hematology

Rochester, Minnesota

Go online to access full CME information, including faculty disclosures.

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2. Our Goals for Today

Augment your knowledge of prognostic factors and
evidence that support modern decision-making in R/R
DLBCL, including with off-the-shelf options

Equip you with the skills you need to develop personalized
treatment plans for patients with R/R DLBCL with unmet
medical needs

Provide you with guidance on strategies for addressing
unique toxicities associated with modern therapy

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3. The Modern Shape of Therapy for DLBCL
and Questions for Treatment Selection

Chemoimmunothera
R-EPOCH,

Better 2L
and

bridging
therapy

Post CAR-T
Teale | Polatuzumab | Loncastuximab ae and post
an u
relapse
Tafasitamab Seimexor | Pembrolizumab a fitamab
nalidomide xo Gu y + Optimal

sequence

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4. More Options for Early Progressors Are Now Included

in the Guidelines!

Second-Line Therapy (Relapsed Disease <12 Months or Primary Refractory Disease)

CAR-T candidates Non-CAR-T candidates
+ Axicabtagene ciloleucel (category 1) Preferred regimens
+ Lisocabtagene maraleucel (category 1) + Glofitamab-gxbm + GemOx
+ Polatuzumab vedotin-piiq + bendamustine + rituximab

Bridging therapy options (21 cycles as + Polatuzumab vedotin-piiq + mosunetuzumab-axgb
needed until CAR-T-cell product is available) + Tafasitamab-cxixlp + lenalidomide
+ DHA+ platinum (excluding primary refractory disease)
+ GDP + rituximab
+ GemOx rituximab Other recommended regimens
+ ICE + rituximab + CEOP
* Polatuzumab vedotin-piiq + rituximab + DHA, ESHAP, GDP, ICE, or MINE + rituximab

+ bendamustine + GemOx + rituximab (if unable to receive glofitamab-gxbm)
+ ISRT

For CD30+ disease: Brentuximab vedotin
For non-GCB DLBCL: Ibrutinib or lenalidomide + rituximab

CN inal rece Guidelines in nology B-CelLymehomas. Version 12025 hip ce agression papa. PeerView

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5. Similarly, More Options Are Available for Later Progressors'

Secon herapy (Relapsed Disease >12 Months)

Proceed to HCT
Preferred regimens

DHA + platinum + rituximab
GDP + rituximab

ICE + rituximab

Other recommended
ESHAP + rituximab
GemOx + rituximab

MINE + rituximab

No intention to proceed to HCT

Preferred

+ CAR-T therapy with bridging therapy as needed;
lisocabtagene maraleucel

+ Glofitamab-gxbm + GemOxn

+ Polatuzumab vedotin-piiq + bendamustine + rituximab

+ Polatuzumab vedotin-piiq + mosunetuzumab-axgbn

+ Tafasitamab-cxixlp + lenalidomide

Other recommended
+ CEOP

+ GDP + rituximab

+ GemOx t rituximab

For CD30+ disease: Brentuximab vedotin
For non-GCB DLBCL: Ibrutinib or lenalidomide

ituximab

{NOON Cinca Practico Guidelines in Oncology. 8 Cal Lycra. Venion 1.2025. ipsum nocn o/potesonslphyskian_glpdtb-allpa PeerView

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6. Preferred regimens Other recommended regimens

+ T-cell engager therapy + Brentuximab vedotin + lenalidomide

- CAR-T therapy (preferred if not previously given) + rituximab (for CD30+ disease)
(in alphabetical order) + Loncastuximab tesirine-Ipyl

> Axicabtagene ciloleucel (CD19 directed) + Selinexor (including patients with
> Lisocabtagene maraleucel (CD19 directed) Mrs use after transplant
> Tisagenlecleucel (CD19 directed)

- Bispecific antibody therapy (only after at least two lines
of systemic therapy; including patients with disease
progression after transplant or CAR-T therapy)

(in alphabetical order)

> Epcoritamab-bysp
> Glofitamab-gxbm

CON Cinca rece Gules in nology Bel Lyon, Verso 12025 Hips unn agression paca. PeerView

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7. What Are the Major Unmet Needs in DLBC

A need for more options for patients For example, outcomes after
A rogression on CAR-T are poor!
+ Who are unable to receive CAR-T fa L
therapy Overall Survival According to Time to Failure

10 + Censored

. . = Logrranked P < 0001
+ Who have R/R disease and require 5 os
effective bridging Bos
&
+ Who have R/R disease after m 090
exposure to CAR-T or bispecifics 502
5 pos
0 3 6 8 2 5 1 À 2
Time, mo
No a Rsk
teow ss 7 Os 2 1 to
boom M ON 7 ® 7 4 |! 0
FD M OR ON M 8 ? 4 1 o
4. DiBlasi et al Blood 2022:140:2504-2503. PeerView

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8. What Are the New Developments
That Can Potentially Address
Unmet Needs in R/R DLBCL?

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9. ECHELON-3: Phase 3 Trial Assessing the Addition of BV

to Lenalidomide Plus Rituximab in R/R DLBCL'

/ Key eligibility criteria \
| + RIRDLBCL with eligibility |
‘subtypes

+ Aged 218 years

1 lines of therapy

bility for or disease
relapse following HSCT or
CAR-T therapy

+ ECOG PS 02

+ FDG-avid, measurable
disease

Key ineligibility criteria
Prior BV or lenalidomide
+ Active cerebralmeningeal
disease
+ Grade 22 peripheral ]

prophylaxis was required .

* Using the response criteria per Lugano 2014,
1. KmJA et al ASCO 2024. Abstract LBA7OOS,

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BV 1.2 mg/kg IV Q3W
+ lenalidomide 20 mg PO QD
+ rituximab 375 mg/m? IV Q3W

Q

4 Stratification

CD30 status (21% vs <1%)

Cell of origin (GCB or non-GCB)

Prior treatment with CAR-T therapy (yes vs no)
Prior treatment with SCT (yes vs no)

Primary endpoint
+ OSin ITT population

Secondary endpoints

Investigator-assessed PFS and

ORR® in ITT population
Investigator-assessed CR rate
Investigator-assessed DOR
OS in CD30+ population
Safety and tolerability

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10. ECHELON-3: Adding BV to Len-R Substantially Improved OS!

+ BV + len-R reduced risk of death by 37% compared with placebo + len-R

se meee 138(103-188) — 85(54-117)
E HR (95% Cl) 0.629 (0.445-0.891)

3

3 Log-ranked P 0085

= Events (deaths) 58 76

2 Median follow-up, 155 189

= mo (95% Cl) (122181) (122-232)

Placebo + Len +R

+ BV +len-R prolonged median OS by
2 a © a DS à à À à & à 5.3 mo compared with placebo + len-R

Time From Randomization, mo + Prespecified O'Brien-Fleming efficacy

No, at Risk boundary was crossed at this interim
BV+ Len mens on mon os 1 1 0 analysis

Placebo Len 118 81 58 3% 28 23 16 12 5 3 0

4. Kim JA etal ASCO 2024. Abstract LEATOOS PeerView

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11. ECHELON-3: Overall Response Rate Was Significantly Higher

With BV + Len-R!

40% CR rate with BV + len-R and ORR improvement regardless of CD30 expression

Total CD30- (<1%) CD30+ (21%)

068 BV +Len-R
= ORR'605 M or rate
S pp ‘ORR: 500 I PRrate

3 ED

ES Es one: 375
2 Placebo + Len-R
2
3 I CR rate
© EN PR rate

+ Inthe total population, the median DOR (95% CI) was longer with BV + len-R versus placebo + len-R: 8.3 mo (4.2-15.3)
versus 3.0 mo (2.8-5.4)
— In patients who had a CR, the median DOR (95% Cl) with BV + len-R was 18.8 mo (11.1-NR) versus NR (2.8-NR) with placebo
— The median time to CR onset (range) with BV +len-R was 1.58 mo (1.2-7.3 mo) versus 1.61 mo (0.7-4.6 mo) with placebo

4. Kim JAet sl ASCO 2024. Abstract LEATOOS PeerView

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12. HELON-3: Adding BV to Len-R Also Improved PFS"

Key secondary endpoint met with significant improvements in PFS.
BV + len-R reduced risk of disease progression or death by 47% vs placebo + len-R

1

HR (96% Cl)
Log-rarked P
Events

mo (95% Cl)
BV + Len-R
+

Median follow-up,

BV+LenR Placebo + Len
(air?) ¢

Median PFS, mo

wont 428871) 2541431)

0527 (03800723)
< oo
n 85
11.4 0186-142) 8369109)

o888858383888

Placebo + Len-R

0 3 6 9 2 15 18 2 2 27 30 33
Time From Randomization, mo
BvelenR m Emm 5 5 2 1 1 0

MB 4 16 8 4 3 2 2 1
PFS was an alpha-controlled key secondary endpoint

1. Kim JA et al, ASCO 2024. Abstract LBATOOS.

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Overall, consistent benefit
of BV + len-R for OS, PFS,
and ORR regardless of
CD30 expression

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13. ECHELON-3 Update: BV + Len-R Effective in Patients Receiving

Prior CAR-T Therapy!
os PFS
boo BVelenR © PlacebortenR on BVelenR Placebos Lem
90 {n = 32) {n= 35) 90 (n=32 {n= 35)
ig ame or 4A OANA WI ec seen 10220
cn MRC) 0384(0.1980.746 P= 0035 SO JW, rene oanmoamoræpe ose
0
= =
go Fl
Es E
30
2
6 Placebo + Len-R
A —— nr o —— —
0 3 6 8 2 mw À À 7 wm à 0 3 6 8 ss
éd Time From Randomization, mo en Time From Randomization, mo
te ee ee gk Mann a aaa 4 «
PR HE RE ti ts emi ff 13

Subgroup analysis supports BV + len-R as an effective treatment option for patients who have not
responded to prior CAR-T therapy

+ Median OS in this patient subgroup was ~3.5 times longer with BV + len-R than with placebo + len-R

1. Hatin Ueli. ASH 2024. Abarat 469, PeerView

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14. ECHELON-3: Consistent and Predictable Safety Profile

With BV + Len-R

Adverse events were manageable with dose modifications and
consistent with the known safety profile of each individual drug

TEAE BV+Len-R(n = 112) Placebo + LenR(n= #6) , reas oran grade occurred in 97% 01
Neutropenia —= A] patients with each treatment
Thrombocytopenia = mn + Grade 23 TEAES
Diarrhea [ | = GES EU AR
Anemia mm eu = 77% with placebo + len-R
| oe |
cain E = 9% febrile neutropenia in each group
Asthenia . a ee
Peripheral sensory neuropathy .a ee acia
Constipation A = Sem piste Lane
Decreased appetite | + Any-grade peripheral neuropathy TEAES
Pneumonia ma = 31% with BV +len-R
Cough | = 24% with placebo + len-R
Pyrexia [Grade 1/2 = Grade 1/2 + Relative dose intensity
Nausea Grade 23 = Grade 23 — 94.4% for BV
Prune, == | = 99.7% for placebo
m 8 6 4 2 0 2 40 60 60 10
Incidence, % =
1.KimdA etal ASCO 2024. Abstract LEATOOS PeerView

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15. STARGLO: Phase 3 Trial Assessing the Addition of Glofitam

to Gemcitabine and Oxaliplatin in R/R DLBCL*

Glofitamab + GemOx*

Key eligibility criteria RAR
up dosing in cycle 1, 30 mg admini SO panne
+ R/R DLBCL NOS after day 1 from cycle 2 onwards on lan ya
21 prior systemic therapy (n= 183) s
+ Patients with 1 prior LOT ER]
uste trerepiant 21 Cycles 1-8 (21-day cycles) Cycles 9-12
ineligible
+ ECOG PS 0-2 Rituximab? + GemOx
\ N=274
Stratification + Primary endpoint: OS
+ Relapsed vs refractory disease” +» Key secondary endpoints: PFS, CR rate, DOCR

+ 1 vs 22 prior lines of therapy

" Gemetabine 1,000 mom? and oxaliplatin 100 mpi: n C1, Gpt administered on D1, GemOxon 02. folowed by gi 25 mg on D8 and gift 10 mg on DAS;
1nC2, itt 30 mg and GemOx are admiistered on O1,°Rtuximab 375 maim < Relapsed disease. recurrence folowng a response that lasted 26 months

‘after completn ofthe last ine of therapy: retractory disease: disease that dd nal respond or that progressed. By IRC assessment PeerView
1. Abramson Jet al. EHA 2024, Abstract LB 3433.

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16. STARGLO: Adding Glofit to GemOx Significantly Improved OS

Versus R-GemOx in R/R DLBC
Updated Analysis

+ Censored R-GemOx Glofit-GemOx
{n= 91) (n= 183)

Primary analysis (median follow-up: 11.3 mo)

Glofit-GemOx (n = 183) Median OS, mo (95% CI) 9(73-144) — NE(13.8-NE)

cl HR (95% CI) 0.59 (0.00.80)
Sos R-GemOx (n = 91) Le m
Updated analysis (median follow-up: 20.7 mo)
i Median OS, mo (95% Cl) 129(79-185) — 255(183-NE)
Gloft-GemOx vs R-GemOx HR = 0.62
(85% Cl, 0.43-0.88) HR (95% CI) 0.62 (0.43-0.88)
o P 006
DS 2 1 M24 27 DES amos esc) 39522449) 528 (48607)
on Time, mo AAA qq AAA

CIOMGEMOX 183 159 135 119 108 86 71 51 40 2% 11 3 NE
RGemox 91 68 55 46 40 29 23 14 10 8 3 2 NE

24-month OS not reported at the primary analysis as data were not suficienty mature
* Pis alpha controled a he pfmary analysis and descriptive at updated analysis. PeerView

1.Abramson Jet al. EHA 2024. Abstract LB9438,

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17. RGLO: Improved CR Rate With Glofit + GemOx

CR rate was statistically significant at primary analysis,
with increased difference between treatment arms at the updated analysis

ORR: 68.3%
+ 33.2% difference in CR rate

between treatment arms
(95% Cl, 19.7-44.5)

2 50
bso ORR: 40.7% + CR rate significantly better with
8 2 Glofit + GemOx vs R + GemOx
& 30 emcees (P< .0001)
20
10 PR rate
Glofit + GemOx (n =183) R + GemOx (n= 91)
4. Aaron Jet al £44204, Ac L2409 PeerView

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18. STARGLO: Improved PFS With Glofit-GemOx!

Updated Analysis

119 + Censored
©
2 Median PFS, mo (95% CI) 3.3 (2.5-5.6) 12.1 (6.8-18.3)
©
6 Glofit-GemOx (n = 183) HR (95% Cl) 0.37 (025.055)
& 40 P < 000001
a mo Updated analysis (median follow-up: 16.1 mo)
Glofit-GemOx vs R-GemOx HR = 0.40 (n=91) Median PFS, mo (95% Cl) 36(2571) — 138(87-205)
(95% Cl, 0.28-0.57)
0 HR (95% Cl) 0.40 (0.28-0.57)
0 3 6 9 2 16 18 21 24 27 30 33 36
com Tine, mo P < 000001
Gloft-GemOx 183 130 107 89 66 54 37 26 14 10 2 1. NE 12-mo PFS, % (95% CI) 25.2 (13.6-36.9) 51.7 (44.0-59.4)
Remor mm 8 6 2 ee e AA AAA AAA

Statistically significant and clinically meaningful PFS benefit for Glofit-GemOx vs R-GemOx

Glofit-GemOx improved OS across subgroups (including based on cell of origin, patients relapsed or

refractory to last line of therapy, and o!

12monih PFS not reported at he primary analysis as data were not sufficiently mature, Three paints proceeded to ASCT ater study treatment: al thee are alv as of today
Pis ajpha controled a the pimary analysis and descriptive at updated analysis. PeerView
1 Abramson Jet al. EHA 2024. Abstract LB3438,

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19. How Do We Apply These Data to Address Unmet Needs

67-year-old man with DLBCL who

relapses 3 months after completion of
polatuzumab + RCHP

+ He has abdominal pain with PET scan
showing FDG avid large abdominal
mass (12 cm), ascites, plural effusion, and
intrathoracic adenopathy

+ LDH is 900

This patient should be considered for
CAR-T therapy and needs bridging therapy
due to bulky symptomatic disease

Patient received polatuzumab in the first
line, hence we would not use polatuzumab
+ rituximab or polatuzumab + brentuximab
vedotin

Glofitinib + GemOx (STARGLO)
represents a good second-line option with
relatively high response rate

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20. How Do We Apply These Data to Address Unmet Needs’

64-year-old woman with R/R DLBCL,
status post ASCT, received CAR-T

th but d if i
erapy Dut developed progressive + This patient had no response to CAR-T

therapy and is not progressing after anti-
CD20 bispecific antibody therapy with
CD20-negative disease

disease on day 30 post CAR-T; she
received epcoritamab with
CR lasting 6 months

+ PET scan now shows progression of the

disease above and below the diaphragm + She would be a good candidate for BV-R2
+ Biopsy of FDG avid cervical lymph node — Although CD30 is <1%, this
shows DLBCL, CD20-negative, CD30 <1% combination is active regardless of
re CD30 expression
on tumor cells

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21. Take-Home Thoughts

One of the biggest advantages of TCE/bispecific antibodies is their ability
to be combined with other therapies

ib + GemOx is a new option in the secon:

+ For patients who are not candidates for CAR-T, HDC, or HSCT
+ Bridging therapy for CAR-T

BV R2 active in R/R setting

+ Including post CAR-T
+ Regardless of CD30 expression

Ongoing studies and real-world data will inform optimal sequence of therapy

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