Stepping Forward to Transform MCL Management: Guidance on the Selection and Use of BTKi Platforms as First-Line Therapy

Chair and Moderator, Pier Luigi Zinzani, MD, PhD, and presenters Dr. Toby A. Eyre, MBChB, DipMedEd, MRCP, FRCPath, MD, and Christine Ryan, MD, discuss mantle cell lymphoma in this CME/MOC activity titled “Stepping Forward to Transform MCL Management: Guidance on the Selection and Use of BTKi Platforms as First-Line Therapy.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3SZekuM. CME/MOC credit will be available until July 17, 2025.

1. Stepping Forward to Transform
MCL Management

Guidance on the Selection and Use of BTKi Platforms
as First-Line Therapy

Pier Luigi Zinzani, MD, PhD Dr. Toby A. Eyre, MBChB, DipMedEd, MRCP,
Head of Lymphoma Group FRCPath, MD

Institute of Hematology "Serägnoli" | Haematology Consultant

Oxford University Hospitals
NHS Foundation Trust
Oxford, United Kingdom

University of Bologna
Bologna, Italy

Christine Ryan, MD
Instructor in Medicine, Harvard Medical School
Leader, Mantle Cell Lymphoma,

Division of Lymphoma

Dana-Farber Cancer Institute

Boston, Massachusetts, US

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

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2. Disclosures

All relevant conflicts of interest have been mitigated prior to the commencement of the activity.

Chair/Planner

Pier Luigi Zinzani, MD, PhD
Head of Lymphoma Group
Institute of Hematology "Serágnoli"
University of Bologna

Bologna, Italy

Pier Luigi Zinzani, MD, PhD, has a financial interest/relationship or affiliation in the form of:

Consultant and/or Advisor for AstraZeneca; BeiGene; Bristol Myers Squibb; F. Hoffmann-La Roche AG;
Gilead Sciences, Inc.; Incyte Corporation; Janssen Pharmaceuticals, Inc.; Kyowa Kirin Co., Ltd.; Merck,
Sharp & Dohme; Novartis; Recordati; and Swedish Orphan Biovitrum AB (SOBI)

Speaker for AstraZeneca; BeiGene; Bristol Myers Squibb; F. Hoffmann-La Roche AG; Gilead Sciences,
Inc.; Incyte Corporation; Janssen Pharmaceuticals, Inc.; Kyowa Kirin Co., Ltd.; Merck, Sharp & Dohme;
Novartis; Recordati; and Swedish Orphan Biovitrum AB (SOBI).

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3. Disclosures

All relevant conflicts of interest have been mitigated prior to the commencement of the activity.

Faculty/Planner

Dr. Toby A. Eyre, MBChB, DipMedEd, MRCP, FRCPath, MD
Haematology Consultant

Oxford University Hospitals

NHS Foundation Trust

Oxford, United Kingdom

Dr. Toby A. Eyre, MBChB, DipMedEd, MRCP, FRCPath, MD, has a financial interest/relationship or
affiliation in the form of:

Consultant and/or Advisor for AbbVie; AstraZeneca; Autolus Therapeutics; BeiGene; Bristol Myers Squibb;
F. Hoffmann-La Roche AG; Galapagos; Incyte Corporation; Janssen Pharmaceuticals, Inc.; Kite, A Gilead
Company; and Loxo Oncology, Inc.

Grant/Research Support from AstraZeneca and BeiGene

Speaker for AbbVie; AstraZeneca; BeiGene; Bristol Myers Squibb; F. Hoffmann-La Roche AG; Incyte
Corporation; Janssen Pharmaceuticals, Inc.; Kite, A Gilead Company; and Loxo Oncology, Inc.

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4. Disclosures

All relevant conflicts of interest have been mitigated prior to the commencement of the activity.

Faculty/Planner

Christine Ryan, MD

Instructor in Medicine, Harvard Medical School
Leader, Mantle Cell Lymphoma, Division of Lymphoma
Dana-Farber Cancer Institute

Boston, Massachusetts, US

Christine Ryan, MD, has a financial interest/relationship or affiliation in the form of:

Grant/Research Support from Genentech, Inc.
Honorarium from AstraZeneca.

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5. Planning Committee and Reviewer Disclosures

Planners, independent reviewers, and staff of PVI, PeerView Institute for Medical
Education, do not have any relevant financial relationships related to this CE
activity unless listed below.

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6. BTKi Regulatory Status in MCL

European Union United States

Approved ar
Ibrutinib* (after 1 prior lino of therapy) ‘Indication withdrawn

Approved

Covalent il
Acalabrutinib? Phase 3 (after 1 prior line of therapy)

as Approved
[Zanubrutinib* Phase 3 (after 1 prior line of therapy)

Approved (after 22 lines
of systemic therapy,
including a BTKi)

Approved for R/R MCL after

ï inipas
pci prior covalent BTKi

Non-covalent

mn x
4. https: www. ema europa eulen/medicines/human’EP# 5. ab) Pi i
ine on Ripka, 6. Jay (obran) Presses Intonation, 5 PeerView.com

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7. Long-Term Outcomes With Ibrutinib Showed
Sustained Clinical Benefits in R/R MCL‘

+ N = 370 (pooled, 3 trials), nearly 10 years of follow-up
+ Overall median PFS and OS of 12.5 and 26.7 months, respectively

100 100
90 90
80 80
70 70

2 60 x 60

g 50 Best response, CR E so

& 40 & 40

1 prior LOT

20 20
10 10 >1 prior LOT
0 o
O 12 24 36 48 60 72 84 96 108 120 0 12 24 36 48 60 72 84 96 108 120
Time, mo Time, mo
No, at Risk No, at Risk
Bestresponse, CR 102 90 77 61 52 39 25 19 3 2 0 ‘priorLOT 99 61 47 31 28 22 17 11 2 2 0
Bestresponse, PR 156 80 35 16 8 5 5 3 1 0 O >pñorLOT 271 117 67 47 33 23 14 11 2 0 0
4. Dreying M et al, HomaSphore. 2022:6:0712. PeerView.com

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8. Final Data From ACE-LY-004 Show Sustained
Efficacy With Acalabrutinib in R/R MCL"

+ After a median follow-up of 38.1 months, ORR and CR were
81% and 48%, respectively

+ Median DOR and median PFS were 29 months and
22 months, respectively

+ Median OS was 59.2 months

Demographics: median age 68 years, 2 prior therapies
(range, 1-5)

ORR was 81%, with 40% attaining a CR; median duration of
13.8 months

10, PFS 10 os
os os
5 8
os go
En os
£ $
02 02
a | + Sensors o | Consors
CIRIA TT RMDHABRH HONEA SO BT
Time From Initiation of Study Treatment, mo Time From Initiation of Study Treatment, mo
oat oat
1. Wang M eta. Hematol Oncol 2021:30(suppl 213-216. PeerView.com

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9. Similarly, Longer Follow-Up Confirms Efficacy

of Zanubru

ib in R/R MCL (BGB-3111-206)!

After a median follow-up of 35.3 months

ORR: 84%

+ Median PFS: 33 months

3
2
E 40 7 Median followup:
w 30 À 33.3 mo (95% Cl, 33.1-34.3) Zanubrutinib
E 20 y Estimated 36-mo PFS rate, %:
10 4 47.6 (95% Cl, 36.2-58.1)
0
0 3 6 9 1215 18 21 24 27 30 33 36 39
Time, mo
No. at Risk

86 73 67 64 60 58 51 48 45 43 38 36 9 0

1. Song eta. Blood. 2022:199:31483158.

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Zanubrutinib

Median follow-up:
36.8 mo (95% Cl, 35.4-37.2)

Estimated 36-mo OS rate, %:
74.8 (95% Cl, 63.7-83.0)

OS Probability, %
a
8

0 3 6 9 1215 18 21 24 27 30 33 36 39 42
Time, mo

No. at Risk
86 79 76 71 65 64 61 59 58 56 56 54 38 7 0

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10. Although CIT Is Effective as Upfront Therapy, Outcomes
With Early Progressors Suggest Better Options Are Needed

Progression of MCL within 24 months of the start Patients With Relapsed MCL

of treatment is associated with inferior OS2— Training cohort: Validation cohort:
can newer upfront options make a difference?! 455 patients 245 patients
Duration of First Remission OS From First Relapse
Training Cohort Validation Cohort
Progression of MCL 10
after 24 months:
POD >24
+ Censored
Progression of MCL within
6-24 months: Logrank P<.001
Vs,

2
pa

o
9 1 2 3 4 5 67689 0 0123456189 ND

No. atruex OS Time From First Progression, y (08 Time From First Progression, y

POD>24 237 175 139 107 76 52 99 22 2 16 13

PODGA 180 67 50 33 21 16 12 7 5 4

PREPODS 65 25 10 6 3 1 1 1 1 1 0

1. Bond DA et al. Blood Adv. 2021:55179:5189. PeerView.com

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11. TP53-Mutated MCL Remains an Area of Unmet Need

Intensified SOC regimens for younger patients with MCL
do not overcome TP53 mutations!

Overall Survival

No TP53 mutation (n = 156)

8

a Is there a

5 potential to

E improve upon
TP53 mutated (n = 20) SOC CIT?

1. Eskelund CW et al. Blood, 2017:130:1903-1910. Time, y PeerView.com

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12. Our Goals for Today

Improve your knowledge of current guidelines and evidence
supporting the expanded use of BTKi platforms in MCL, including as
first-line treatment options

Equip you with the skills you need to prepare for the use of

modern BTKi options in the management of newly diagnosed MCL

Provide you with guidance on practical aspects of modern MCL
care, including dosing and safety considerations associated with
BTKi-based strategies

Copyright © 2000-2024, Peerview

13. MasterClass
The Growing Evidence
for “Starting Strong”
With BTKi Platforms

in Newly Diagnosed MCL

14. Moving Upfront:
BTKi Combinations With CIT

Dr. Toby A. Eyre, MBChB, DipMedEd, MRCP, FRCPath, MD
Haematology Consultant

Oxford University Hospitals

NHS Foundation Trust

Oxford, United Kingdom

15. CIT Remains a Mainstay of Frontline Care for MCL in the
United States and Is Now Joined by BTKi-Based Regimens’

Induction Therapy

Preferred regimens

+ LyMA regimen: RDHA followed by R-CHOP for
non-PET CR

+ NORDIC regimen: dose-intensified rituximab + maxi-

CHOP alternating with rituximab + HD cytarabine

Rituximab + bendamustine followed by rituximab + HD

cytarabine

+ TRIANGLE regimen: alternating R-CHOP + covalent
BTKI/RDHA + platinum (category 2A for ibrutinib;

‚Aggressive
therapy &

category 2B for acalabrutinib or zanubrutinib)

Preferred regimens
+ Bendamustine + rituximab

ase + VR-CAP
aggressive - R-CHOP
therapy * Lenalidomide (continuous) + rituximab

Other recommended regimen
+ Acalabrutinib (continuous) + rituximab

1.NCCN Clinical Practice Guidelines in Oncology. 8-Call Lymphomas. Version 22024. hps:/wuw.ncen orpprofesionalsphysician_glspdb-col pt

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Maintenance After HD Therapy/ASCR
or Aggressive Induction Therapy

Covalent BTKi for 2 years (category 2A for

ibrutinib; category 2B for acalabrutinib or
zanubrutinib) + rituximab every 8 weeks for
3 years

Maintenance After Less Aggressive Therapy

+ Rituximab every 8 weeks for 2-3 years
following R-CHOP (category 1) or BR

+ Maintenance rituximab following VR-CAP or
RBAC500 has not been evaluated

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16. BTKi Are Also Being Included

elines for MCL in Europe

Frontline therapy
recommendations
for MCL"

Unfit for ASCT

Younger fit patients: first-line induction regimen Rituximab + chemotherapy combinations are
containing rituximab and HD cytarabine the current standards of care

After objective response, offer consolidation Offer R-CHOP, BR, R-BAC, and VR-CAP
ASCR Rituximab maintenance post-R-CHOP
Maintenance rituximab post-ASCT induction

Consider ibrutinib during the R-CHOP Consider rituximab maintenance post-BR
component of R-CHOP/R-DHAP induction and
for 2 years maintenance in place of ASCT if
licensed and reimbursed

Do not offer rituximab maintenance following
R-BAC outside of a clinical trial

la TP59 mutation present, consider aternatve consoldation strategies (iical na prefered). a
1. Eyre Total, Br Haomatol 2024.204:108-128, PeerView.com

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17. Phase 3 SHINE Trial: Adding Ibrutinib
to Upfront CIT Prolonged PFS‘

8

N = 523 patients

aged 265 years with MCL = 90
23 00
<2 70
2
¿80
E
Ibrutinib 25°
560 mg once Placebo + 3 g 40
daily + 6 cycles bendamustine 50 30
bendamustine and rituximab 53 20
and rituximab “E
= 10
Primary endpoint: PFS 9
No. at Risk
OS: stratified HR for death = 1.07 is
(95% Cl, 0.81-1.40) terne
Placebo +
bendamustine
and rituximab

1. Wang ML eta. N Engl J Med. 2022:386:2482-2494

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PFS

Ibrutinib + bendamustine
and rituximab

Placebo +
bengamustine
and rituximab

Stratified HR for progression or death = 0.75 (95% Cl, 0.59-0.96)
P= 01

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Time, mo
261 228 207 191 182 167 152 139 130 120 115 106 95 78 39 11 0

262 226 199 177 166 158 148 135 119 109 103 98 90 78 41 11 0
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18. TRIANGLE: Does Adding a BTKi Upfront + ASCT
Improve Outcomes?!

+ Patients with MCL Arm A (control)

+ Previously untreated R-CHOF

+ Stage I-IV ==

+ Younger than 66 years 4:4:1 Arm A + | (experimental)
+ Suitable for HA and ASCT OP + UR-DHAP

+ ECOG0-2 =

+ Primary outcome: FFS Arm I (experimental)
+ Secondary outcomes R-CHOP + I/R-DHAP

2-y | maint
— Response rates x3 y | maintenance

- PFS
= Response duration Rituximab maintenance was added following national guidelines in
- os all 3 trial arms
Rituximab maintenance (+ ibrutinib) was started in 168 (58%)/165
— Safety (57%)/158 (54%) of A/A + I/l randomized patients
1. Droyling M ot al. ASH 2022. Abstract 1. PeerView.com

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19. TRIANGLE: Adding Ibrutinib During Induction and as
Maintenance + ASCT Is Effective in ND MCL‘

13-year FFS: 88%

10 i creo 1?
> i eu
2 075

3 i _ 3
À 6 Lever 2 5
à i é
2 025 1 2 025

52 (1-sided 98.3 Cl, 0.00-0.86); 1-sided P = .0008 i HR = 1.77 (1-sided 98.3 Cl, 0.00-3.76); 1-sided P = 9979

0 6 12 18 24 30 36 42 48 54 60 66 72
Time, mo
No, at Risk (No.

Censored)
A 288 282 207 206 162 126 85 m 27 12 2

O, (in) Ga) (2) 00 die cn ci che a ezo
noi 292 270 253 226 184 137 109 65 41 17

O Ho) Ge) (as) (02) (125) 158) 19) (10) 10) (23 (230) (287)

+ After a median follow-up of 31 months, ASCT
(A) + ibrutinib (I) was superior to A alone

+ 3-year FFS of 88% (A + I) vs 72% for A alone
+ HR =0.52; P= .0008

o
0 6 12 18 24 30 36 42 48 54 60 66 72

Time, mo
No, at Risk (No. Censored)
A 20 269 257 229 160 133 100 68 35 16 4
O 62 Go 6 ca) ds fn oer cao cdo a)
ast 28 252 237 206 162
O ry Gz) Ge) (70) (105) (140) dé) don (208) (2) (220) 220)

Ais not superior to | alone
3-year FFS of 72% for A vs 86% for |
HR = 1.77; P = .9979

1. Dreying M eta. Lancet. 2024:403:2289-2308.

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20. Early Evidence Supporting the Addition
of Acalabrutinib to BR in TN and R/R MCL

Phase 1b Assessment of ABR in TN and R/R MCL Cohorts (N = 38)1?

TN Cohort R/R Cohort OS for TN and R/R Cohorts
Response, %

18) 0) 100
80 y
ORR 94.4 0 ; en
CR 77.8 70 a !
— 0 H
1 mos,mo s2moos, 26.008,
+ After a median follow-up of 47.6 months, 20 | rl — NO) RG
PFS and OS were not reached in the a À RR Ne(ieone) 8871014871) 697.41502)
TN cohort O 6 12 18 24 30 36 42 48 54 60 66 72 78
+ After a median follow-up of 20.4 months, No. at Riek ‘Time, mo;
m 18 16 16 11 11 10 10 10

PFS was 28.6 and OS was not reached in
the R/R cohort
+ No new safety signals were identified, and
most AEs were grade 1 or 2
1. Philips Tet al. ASCO 2023. Abstract 7546. 2. Philips T et al. EHA 2023. Abstract P1094 PeerView.com

RR 2 19 14 12 9 7 7 7

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21. The Phase 3 ECHO Trial Tested Acalabrutinib + BR in MCL’

Kev incluel iteri Acalabrutinib BID orally +
Sync 0) bendamustine on days 1 and 2

+ Aged 265 years and rituximab on day 1; cycles are
+ Pathologically repeated every 28 days
confirmed MCL

+ MCL requiring treatment Primary endpoint: PFS

and for which no prior
systemic anticancer
therapies have been Placebo + bendamustine on days 1
received and 2 and rituximab o
+ ECOG PS <2 are repeated e

1. ps cinicolials.gou/ct2/showNCTO2972840. PeerView.com

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22. ECHO: PFS Improvement With A + BR vs BR!

100 Full Analysis Population 100 COVID-19 Deaths Censored

80 80

Acalabrutinib + BR
Acalabrutinib + BR

X60 X60
6 6
2 2
Eo Eo um
ma
a ES
An ne ean F8, no se
20 o 20 e e cs
res = 064 09% 6, 040004;
; ; A
O 6 12 18 24 30 36 42 48 64 60 66 72 78 O 6 12 18 24 30 36 42 48 54 60 66 72 78
Time, mo Time, mo
No. tsk No. at Rak
ABR me 258 202 205 102 150 100 122 90 72 50 M 2 0 ACER 20 258 232 205 182 150 136 122 38 73 59 m 2 0

Placebo + BR 200 243 204 181 159 142 118 102 64 63 44 25 4 0 Placebo+BR 200 243 204 181 159 142 118 102 B4 63 44 25 4 0
36% risk reduction when censoring COVID-19 deaths
+ OS for A+ BR vs P + BR: HR = 0.86 (95% CI, 0.65-1.13); P= .27

+ OS sensitivity analysis: HR = 0.75 (95% CI, 0.53-1.04); P= .0797
1. Wang Metal. EHA 2024. Abstract LB3430. PeerView.com

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23. ECOG-ACRIN EA4818 Will Provide More Information
on Potential Future SOC Regimens in ND MCL'

rituximab 375 mg/m:
90 mg/m? IV every 12 hou

Key eligibility criteria les 1-3: rituximab 375 mg/m? IV day 1 or 2 followed by
bendamustine 90 mg/m? IV day 1 and 2 and
acalabrutinib 100 mg PO days 1 through 28

+ Patients with ND
MCL 218 and

$70 years of age
+ ECOG PS of 0-2 acalabrutinib 100 mg PO days1 th

Cycles 4-6: rituximab 375 mg/m? IV day 1 followed by
cytarabine 2,000 mg/m? IV every 12 hours da;

ycles 1-6
bendamustine

+ Primary endpoint: MRD- CR post-induction

Dose reduction for age and CICL. en
1. hitpsicinicalrals.gov'studyINCTO$115631 PeerView.com

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24. The “Chemo-Sparing”
BTKi Option in MCL

Christine Ryan, MD

Instructor in Medicine, Harvard Medical School
Leader, Mantle Cell Lymphoma, Division of Lymphoma
Dana-Farber Cancer Institute

Boston, Massachusetts, US

Copyright © 2000-2024, Peerview

25. “Chemo-Free” Doublet and Triplet Regimens
With BTKi Are in Rapid Development for MCL

Study Popul

Ibrutinib + rituximab (MDACC, ENRICH)
Older/frail patients
Acalabrutinib + rituximab

Patients ineligible for ASCT Zanubrutinib + rituximab (MANGROVE)
Patients >18 years with R/R or ND MCL (OASIS I) Ibrutinib, venetoclax, obinutuzumab
Patients with ND MCL aged 218 and <80 years (OASIS II) (OASIS | and II)

Patients with ND MCL 218 years of age

(range, 51-85 years) Acalabrutinib, venetoclax, rituximab.

Patients with ND MCL 218 years of age Acalabrutinib, lenalidomide, rituximab

Zanubrutinib, venetoclax, obinutuzumab

Adults with ND MCL (range, 60-73 years) (BOVen)

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26. Ibrutinib + Rituximab in Older Patients With ND MCL‘

Ibrutinib + Rituximab as 1L Summary from the MDACC
in Older Patients (N = 50) experience
Median follow-up: 45 mo + Ibrutinib + rituximab showed
high response rates and
mPFS and mOS not reached durable survival in elderly
patients with MCL
ORR: 96%; CR: 71% + Because of cardiac toxicity,

careful evaluation for cardiac
risk factors before receiving
ibrutinib + rituximab is

56% of patients discontinued treatment recommended

Notable AEs: 11 (22%) patients had grade 3
AF; <5% had grade 3-4 myelosuppression

1. Jain P et al. J Cin Oncol. 2022:40:202-212. PeerView.com

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27. BTKi Doublets: Acalabrutinib + Rituximab
Is Highly Active in Older Patients With MCL

+ 50 previously untreated patients receiving

Response

acalabrutinib 100 mg orally twice a day and IV + ORR: 92%
followed by SC rituximab for 24 months! + CR: 74%
+ Median age was 69 years (range, 65-81) + _MRD- status at LFU: 60%
100
x
g 80
É
E 60
El
240
4 Progressed/Total à Deaths/Total
¿> 4150 E Median: NR 3/50
&

12 15 18 21 24 3 6 9 12 15 18 21 24
Time, mo Time, mo

CARAMEL UK is testing acalabrutinib and rituximab for elderly or frail patients with previously untreated M

1. Jain P etal, ASH 2023. Abstract 3096. 2. ps ciicalials-govstudy/NCTOS004064. PeerView.com

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28. OASIS I: Can Triplets Overcome High-Risk Genetics?

E

Ibrutinib, obinutuzumab, and venetoclax

combination is well tolerated in relapsed/TN

patients with MCL

+ 4 (27%) patients in TN cohort were MIPI high-risk,
2 (13%) with TP53 mutation, 6 (40%) with del(17p)

+ Durable remissions in patients with TN or relapsed
and high-risk genetics

+ End of cycle 6 CR (by PET): 67% in relapsed and
86.6% in TN patients!

8

8

8

30 48-month PFS: 80%
in ND MCL cohort

Patients Alive and Free From Progression, %
g

Updated results showed sustained disease control ai
both in patients with R/R (4-year PFS of 50%) and
ND (4-year PFS of 80%) disease?

No. at Risk

1. Le GouilS et a. Blood. 2021:137:877-887,2. Le Gouil Set al. EHA 2023. Abstract P1090. PeerView.com

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29. ACE-LY-106: Acalabrutinib + Venetoclax
and Rituximab in TN MCL

+ N=21 patients with TN MCL receiving so
acalabrutinib + venetoclax and 09
rituximab for six 28-day cycles with as
maintenance rituximab for up to 2 years or
for responders and oral acalabrutinib

x
continuously until PD or toxicity* gos 4 Uncensored by death
Eos due to COVID-19
+ After a median follow-up of 25.8 months ad
— ORR was 100% (N= 21); A

CR rate was 90% (n = 19) 5

— Median DOR was not reached even
after censoring COVID-19 deaths no, sur

os 6 ok Em À À 2 © à %
Time From Initiation of Study, mo

Come 2 21 20 19 18 18 16 4 4 2 2 o
— Median PFS and OS were Uncensored 21 21 20 19 18 18 16 11 4 4 2 2 0
not reached
1. Wang Metal. ASH 2022. Abstract 2804, PeerView.com

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30. The AVO Triplet Appears Active in High-Risk R/R MCL,
Supporting Further Investigation’

AVO in patients with R/R MCL (44% Ki67 250%;
22% TP53 aberrant)

Disease Response — Primary 70 on CR: 56 (8/9)
Reassessment Assessment Endpoint cr:67(69) | Best
A | ; x 60 ORR:
| | H ö 78%
go
i Ss
n 0 PR: 11 (1/9)
erat orar 20
+ ; + >
1 2 3 4 5 6 7 8 9 10 11 12 10
cycle a
Best Response cet

+ Encouraging preliminary efficacy in this high-risk population

+ Phase 1 R/R MCL expansion cohort and phase 2 TN transplant-ineligible/TP53-aberrant MCL cohort
are now open and enrolling
1. kim Al ot al. ASH 2023. Abstract 3031, PeerView.com

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31. Acalabrutinib/Lenalidomide/Rituximab (ALR)
Is a Highly Active Triplet in TN MCL‘

Study assessing ALR and its potential to synergize activity and accelerate MRD-negative CR,
allowing response-adapted adjustment of treatment intensity to minimize AEs (N = 24)

PFS os
Main Findings
Response uPB-MRD .
+ ORR: + Gcycles: 50% 2 Median follow-up: 23 mo 2 | Median follow-up: 23 mo
100% + 12 oyoles: 67% 2 °° 2ey PFS, %: 86.7 (95% Cl, 69.5-100) 3 06 | 2 08, %: 100 (95% Cl, 100-100)
+ CR:83% + 24 cycles: 83% i ws Eos
GEE<EAA>XÁAPS | 8
ALR was well tolerated, highly 02 02
effective, and produced high + Censored + Censored
rates of MRD-negative CR as at 5 ps = ue D D a
initial treatment for MCL, — [MM Time, mo wa Time, mo
including in high-risk patients FPE 2 12 4 Mit m5 o
with TP53 mutations
1. Ruan J etal. ASH 2022. Abstract 73. PeerView.com

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32. BOVen: BTKi Triplets in Higher-Risk ND MCL

+ Zanubrutinib, obinutuzumab, and venetoclax in ND MCL (N = 25)!
+ All (100%) of patients had TP53-aberrant disease

Progression-Free Survival

Responses to BOVen ®
100 96% Ss
90 Partial u
metabolic 5
80 response E
70 2
so F
Complete 2
40 ‘metabolic El
30 > response 5 +
20 ao 6 12 18 24 30 36
10 Time From Treatment Start, mo
No. at Risk
5 2m a os 2 1
Cycle 3 Day 1 Best Overall
Response
1. Kumar À et al, ASH 2023. Abstract 738. PeerView.com

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33. ENRICH: Phase 3 Trial of Rituximab + Ibrutinib vs
Rituximab + Chemotherapy in Elderly Patients With MCL‘

Fully recr

R-chemo/R

Standard care

IRR
Intervention

1. ps cinicatias gouct2/shom/NCTO 1880567.

PeerView.com/QHV827

ng results

Rituximab
(every

Follow-up
until PD

21 days) for

56 days) for
6-8 cycles 2

Ibrutinib daily

Ibrutinib daily

+ rituximab + rituximab Ibrutinib to
(every (every continue
21 days) for 56 days) for until PD

8 cycles 2 years

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34. MANGROVE Will Assess Zanubrutinib/Rituximab vs BR
in Previously Untreated MCL‘

Arm A: zanubrutinib Arm A: zanubrutinib
(160 mg BID) + (160 mg BID) Response

rituximab (375 mí monotherapy until PD or assessed by

Previously on day 1 of cycles 1-6 unacceptable toxicity imaging every

untreated 3 months for

MCL 3 2 years, then
(N = 500) Arm B: bendamustine every

(90 mg/m?/day IV) on mont
days 1 and 2 + Arm B: observation only until PD

rituximab (375 mg/m?)

on day 1 of cycles 1-6

1. Dreyting Metal, Future Oncol. 2021:17.256-262. PeerView.com

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35. OASIS II Will Provide Additional Insights

on Triplets vs Doublets in ND MCL"
+ Interventional, multicentric, open-
label phase 2 trial
+ Population: previously untreated 7 RD Bu ond Cat.
patients with MCL aged 218 and Aurore Aurore À revenons
<80 years

+ Randomized (1:1) | IE
— ArmA: ibrutinib + CD20 Ab

— Arm B: ibrutinib + CD20 Ab
+ venetoclax

54 bi AmB
+ Stratification ona

Cr 02 ca cs cs chy cr ca ca cw cn CRC — on
— Age (<66/266 years) Screening
284

Induction Consolidation Maintenance Follow-Up
6 6mo

mo 30mo 24mo

— MIPI (high/nonhigh)
— Country

+ Primary objective: MRD rate in
BM and/or PB at the end of
induction (after C6)

1. htpscinicatrals govistudy NCTOA802590, PeerView.com

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36. BTKi Safety Principles in MCL:
What Have We Learned?

Pier Luigi Zinzani, MD, PhD

Head of Lymphoma Group;

Institute of Hematology "Seragnoli"
University of Bologna
Bologna, Italy

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37. The Overall Safety Experience to Date With BTK Inhibitors’

Selected Toxicities With BTKi + Do not give concomitantly with warfarin

+ For new-onset AF, consider non-warfarin
Bae anticoagulation + monitoring
Arthralgia

+ Hypertension: manage with antihypertensives

+ Monitor for and manage cardiac arrhythmia/AF;
treat appropriately

+ Monitor patients for signs of bleeding

+ Monitor for infections and secondary malignancies

BTK

+ Acalabrutinib: manage headache with
acetaminophen + caffeine

+ Zanubrutinib: neutropenia; for first occurrence,
dose interruption is recommended (growth factor
support for more severe manifestations)

4. Lipsky A Lamanna N. Hematology Am Soc Hematol Edu Program. 2020.1:336:345. 2. NCCN Cinical Practico Guidelines in Oncology. B-Cel Lymphomas.
Version 2.2024. Mis nm ncen orpprotessionalsphysician_a/pd/b-cel pl. 3. Calgvence(acalbrutin) Prescribing Ifornaten.

nos www ccosedata 1d gowdrogsatida_docsabel20177210250500001 al 4. Brisa (anubruin) Prescribing Infomation. À

ps: accessdata.(da govidrugsatida_docs/abel2023/213217801010 pa. PeerView.com

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38. Safety Summary From Pivotal
BTKi Trials in R/R MCL14

Median prior lines
of treatment 5 2 2
Median age, y 68 68 60.5
Discontinued due to
AE n(%) 8(7) 7 (6) 8 (9.3)
Grade 23 AEs, %
Neutropenia 16 10 19.8
Major hemorrhage 45 0.8 3:5
AF 4.5 0 0
1 NGGN Cine Pacts Gutnes bo Oncngy. Got Dynpnonas Von 22024 hips ana ee opera pci. DID ce PeerView.com

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39. What Is the Safety Experience With 1L Ibrutinib?
Evidence From the SHINE Trial?

+ Incidence of grade 3/4 AEs during treatment was 81.5% in the ibrutinib group and
77.3% in the placebo group’

+ 220 patients (84.3%) in the ibrutinib group and 201 patients (76.7%) in the
placebo group discontinued therapy

+ Most common reasons included
— AEs (39.5% in the ibrutinib group and 24% in the placebo group)
— PD or relapse (in 10.7% and 34.7%, respectively)

n (%) Ibrutinib + BR (n= 261) Placebo + BR ( 62)
Death due to
treatment-emergent AEs AI) Gi)
1. Wang ML etal. N Engl J Med. 2022:386:2482-2494. PeerView.com

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40. What Is the Safety Experience From TRIANGLE?"

Blood and lymphatic system disorders|
Infections and infestations

Gastrointestinal disorders

Nervous system disorders

Cardiac disorders

General disorders and administration site conditions

Musculoskeletal and connective tissue disorders

‘Neoplasms benign, malignant, and unspecified (incl cysts
and polyps)
Investigations

Injury, poisoning, and procedural complications
Respiratory, thoracic, and mediastinal disorders|
Vascular disorders

Metabolism and nutrition disorders

Skin and subcutaneous tissue disorders

MA (n=230)
MA +1(n=230)
Bi (n= 268)

+ No differences in toxicity when adding ibrutinib
to induction vs CIT

+ Increased toxicity with ibrutinib post-ASCT

7
1. Dreyling M et al. ASH 2022. Abstract 1. a

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2 = “© > PeerView.com

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41. The Safety Experience to Date
With Acalabrutinib Combinations in ND MCL

50)"

Most Common All-Grade AEs,%

Acalabrutinib + Rituximab (N

Acalabrut

ib + BR? TN Cohort (n= 18)

I
| Events of Clinical Any
ini y
Er = | interest, n (%) Gracie | Sa
ous An I Cardiac events 4(222) 3(167)
en = | Hypertension 3(167) 3(167)
Bruising 28 I Neutropenia cay 8 (44.4)
Most AEs were grade 1 or 2; <1% were | r ;
fate Sioa ON 1 Thrombocytopenia 2(11.1) 2(11.1)
1 Hemorrhage 844) 2(11.1)
Acalabrutinib + Venetoclax + Obinutuzumab* | Major hemorrhage __2(11.1) 2(11.1)
Ani, Grades Grades Grades MM
ECHO: grade 23 AE
Cardiacevents 4(19) 00) 0 (0) 0 (0) | well balanced between ABR and PBR?
AF 00) 00) 0(0) 0(0) 1
00) 0(0) |
Hypertension 16) 16) qu a |
I

1 dain P et al ASH 2023, Abstract 3096. 2 Pips Tat al. EHA 2023. Abstract P1094.3. Wang Mat al. EHA 2024. Abstract LB3430. 4. Wang Meta ASH 2022 —
Abstract 2884, PeerView.com

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42. PeerView.com/QHV827

The Safety Experience With the BOVen Platform in ND MCL"

"Grade 1 mGrade2 mGrade3 mGrade 5

Era + Overall, the BOVen treatment was
Year tract hiecion well tolerated and safe
Myalgia
Constipation Most common AEs were diarrhea,
‘Aspartate aminransferase increased COVID-19 infection, neutropenia,
Rash maculopapular and infusion-related reactions
FERA un reer Grade 3 neutropenia (16%) resolved
Fatigue with growth-factor support
Bruising Diarrhea was predominantly grade 1

‘Alanine aminotransferase increased and manageable
Infusion-related reaction

Neutrophil count decreased

COVID-19 infection

Diamhea

0% 10% 20% 30% 40% 50% 60% 70%
Patients

1. Kumar À et al ASH 2023. Abstract 738. PeerView.com

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43. What Can We Learn
From Head-to-Head Evidence

in Other Cancer Settings?

44. BTKi Selectivity Has Implications
for Safety and Treatment Selection'$

Ibrutinib Acalabrutinib Zanubrutinib
se a ntial off-target effects include

Covalent BTKi

Head-to-head trials confirmed the ELEVATE-RR (CLL)
hypothesis that more selective Acalabrutinib vs ibrutinib”
BTKi have fewer off-target effects,

MESS) ALPINE (CLL) and ASPEN (WM)
vs ibrutinib? + Zanubrutinib vs ibrutinib®*

4. Kaptei A et al, ASH 2018. Abstract 1871. 2. Bose Petal, Expert Opn Drug Motab Toxicol. 2016;12:1381-1992. 3. Herman SEM e al. Clin Cancer Res
2017.232891-2841. 4. Owen C et al. Curr Oncol, 2019:26:0299-0240.5. Mato A et al. Lancet. 2021.397.292.901.6, Brandhuber BJ et al. Cin

‘Lymphoma Myeloma
Luk. 2018:18:5216.7. Seymour JF etal. Blood. 2023:142.587.699. 8. Brown JR otal N Engl J Mod. 2023:388:319-332.9. Dimopoulos MA et al. J Cn Oncol.
2023,41:5000:5106.

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45. Case Forum
Practice Makes Perfect
Preparing for Upfront Therapy

With BTKi Platforms

46. Case 1: A Patient With ND MCL Eligible for CIT and ASCT

Max is a 62-year-old TN patient He presents with
with symptomatic, stage IV MCL + Weight loss and fatigue

+ Eligible for CIT induction and + Ki67 30%; no TP53 mutation
ASCT + PSof1

Discussion

+» Cana BTKi-based combination be considered here based on current evidence? What is the
current thinking in the United States and the European Union on this topic?

+ What factors can help determine patient candidacy for upfront BTKi-based platforms?

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47. Case 1: A Patient With ND MCL Eligible for CIT and ASCT

Max is a 62-year-old TN patient He presents with
with symptomatic, stage IV MCL + Weight loss and fatigue

+ Eligible for CIT induction and + Ki67 30%; no TP53 mutation
ASCT + PSof1

Discussion

+ If this patient elected to forgo ASCT, would a CIT/BTKi regimen be appropriate as 1L therapy?
+ Can you extrapolate from TRIANGLE and head-to-head trials and substitute a second-
generation BTKi for ibrutinib?

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48. Case 1: A Patient With ND MCL Eligible for CIT and ASCT

Max is a 62-year-old TN patient He presents with
with symptomatic, stage IV MCL + Weight loss and fatigue

+ Eligible for CIT induction and + Ki67 30%; no TP53 mutation
ASCT + PSof1

Recommendations

+ Assuming access to 1L BTKi, frontline BTKi + chemotherapy enables potential omission
of ASCT
+ Atime-limited upfront BTKi approach is feasible and tolerable

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49. Case 2: An Older Patient With ND MCL and a PS of 2

Michela is a 74-year-old TN patient She presents with
with symptomatic, stage IV MCL + PSof2

Discussion

+ Would this patient normally be a candidate for a BR platform?
+ Is there a rationale for adding a BTKi?
+ How do SHINE and now ECHO inform the present/future of BTKi/BR combinations?

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50. Case 2: An Older Patient With ND MCL and a PS of 2

Michela is a 74-year-old TN patient

She presents with
with symptomatic, stage IV MCL

+ PSof2

Recommendations

Current SOC is BR + R maintenance; however...

- SHINE first showed the efficacy of adding a BTKi (challenges with ibrutinib toxicity)

— ECHO: ABR appears effective and tolerable; regulatory decisions/longer follow-up are anticipated
Ongoing question: concomitant vs sequential use of BTKi with CIT?

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51. Case 2 Revisited: What If This Patient
Were Older or Less Fit?

Michela is an 81-year-old TN

5 > She presents with
patient with symptomatic,

stage IV MCL + PSof2

Discussion

Would a chemo-sparing BTKi platform potentially be a consideration?

How might EU and US practices change with the availability of chemo-free strategies
comprised of targeted agents?

How might you decide between targeted doublets or triplets?
What would you do if this patient had high-risk features?

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52. Case 2 Revisited: What If This Patient
Were Older or Less Fit?

Michela is an 81-year-old TN
patient with symptomatic,
stage IV MCL

She presents with
+ PS of2

Recommendations

+ Doublets and triplets appear to be active in older patients

+ Trade-off between toxicity and efficacy in patients of this age
+ With triplets, carefully assess toxicity and patient fitness

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53. Audience Q&A © |

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54. Symposium Summary & Take-Home Messages

We are facing a real “Copernican revolution” in the world of MCL

+ The TRIANGLE and ECHO studies will completely change 1L treatment
with the introduction of BTKi and the definite deletion of ASCT

+ The advent of second-generation covalent BTKi and the introduction of
the first non-covalent BTKi, pirtobrutinib

+ The potential role of “triplets” (OASIS, ALR, AVO, BOVen, Window2) for
high-risk patients

+ The forthcoming arrival of definitive data from the ENRICH and
MANGROVE trials
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55. Symposium Summary & Take-Home Messages (Cont'd)

+ Let's not forget the role of T-cell-engaging therapy

— Recent FDA approval of a second product (liso-cel) for the third-line
management of MCL

— Preliminary but very interesting data for glofitamab

All these data point to and will inform a new therapeutic algorithm

and continuous and dynamic evolution, which will significantly raise
the bar of therapeutic successes for our patients with MCL

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