Exceeding Expectations in CLL: Workshops on Targeted Standards, Sequential Options, and Emerging Therapeutics for Team-Based Care

Chair and Presenter, William G. Wierda, MD, PhD, John N. Allan, MD, and Nicole Lamanna, MD, discuss chronic lymphocytic leukemia in this CME/MOC/NCPD/CPE activity titled “Exceeding Expectations in CLL: Workshops on Targeted Standards, Sequential Options, and Emerging Therapeutics for Team-Based Care.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/CPE information, and to apply for credit, please visit us at https://bit.ly/3Xtt5bH. CME/MOC/NCPD/CPE credit will be available until October 3, 2025.

1. Exceeding Expectations in CLL

Workshops on Targeted Standards, Sequential Options,
and Emerging Therapeutics for Team-Based Care

William G. Wierda, MD, PhD John N. Allan, MD

Professor, Department of Leukemia, / ‚Associate Professor of Clinical Medicine
Division of Cancer Medicine Division of Hematology &

Jane and John Justin Distinguished Chair in Medical Oncology

Leukemia Research in Honor of Dr. Elihu Estey Weill Comell Medicine

Section Chief - Chronic Lymphocytic Leukemia New York, New York

Center Medical Director, Leukemia

Executive Medical Director, Inpatient Medical Services

The University of Texas MD Anderson Cancer Center

Houston, Texas

Nicole Lamanna, MD

Professor of Medicine, Leukemia Service

Director of the Chronic Lymphocytic Leukemia Program
Hematologic Malignancies Section

Herbert Irving Comprehensive Cancer Center

New York-Presbyterian/Columbia University Medical Center
New York, New York

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

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2. Multiple Targeted Agents and Now Cellular Options
Are Available to Manage CLL/SLL

Covalent BTKi
+ First cBTKi approval was Ibrutinib
in 2013 Acalabrutinib

+ Subsequently, multiple Zanubrutinib

BTKi options approved

targeted and
+ Most recent approval was fj cellular therapies

CAR-T therapy in 2024 Lin CLLISLLTS

+ Represents an
advancement over the
CIT era

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3. An Evolving 1L Landscape
Real-World Data Suggest More Work Needs to Be Done

Real-world assessment of 1L use of
modern CLL therapy (based on Integra
Connect PrecisionQ real-world

deidentified database)!

+ N = 6,328 CLL patients receiving treatment
between 1/1/2020 and 6/30/2023

Drug Class

+ BCL2i and BTKis represented the majority
of 1L treatment choices

However, in 2023

+ >33% of patients did not receive
recommended regimens per guidelines

+ Nearly 20% continue to receive
chemotherapy-based treatment

Drugs Utilization in 1L: 2020 to June 2023

BTKi

BCL2i
Anti-CD20
Chemotherapy

1. Hou JZ otal ASH 2023, Abstract 130

PeerView.com/THK827

2020, n (%) 2021, n (%) 2022, n (%) Jan-June 2023, n (%)
1,065 (55.8) 1,069 (56.6) 984 (58.2) 473 (56.3)
278 (146) 305 (16.1) 317 (18.7) 166 (19.8)
186 (2.8) 107 (5.7) 67 (4) 44 (6.2)
377 (19.8) 409 (21.6) 322 (19) 156 (18.6)
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4. Other Data Suggest a Need to Optimize Later-Line Outcomes

+ Assessment of patient outcomes from the Fred Hutchinson Cancer Center
+ Patients with double-refractory CLL had a significantly shorter PFS and OS compared with those who were double exposed!

PFS in “Double-Refractory” Patients OS in “Double-Refractory” Patients
vs Double Exposed vs Double Exposed

Double Refractory Double Exposed Double Refractory Double Exposed

100

00
Modan OS, mo 212 NR

96% 1 1446 7

Medan PFS.mo 68 154
95% ci 39 399
Other couble-exposed patients

5
Other couble-exposes patents g

Double refractory Lo cBTKI and venetociax

Lo,
o LLogrank P = 004

o
o E Py > ® ° = 5 pi
"Tine: me! Overall, more effective options are Time, mo
needed for many patients previously
treated with a cBTKi and venetoclax PeerView

1. Samples LS otal ASH 2023. Abstract 4850.

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5. Our Goals for Today

Improve your knowledge of supporting 1L and sequential use of
modern therapeutics in CLL

Equip you with the skills you need to develop treatment plans
with continuous or time-limited strategies in TN and R/R CLL

Provide you with guidance on managing dosing, safety, and
treatment planning in modern CLL care

Copyright © 2000-2024, PeerView

6. New Expectations for Upfront Care
and Sequential Therapy

John N. Allan, MD

Associate Professor of Clinical Medicine
Division of Hematology & Medical Oncology
Weill Cornell Medicine

New York, New York

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7. Case Workshop: A Patient With CLL and Unmutated IGHV
But No Additional High-Risk Features
David presents in 2024 Laboratory Testing
with symptomatic CLL + CrC1 66 mL/min

after a watch and wait + Hb: 11.0 g/dL
period of 4 years
+ He's 72 years old with a Prognostic Assessment
PS of 1 7
symptoms (including FISH: del(11q), no del(17p)

+ DNA sequencing: unmutated

weight loss) IGHV, no TP53 mutation

+ Lymphadenopathy
(7 cm)

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8. Case Worl p: A Patient With CLL nmutated IGHV

But No Additional High-Risk Features

Patient summary Discussion (2

+ David is 72 years old with a a
aPS of 1

+ Symptomatic CLL,
unmutated IGHV, anemia, + Given this presentation, what options
CrCl 66 mL/min could be considered?

+ Lymphadenopathy (7 cm) . ee

+ Del(11q), no del(17p) ron leales and continuous

+ How do patient preferences inform the
choice between time-limited and
continuous therapy?

+ What if del(17p)/TP53m were present?
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9. But Eventually Progressed While on Treatment

Patient summary

David is 72 years old with
aPS of 1

Symptomatic CLL,
unmutated IGHV, anemia,
CrCl 66 mL/min
Lymphadenopathy (7 cm)
Del(11q), no del(17p)

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Treatment History
+ Ibrutinib 420 mg QD (2014)

+ Progression after 7 years (2021)
+ Testing shows BTK C481

Would you now retest for del(17p)/TP53m?
Test for BCL2 mutations?

How do you choose the best option now that
progression has been confirmed?

How do you decide between continuous
therapy and time-limited options when
resistance mutations are present?

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10. Patient summary

David is 72 years old with
aPS of 1

Symptomatic CLL,
unmutated IGHV, anemia,
CrCl 66 mL/min
Lymphadenopathy (7 cm)
Del(11q), no del(17p)

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* Ibrutinib 420 mg QD (2014)

+ Progression after 7 years (2021)

« Testing shows BTK C481

+ Time-limited venetoclax + R

+ Progression 10 months after
EOT (in 2024)

What testing would you now recommend?
What next steps would you take?

Pirtobrutinib? CAR-T? What are the
practical/logistical considerations with each?

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11. Recommendations for David

Scenario 1: TN CLL, ulGHV, del(11q), no del(17p)
Multiple options could be considered

* Time-limited venetoclax regimen or continuous therapy with BTKi;' however,
presence of del(11q) and ulGHV, age, and bulky disease support leaning
toward continuous therapy

+ Weigh safety considerations when choosing among 1L cBTKi23

If del(17p)/TP53m had been present, current evidence also favors BTKi*+®

1. NCCN Cina Practica Guidelines in Oncology. Croni Lymphocytic LevkenalSmalLymphogy Lymphoma, Version 32024
Mis law acen ogprotesionalptysian gpa pl. 2 yd et al J in Oncol 202139344 0482 3. Brom Jet al ASH 2023. Abstract 202. 5 N
‘Alan JN et BrJHocmatl2022.100:947:959.5. Davis Metal Blood Ad. 2026 8:39455399, 6, Mune tl EHA 2023, Abstract PO PeerView

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12. Workshop Summary: Recommendations for David

Scenario 2: R/R CLL, long remission to 1L cBTKi,

BTK C481m present at relapse
Time-limited venetoclax + CD20 is a 2L SOC!

+ Pirtobrutinib is an alternative 2L option in cases of resistance to cBTKi,
supported by guidelines and evidence in cBTKi-exposed but BCL2i-naive CLL12

After progression on a 2L venetoclax platform, given the presence of BTK
resistance, double-exposed status, and long remission to prior BTKi,
evidence supports pirtobrutinib as a SOC!

CAR-T is an option in this setting, requires planning 1 LOT before use,
coordinated management

JNCEN Cat Pu Olas Onn. Cron Lyngdal Lyre tyme, Verso 32024 5 a
apse con o proessionak physician pai pi 2 Woyach Jot a ASH 2023 Abstract PeerView

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13. BTKi Options and BCL2i Combinations Are Well-Represented in
Practice Guidelines f

1L Therapy
With del(17p/TP53
+ Acalabrutinib + obinutuzumab (category 1) + Acalabrutinib + obinutuzumab
Preferred | - Venetoclax + obinutuzumab (category 1) + Venetoclax + obinutuzumab
+ Zanubrutinib (category 1) + Zanubrutinib
Sa Ibrutinib (category 1)
recommended | * [brutin (category + Ibrutinib (category 1)
= + Ibrutinib + CD20 mAb toc
(BTKi-based (ceja 28) El ii - Ibrutinib + venetoclax (category 2B)
only)
EN Ge Pt cust no OLEA ros or Vs 0 PeerView

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14. Longer Follow-Up Confirms the Efficacy of Continuous BTKi

A041202' ELEVATE-TN? SEQUOIA?
oa Acalabrutinib + G Zanubrutinib
Ibrutinib + Rvs BR vs GCIb vs BR
45 6 ~4 (44-48 mo)
48-mo PFS estimates ns 42-mo PFS was 82.4%
=> were 76% for ibrutinib | 622 (A) with zanubrutinib
9 o
arms vs 47% for BR 17% (GClb) vs 50% for BR (cohort 1)

Up to 10 years follow-up from RESONATE-2*
+ Median PFS of 8.9 y with ibrutinib vs 1.25 for chlorambucil
+ HR=0.16; P< .0001

1. Moya Jota, Bo, 2024148 1616-1627. 2. Shaman Jet al. ASH 2023 Abstract 638, 3. Muni Tot al EMA 2023, Attract POD Da air
À Burger etai EHA 2024, Abstract PEO. PeerView

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15. Optimizing Continuous Therapy in
High-Risk CLL

16. BTKi Therapy Was a Major Step
Forward Against Del(17p)/TP5

Pooled analysis of patients receiving

+ Single-agent ibrutinib in PCYC-1122
or RESONATE-2 trials

+ Ibrutinib-CD20 combination therapy
in ¡LLUMINATE or E1912 trials

+ All 89 patients had del(17p) and/or
TP53 mutation

79% PFS

PFS, %
838828388

Median follow-up of 49.8 mo
+ Median PFS not reached
+ PFS and OS estimates at 4 years 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 9 9%
were 79% and 88%, respectively Time, mo
No.atRisk 89 86 82 79 75 66 60 49 39 33 29 28 20 16 5 5 0

o 8

1. Alan AN et a. Br Hoemao. 202,106 947-953, PeerView

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17. PFS in TN CLL With Acalabruti

100
80

5 60 A-based combined
E 4
20
o
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84
Time, mo
No. at Risk
A+G 28 2% 2 2% 2 2 2 2 2 2 9 3 0 0
A 3% 3 32 3 9 2 2 2 2 2 4 9 5 O
Abased combined 64 59 7 56 53 52 51 46 45 43 23 12 5 0
1 One Meta Bad Ae 2024969045330 PeerView

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18. Evidence From Coh
Efficacy of Zanubru

2 of the SEQUOIA Trial Showed the
Del(17p) CLL

PFS and OS Outcomes With Zanubrutinib in 110 patients With TN Del(17p) CLL"

100
a os
a | PFS
= , H
= ® Median H
2 50 1
$ PFS not H
40 |
B x 42 mo (95% Cl) reached H
20 os 89.5 (81.9-94.1) H
PFS 79.4 (70.4-85.9) H
10 À + Censored H
0 +
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57
Time, mo
No. at Risk

OS 110 110 109 108 108 105 104 104 102 102 102 100 99 87 72 52 33 9 1 0
PFS 110 109 106 104 104 101 98 96 94 93 89 89 88 85 75 32 2 3 2 0

{Murr eL EMA 2029. Abstract P63. PeerView

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19. Optimizing Continuous Therapy:
Head-to-Head Evidence

20. h Acalabru

ELEVATE-RR: Lower Incidence of Key AEs

vs Ibrutinib*

After Median Follow-Up of 40.9 Months

Non-inferior PFS (primary

endpoint)

+ Median PFS of 38.4 mo in both
arms (HR = 1.00)

Lower cumulative incidences of
+ AFiflutter (HR = 0.52)

+ Hypertension (HR = 0.34)

+ Bleeding (HR = 0.63)

+ Diarrhea (HR = 0.61)

+ Arthralgia (HR = 0.61)

1. Byrd JC et al. J Gin Oncol. 2021;98:3441-9482

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Patients, %

All-Grade AF/Flutter, HTN, and Bleeding

Key secondary
‘endpoint

HTN

Bleeding

mAcalabrutinib mIbrutinib
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21. ALPINE: Improved PFS, Lower Rates of AF/Flutter
With Zanubrutinib Compared With Ibrutinib!

After a Median Follow-Up of 39.0 Months

Zanubrutinib demonstrated dde ii
PFS benefit over ibrutinib e
2 50
Median PFS, mo g 40 238 UN
+ Zanubrutinib: 64.9 Ss
+ Ibrutinib: 54.8 &”

+ HR (95% Cl): 0.68 (0.53- 20 265 (pam
0.86); 2-sided P = .0011

6.8
o - -

AF/Flutter HTN Hemorrhage

1.Brom Jet, ASH 2029, Abstract 202 PeerView

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22. Optimizing Continuous Therapy in
R/R CLL: Sequential BTKi Options

23. rrent Guidelines Suggest ncBTKi and Other Novel

CLL/SLL With/Without Del(17p)/TP53m

Second: e or Ti

Other recommended

Preferred regions Palmers + For relapse after a period of remission

(if previously used)

+ Acalabrutinib (category 1) + Ibrutinib (category 1) Fi

+ Venetociax + rituximab (category 1) - Venetociax 7 da dei)

+ Venetoclax (del[17p] only) (no del[17p] only) Ano be

+ Zanubrutinib (category 1) + Ibrutinib + venetoclax a E
(category 2B) PY

- Pirtobrutinib

1. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia‘Small Lymphocyte Lymphoma, Version 3.2024 A
ps ue ncen.orgpcoessionalipisiian_gls/pdtcl pal PeerView

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24. urrent Guidelines Suggest ncBTKi and Other Novel
Therapeutics in Treatment-Refractory Settings!

Therapy for Relapsed or Refractory
After Prior BTKi- and Venetoclax-Based Regimens

CLL/SLL With/Without Del(17p)/TP53 Mutation

Other recommended regimens (alphabetical order by category)
+ Chimeric antigen receptor (CAR) T-cell therapy: Liso-cel
+ Small-molecule inhibitors

- Duvelisib

- Idelalisib + rituximab

- Pirtobrutinib (if not previously given)

= Ibrutinib + venetoclax (category 2B)

With Del(17p)/TP53 Mutation Without Del(17p)/TP53 Mutation

FOR

Lenalidomide + rituximab

Obinutuzumab

Bendamustine + rituximab (category 28 for patients 265 y
or patients <65 y with significant comorbidities)

+ HDMP + anti-CD20 mAb (category 2B)

+ Alemtuzumab + rituximab
+ HDMP + anti-CD20 mAb
+ Lenalidomide + rituximab

1. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 3.2024
ps ue ncen.orgproessionalsipisician_gls/patcl pal

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25. The BRUIN Study Demonstrated Pirtobrutinib Efficacy in

R/R CLL/SLL Patients!

Prior BTKi Prior BTKI+ BCL2i
(n=247) (n= 100)
naa "
nn Dechroner | Overall response rate, %(95% Cl) 822768867) — 70.0(69.7365)
++ Prior BCL2 inter Best response, n (%)
CR 415) 000)
PR 477 (71.7) 70 (70.0)
PRL 22 (89) 9 (0.0)
sd

Pirtobrutinib (200 mg daily)

demonstrated durable efficacy

in patients treated with a prior

covalent BTKi, regardless of

+ Prior therapy, reason for
prior BTKi discontinuation,
or age

+ TP53 mutations, C481S
mutational status, and/or
del(17p)

LE.
ee

PeerView

1. Mao À et al. N Engl J Med 2023:280:33-44.

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26. BRUIN: PFS in cBTKi-Pretreated R/R CLL/SLL

100
90
80
70
60
50
40
30
20
10

0

Median PFS: 19.6 mo
95% CI: 16.9-22.1
Median follow-up: 19.4 mo

PFS, %

0 2 4 10 12 14 16 18 20 22 24 26 28 30 32 34 36
No. at Risk Time Since First Dose, mo

247 228 215 202 182 162 144 113 103 82 57 46 22 19 5 4 4 1 0

{Mato À ta. Eng Med. 2023380534. PeerView

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27. regardless of prior BCL2i status!

BCL2i-Naive

BCLZi-naive
‘Median (95% Cl, mo: 23 (19.6-28.4)

ORR for all post-cBTKi patients: 72%

BCL2i-Exposed

»
»

à

o

do

do

co BCL2i-exposed

E» Rodan 05% I, mo: 188 (136-75)
»

02 4 6 8 10 12 14 16 16 20 22 2 2 26 WMH O 2 HAS
Time From First Dose, mo

AAA
O24 6 BWM 1102 2M MBH A AM AD
Time From First Dose, mo

BA EN es 1412411410460 ge ap 04 TA 70 47 44 28 2221 10 7 7 9 3 9 1 0 BULMETDONISHCOSD 88 16615247 4 25 20 12 1 9 2 22220 0 00 0

ORR of 83.1% for BCL2i-naive patients

Median PFS: 23 mo

1. Woyach Je al. ASH 2023. Abstract 325.

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ORR of 79.7% for BCL2i-exposed patients

Median PFS: 15.9 mo
PeerView

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28. Practical Summary and Take-Homes
With Continuous BTKi Therapy

29. Be Prepared to Review Dosing and Safety Monitoring
Recommendations With al on BTKi Thera

Ibrutinib? E
420 mg once daily Er
Acalabrutinib maleate salt Arthralgia

(IR film-coated tablet)?
100 mg every 12 hours

BTK
Zanubrutinib* Inhibitors
160 mg orally twice daily or ° Iofoclen
320 mg orally once daily
Pirtobrutinib? qe
200 mg orally once daily Hypertension

1. Weis TH et a. Oncol Pham Pract 202228:1411-1499, 2. Indra (rain) Presebing nomatn.
_docaliabe/2015/20558220020 p09 Calquenc (cabrio) Prescribing forty
LO 4 rion anaes Peer oma
ocslabel2023/21321730071 POL. Jayptea (pn) Present
Ph cta ta gover gate, scalobev20/1ebs0ongedo0Garecad Bld Listy A Loman N Hemtlegy Am Soc Hamas Eve N
Program. 20201 398-945, PeerView

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30. Itiple Disciplines Contribute to CLL Management,

Including Treatment Planning With Continuous Therapy

Overview of the CLL Management Team

For example, monitoring for
drug interactions and
coordinating care

PA Patholo

Molecular testing
and quickly communicating results

Assessing patients and
planning treatment

Hematologist-oncologist Pharmacist

© Patient with
x symptomatic

CLL

Educating patients and

ee Cardio-oncologist

Consult with cardio-onc, if available, to
anticipate/adaress CV complications

Oncology nurse

Treatment selection Di

progression

On-therapy management

PeerView

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31. Progress in Optimizing Time-Limited
Therapy for Patients With CLL

Nicole Lamanna, MD
Professor of Medicine, Leukemia Service

Director of the Chronic Lymphocytic Leukemia Program
Hematologic Malignancies Section

Herbert Irving Comprehensive Cancer Center

New York-Presbyterian/Columbia University Medical Center
New York, New York

1000-2024, PeerView

32. Case Workshop: An Adult Patient With CLL and
Non-Bulky Disease
> Laboratory Testing
Charlotte presents with E + WBC: 95 x 10%L
confirmed, symptomatic CLL

+ ANC: 2.5 x 9/L, ALC: 91 x 10%/L

+ She's 62 years old with a PS + Hb: 9.0 g/dL; PLT: 72 x 10%L
ct = Prognostic Assessment

+ Progressive
lymphadenopathy (4 cm) + FISH: no del(17p)

+ Splenomegaly + DNA sequencing: unmutated

IGHV, no TP53m

PeerView

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33. Case Workshop: An Adult Patient Wi
Non-Bulky Disease

Patient summary

+ Charlotte presents with
symptomatic CLL

+ ulGHV, no del(17p)

+ 62 years old °

+ PSof1

+ Progressive
lymphadenopathy (4 cm)

+ Splenomegaly

PeerView.com/THK827

LL and

Discussion y,
24

Given this presentation, is time-limited
therapy the optimal approach?

How would you counsel this patient on

time-limited venetoclax and
obinutuzumab?

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34. Case Workshop: What if

Bulky Disease?

lotte Had Presented Wi

Patient summary

Charlotte presents with
symptomatic CLL

ulGHV, no del(17p)

62 years old

PS of 1

Progressive
lymphadenopathy (10 cm)
Splenomegaly

Discussion y,
22

+ If available, would a BTKi-ven regimen
be appropriate to consider?

+ What is the clinical experience with 1st
gen and 2nd-gen BTK-ven time-limited
combinations?

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+ What factors can be used to help
choose a BTKi component in a time-
limited combination?
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35. Workshop Summa

Scenario 1: 62 years old, non-bulky CLL, ulGHV

For this younger patient with non-bulky disease, a time-limited approach with
venetoclax + obinutuzumab is useful and supported by CLL1412

+ Careful monitoring for TLS (moderate to high risk) is recommended

Scenario 2: 62 years old, bulky CLL, ulGHV

When available, time-limited therapy with a BTKi + venetoclax platform is an attractive
option for a patient with bulky disease/ulGHV

+ Lead-in BTKi can help address disease burden prior to starting venetoclax?

+ Increasingly, data from studies of finite therapy with second-generation BTKi + venetoclax
are supporting this option as an effective and tolerable strategy in this setting“

1. ASS aval © et al EHA 2023 Abstract S145 2. NCCN Clinica Prato Guidelines in Onelogy. Crni Lymphoc Leukema/Smal Lymphocyie Lymphoma, Versen 2 2024
pe lancen rproissorluphyacn. ltl pl 3 Marca W et a Cin Oncol 204130 2053-008 à. Gna Peta EI 2021 Abat SIGO, 5
5 hos ni carcemetwork comvienecaiabrut-comeo-sgniicanty-enprovespa-s-chemomnunotherapyn-l PeerView

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36. Why Choose Time-Limited Therapy in CLL?

+ Potential to stop treatment when disease is in remission

+ Potentially limits prolonged toxicities and mild toxicities
can be less burdensome

* Cost-effectiveness

» May prevent the development of resistance mechanisms
in CLL

-Potentially allows for retreatment

1. Moi Sat al. Expert Rev Anteancor Ter 202424:101-106. PeerView

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37. CLL14: 6-y Follow-Up" MURANO: 7-y Follow-Up?

VenG GCib VenR BR

Median PFS, mo 762 364 Median PFS! mo ze m
6-y OS, % 787 69.2 7 08,% 5 a
Median TTNT, NR 62.9

Se Median TTNT, mo 63 24

PFS in patients with u u
uMRD at EOT, mo : PFS in patients with 656 48
uMRD at EOT, mo “

Median PFS in del(17p),
mo 51.9 38.9

1 AsSawaf Oot al. EHA 2020. Abarat S145 2. Koer A et al. HomaSphere. 20291 supplke492010. PeerView

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38. Rationale for BTKi/BCL2i Combinations

Distinct and Complimentary Mechanisms of Action for Ibrutinib and Venetoclax in CLL'+

Lymph node i
izes CLL cells out of | Ibrutinib accelerates apoptotic cell
e lymph nodes and other protective | killing by sensitizing CLL cells to E
Ÿ © lymphoid niches and inhibits + BCL2 inhibition
Stromal Y — 9. & proliferation :
om % Ibrutinib =. “ Venetoclax
Ibrutinib mul sal
Ne + venetoclax eliminates
Peripheral resting and dividing en
blood CLL cell populations @ Dividing CLL cells

@ Resting CLL cells
eo, 09 48 Apoptotic CLL cells
o. se X Dead CLL cells

Studies such as CAPTIVATE and GLOW tested time-limited ibrutinib + venetoclax combinations

1. Lu P et al. Blood Cancer 2021:11:39. 2 Deng J tal Loukomio.2017.31:2075-2084. 3. Herman ES etal. Cin Cancer Res. 2015.21:4642:4661 á
4 Cowantes-Gomez Fetal Gin Cancor Ros 2018.21 3708-3715. PeerView

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39. Time-Limited | + V Continues to Show Robust
Activity Against TN CLL

CAPTIVATE: | + V, 12 Cycles* MDACC: | + V, 24 Cycles? FLAIR UK: I + V, 2:6 Years?
« #0
pa © so i
so A ®
2 er © 4 > Median fotow-up: 43:7 mo. a
# -Atinatedpaters {EM F
A É a
Es wann" lr
» HERE
20 | Mtv patri = 10 mo o 5 à à à à ES
mme oem eee ota ee on ee BP y
19] mo autt7p Pam or GK nes) Tes Time, mo Time, mo
o No. at Risk RB.
RELEEXITETTE TeV 120 107 103 100 100 77 a 3 0 WY 8 ERROR
+ N= 159 + N= 120 + N= 260
+ Median age = 60 y + Median age = 64.5 y + Median age = 62 y
+ UIGHV = 56% + UIGHV = 86% + uIGHV = 48%
+ Del(17p)TP53m = 17% + Del(17p)TP53m = 23% + Del(17p)TP53m, excluded
5-y PFS = 67% 5-y PFS = 89.8% 3-y PFS = 97.2%
1. Warda W el, ASCO 2024, Abst 70082 Jain Not. ASH 2020. Abstract 6595.9. Hillmen Pat ASH 2023. Abstract 631 PeerView

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40. The Experience of Finite Therapy With
Second-Generation BTKi

41. Patients, %
PFS, %

izo 240
10 À + Consorod AA à
"oa ee Rw wT ss
Zanubrutinib + venetoclax Time, mo,
(n = 65)
Median study follow-up: Zanubrutinib triplet (BOVen): 89% of
31.6 (0.4-50.5) mo patients had uMRD after 10 months?
1. Ohi Pet. HA 2024, sac 160.2 Soumet D tl Lance Homo 292.287. PeerView

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42. Time-Limited Acalabrutinib, Venetoclax, and Obinutuzumab

(AVO) Is Active in CLL With Multiple High-Risk Features

68 patients were enrolled in a phase 2 study ey CYEle16,Day1PB Cycle 16, Day 1
testing AVO in a population enriched for IGLL Criteria MRDStatus BM MRD Status
high-risk features?

+ 60% TP53-aberrant (del[17p] or mut)
+ 24% complex karyotype (23 abnormalities)
+ 74% unmutated IGHV

Patients, %

+ AVOis a highly active, well-tolerated triplet

+ BM-uMRD of 83% in TP53-aberrant patients
after 15 months of treatment

+ Responses are durable, with 93% PFS in all Alc Aeon Pagita Aue ove Pune Aton

= E Patients Aberrant Patients Aberrant Patients Aberrant
patients at a median follow-up of nearly 3 years

"CR =PR "uMRD =dMRD mNo available
1. Davis MS tl, Lancet Oncol 2021:22.101-1402.2. Ryan Cet al. ASH 2022. Abstract 44. PeerView

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43. + Venetoclax +

hout Del(17p)/TP53m

Key eligibility criteria

Previously untreated CLL
+ Without del(17p) or TP53 mutations
+ ECOG PS <2

Acalabrutinib + venetoclax (AV)

Primary endpoint

+ PFS (IRC assessed) of AV vs FCR/BR

Key secondary endpoints

+ PFS (IRC assessed) of AVO vs
FCRIBR

+ PFS (INV assessed) of AV vs FCR/BR

Up to 1 year
R
A
à Acalabrutinib + venetoclax + Update
o obinutuzumab (AVO) Primary endpoint met
bo Up to 1 year
E FD acalabrutinib + venetoclax +
FCR or BR obinutuzumab significantly
Manors improved PFS vs standard CIT?
y Morena oe nou NcTON204 P Lew
AAA —_—————— 1 'eerView

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44. New Developments in Time-Limited
Treatment: CAR-T and ncBTKi

45. TRANSCEND CLL 004: Exploration of CAR-T in CLL"

iso-cel: CD19-directed CAR-T with a 4-1BB costimulatory domain,

sé Measurable disease. Which enhances the expansion and persistence of the CAR-T cells
Teukapheresis. reconfirmed

Lymphodepletion Follow-up

dates a On study: 24 months
ERD ARTE Long terme up to 15 years
c me 3 E :
Liso-cal manufacturing" mee
96% success manufacturing rate
Key Eligibility Dose Escalation: mTPI-2 Design®
+ Relapsedirefractory CLUSLL 28-day DLT period
Falled or ineligible for BTKI® prey sci
High-risk diseases: failed 22 prior therapies + Determine recommended dose
‘Standard-risk disease: failed 23 prior therapies Exploratory objectives
+ ECOG PS of O41 + Antitumor activity
+ Pharmacokinetic profile
Do: Dose Evaluable (N
50 x 10% CAR-T cells 9
2 100 x 10° CAR-T cells 14

Inekgy deine as roqueemon! tr fl-dose antccaguiaton or Mito) of armythma. * Complex ey
Guo W ot al. Contomp Cía Trials. 2017.58:23:33.
1. Sidi Total. ASH 2020. Abstract 546,

PeerView

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46. Liso-Cel Effective in Patients With CLL Progressing After
Prior BTKi and Venetoclax Therapy

Updated Efficacy Outcomes:

A single infusion of liso-cel BTKi Progression/Venetoclax Failure Subset at DL2 (N = 49)?

Induced complete response or

remission (including with 100 een

incomplete marrow recovery) 90

in patients with R/R CLL/SLL' >

+ 18.4% CR/CRi in patients with & 60 PRINPR.

R/R CLL after BTKi £ 2 co dit)
progression/venetoclax failure pos
20 Nonresponder |, „,,
3.7 mo (21-64)

+ Led to FDA approval in patients a | a à 11.9 mo (5.7-26.2)
with R/R CLL who have 0 6 2 18 24 30 36 42
received 22 prior LOT, including ic Time From Liso-Cel Infusion, mo
a BTKi and a BCL2i cn D 6 & % à à 5

PR/NPR 12 12 9 6 5 a 1 o

Nonresponder 28 6 2 2 0 0 0 0

Total 49 8 19 13 7 2 1 0
PeerView

1. SiddiqhT et al Lancet, 2025:402:681-854, 2, Sd! T et al ASH 2023. Abstract 93.

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47. Phase 1b portion of the 1/2 BRUIN study (N = 25)
Patients with R/R CLL enrolled into sequential cohorts
+ Pirtobrutinib + venetoclax (PV; n = 15) or

+ PV + rituximab (PVR; n = 10)

+ ORR was 93% with PV and 100% with PVR
+ High rates of UMRD with both regimens after
multiple timepoints

The BRUIN CLL-322 phase 3 tı
RIR CLL is currently enrolli

1. Rooker LE eta. Blood. 2024 Blood 2024024510. Online ahead of print.

PeerView.com/THK827

(both cohorts)

limiting toxicities

+ Most common all-cause AEs:
neutropenia, diarrhea, fatigue, nausea

Common Grade 23 AEs

16%
D i B
Anemia

Noutropania
44444 AE-related

4444444444 Dose reduction (n = 3/25)
4444884444 Discontinuation (n = 2/25)

ial comparing PVR vs VenR in
g patients (NCT04965493)

PeerView

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48. ime-Limited Pirtobrutinib Regimen’

GE CT
Enrollment BMBx (NGS MRD) BMBx (NGS MRD)
cr CT for TLS Blood (NGS MRD) Blood (NGS MRD) | [Blood (NGS MRD) | | Blood (NGS MRD)
BMBx risk (end of C4) (At LE (end of C9) (end of C13)
e
| | | ||
ct c2 03-6 c7 || c8-13
+ Pirtobrutinib || + Pirtobrutinib + Pirtobrutinib irtobrutinib 200 mg once daily
200 mg once 200 mg once 200 mg once + Vonetoclax 400 mg once daily
daily daily daily
+ Obinutuzumab || + Obinutuzumab || + Obinutuzumab
100 mg D1 1000 mg Dt 1000 mg D1
900 mg D2 + Venetoclax + Venetoclax
1000 mg D8 weekly dose 400 mg once
1000 mg D15 ramp-up dally

Very high rates of uMRD remission at 10% sensitivity with combined pirtobrutinib, venetoclax,
and obinutuzumab as 1L treatment for patients with CLL (N = 40)

+ 6 mo of combo: U-MRD6 BM 64%; PB 79%

+ 12 mo of combo: U-MRD6 BM 85%; PB 90% .
1. in Net EMA 2024, Abstract 168, PeerView

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49. Practical and Safety Considerations
With Time-Limited Therapy

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50. Venetoclax Dosing and Administration

With Time-Limited CD20 Antibody Regimens‘

Week 5

400 mg
Venetoclax Ramp-Up, Once-Daily Dosing in CLL 200 mo
Week 3

Week2 100 mg
Week 1 50 mg
20 mg

When used with rituximab, start rituximab after the
patient has completed venetoclax 5-week ramp-up
dosing and the patient has received
400 mg once daily for 7 days

When used with obinutuzumab,
initiate venetoclax (according to the
5-week ramp-up dosing) cycle 1, day 22

1. Venen (veneocos) Presta Information. tos ln ccesscaa Ja gowsrugsalda_cocsabel 2018720872501 pt PeerView

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51. Debulking Strategies Lead-In BTKi Reduce Risk of TLS

CAPTIVATE Dosing Schedule
Time Limited MRD

When ibrutinib + venetoclax are used in
combination, debulking with lead-in
ibrutinib (3 cycles) reduced the risk of TLS!

Standard dosing and lead-in period are also used when second-generation
agents are used as time-limited therapy with venetoclax

+ SEQUOIA Arm D: proportion of patients at high risk for TLS decreased by 91%
after zanubrutinib lead-in?

+ AVO: acalabrutinib lead-in resulted in lower TLS risk before initiation of
venetoclax (no patients were characterized as high risk prior to cycle 4)?

1. Werda Wet al. J Gin Oncol. 2021°9:3889-986 2. Ghia P tal EMA 2028, Abstract S160. 9, Davids MS el Lancet Oncol 202%:22: 1301-1402 PeerView

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52. Phase 3 GLOW!
Median age: 71 y

=GClb mi+V

Infections (grade 23)
2 (1.9%) patients in the
1+ V arm discontinued
ibrutinib because of AF

1. Kater À tal. MEJM Evidence. 2022:1. 2, Tom CS et a. Blood. 2022:139:3278-3280,

PeerView.com/THK827

CAPTIVATE?

M n age: 60 y

Selected grade 23 AEs
+ Neutropenia (33%)
+ Hypertension (6%)

+ Infections (8%)
Any-grade AF: 4%

+ 1 sudden death during
ibrutinib lead-in out of 159 total
patients treated

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53. Time-Limited Zanubrutinib + Venetoclax Was Safe a

With Low Rates of CV Events (SEQUOIA Arm D)!

TEAEs in >10% of Patients TEAEs of Special Interest

CovD-19 Infections

Diarhe
dl Hemorrhage
Nausea
Neutropenia

Contusion

Second primary =
Fatigue malignancies Of al infections, 36 patients
Gere k (65%) had COVID-19, 2 (3%)
ey Hype of whom experienced a
Arte Median study follow-up: Anemia grade 23 event
Epistaxis 31.6 (0.4-50.5) mo
Fall Thrombocytopenia
. = Grade 1/2 mGrade 23 ar hy = Grade 1/2 m Grade 23
Petechiae use:
0 1 2 a 4 50 60 o 10 2 30 40 60 60 70 80

Patients, % Patients, %

Low rates of AF/flutter and hypertension (2% and 9%, respectively)
Ona Peto HA 2026, sac 160. PeerView

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54. Time-Limited AVO Safety Summary!

Hematologic Toxicities
"Grade 1 mGrade 2 mGrade 3 mGrade 4 Grade 3/4: 37%
Neutropenia
Thrombocytopenia

Anemia

0 10 20 30 40 50 60 70 80
Patients Experiencing Toxicity, %

Median follo, 35 months (range, 2-45)
AEs of special interest Dose reductions
+ Grade 3 non-COVID infections: 5.8% (pneumonia [n = 3], colitis [n = 1]) + Patients with any dose reduction:
+ COVID-19 infections: 9% (grade 2 [n = 4], grade 3 [n = 1], grade 5 [n = 1]) n=14 (21%)
+» AF: 3% (grade 2 [n = 1], grade 3 [n no ventricular arrhythmias: * Acalabrutinib only: 3
+ No febrile neutropenia or opportunistic infections + Venetoclax only: n=
+ No major bleeding events + Both drugs: n=5
{Ryan C etal, ASH 2022. Abstract 348. PeerView

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55. Expectations for the Future and
Audience Q&A

William G. Wierda, MD, PhD

Professor, Department of Leukemia, Division of Cancer Medicine

Jane and John Justin Distinguished Chair in Leukemia Research in Honor of Dr. Elihu Estey
Section Chief - Chronic Lymphocytic Leukemia

Center Medical Director, Leukemia

Executive Medical Director, Inpatient Medical Services

The University of Texas MD Anderson Cancer Center

Houston, Texas

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56. BGB-16673:
ABTK-Targeted CDAC*

@ so

Bates cie

Ternary Complex Formation
ev

os

Polyubiquitination

Target Degradation

D-E—
= …

#— UN

Ug

1. Seymour Jet al, ASH 2023. Abstract 4401. 2. Linton K et al. EHA 2024, Abstract $155. 3

PeerView.com/THK827

NX-5948 Utilizes the Ubiquitin-
Proteasome Pathway to Degrade BTK?

ES ligase binder @_@ Target binder
Ternary complex

formation
Le

Usiquiin

rousse
|
y

Proteasomal
degradation

ABBV-101 Degrades BTK
Targeting in Both the Catalytic
and Scaffolding Functions?

Degradation

men POPP POE

pobdbbbbbossdodsd
|

oo

Wror | Degrader
Resistant
Mutants | ves
an:

pd

Targeting catalytic and
scaffolding functions

PeerView

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57. ext-Generation BCL2i

+ Next-generation BCL2i
— Sonrotoclax + zanubrutinib
combination is highly active in R/R CLL"

+ Bispecific antibodies
— Epcoritamab binds to CD3 on T cells
and CD20 on B cells to induce T-cell-
mediated killing of CD20+ B cells?

nr bu

ORR 97%

Patients, %

Cytotoxic activity

+ Efficacy in R/R CLL: ORR = 62%;
Effi Evaluable Populati =3 CR = 33%
ENR PM EAE + In RT: ORR = 53%; CR = 142%
1.0901 etal. EHA 2024, Abstrac $158.2. Kaler AP etl. EHA 2024 Abstract S163 PeerView
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58. Symposium Summary and Take-Home Thoughts

izing treatment

For modern CLL care, individualize Opti
treatment to patients’ needs and
preferences

+ Del(17p)/TP53 mutated
+ Age, comorbidities, and renal function

+ Continuous treatment

— Reducing toxicities and improving
tolerability
+ Consolidation options

+ Access to clinic for venetoclax ramp-up - Time limited: maximizing uMRD4

+ Commitment to overall treatment rate (remission depth)
strategy — a
+ Combinations and treatment duration
+ Long-term costs
+ Patient preferences

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59. Audience Q&A