Opening With Innovation in CLL: The Practicalities and Potential of Finite Therapy With BTKi Platforms

Chair and Moderator, Paolo Ghia, MD, PhD, and presenters Nicole Lamanna, MD, and Dr. Lydia Scarfò, MD, discuss chronic lymphocytic leukemia in this CME/MOC activity titled “Opening With Innovation in CLL: The Practicalities and Potential of Finite Therapy With BTKi Platforms.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/471gnBT. CME/MOC credit will be available until July 15, 2025.

1. Opening With Innovation in CLL

The Practicalities and Potential of Finite Therapy
With BTKi Combinations

Nicole Lamanna, MD
Professor of Medicine, Leukemia Service

Director of the Chronic Lymphocytic Leukemia Program
Hematologic Malignancies Section

a Herbert Irving Comprehensive Cancer Center
Recto Chis, MD 200 New York-Presbyterian/Columbia University Medical
Center

New York, New York

Full Professor, Medical Oncology
Director, Strategic Research Program on CLL.
Head, B-Cell Neoplasia Unit
Universita Vita-Salute San Raffaele
IRCCS Ospedale San Raffaele Dr. Lydia Scarf, MD D

Milano, Italy Assistant Professor, Internal Medicine

Strategic Research Program on CLL

Universita Vita Salute San Raffaele and

IRCCS Ospedale San Raffaele

Milano, Italy

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

Copyright © 2000-2024, Peerview

2. The Path Forward in CLL, Current
Practice, and Ongoing Challenges

Paolo Ghia, MD, PhD

Full Professor, Medical Oncology

Director, Strategic Research Program on CLL
Head, B-Cell Neoplasia Unit

Universita Vita-Salute San Raffaele

IRCCS Ospedale San Raffaele

Milano, Italy

Copyright © 2000-202:

3. BTK Inhibitor Regulatory Status in CLL/SLL
Covalent

Ibrutinib?2 Approved Approved (including in combination with venetoclax)

Approved; FD combinations being assessed

Acalabrutinib®4 (AMPLIFY; MAJIC)

Approved (in combination with CD20)

Approved; FD combinations being assessed

on
Zanubrutin (SEQUOIA; NCTOS168930) Approved
Non-covalent

Pirtobrutinib” Approved (RR CLL) Phase 3
Nemtabrutinib® Phase 3 (NCT04728893)

What are the next steps with fixed-duration (FD) BTKi-venetoclax combinations?

1 roca (ru) FDA Proserng Information. ps yu com nase. 2 Imbruin (Brin) EMA Prosrbing Intormaton. psu mm.
3 Catuence (actes) FDA Poser noma, pa Manu COMAPESOZ 4. Cauerco (aa. an) EMA Prescräng Inormaton Mos mu comidas
5 Bra (zara) FDA Prog nermatn. ps nyu comvSA 8. 6 Brea (an) EMA Presring bormaton. os Ryu comma, is
7. Jayprea (eis) FA Prescong Infomation MS Mayu cam Oje 8. hips ask cali Jovi sho NCTOST2E88S PeerView.com

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4. EU Guidelines Support Use of Modern Targeted Strategies
Coming Soon—Updated ESMO Guidelines

ESMO recommendations Symptomatic early-stage CLL or
last published in 2021" advanced-stage CLL

IGHV unmutated IGHV mutated

No TP53 mutation or del(17p) No TP53 mutation or del(17p) TP53 mutation or del(17p)

All patients
Fit patients Unfit patients Fit patients Unfit patients

Ibrutinib or acalabrutinib

Ibrutinib or acalabrutinit)
CIT: GCHb [I, A]

+ ESMO guidelines also recommend ibrutinib or acalabrutinib in cases of symptomatic relapse
+ BTKi-venetoclax combinations have yet to be included

1. Ehorst Beta. Ann Oncol 2021:9223-33. PeerView.com

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5. Other EU Guidelines Also Support the Use of
Modern Targeted Strategies in TN and R/R CLL"

No del(17pTP53m del(17pYTPS3m
No complex karyotype Fears | plo)

à |

«Noto benavr Ace esse sccoróng a nCLL 2018 tra: The rang ol lowing eas presents one posi, Due oh cen aa stat,
ine nor Binding. The India Comer pöle, apects of adherence, platon oops fhe trapos mterenión, and patent pelerence forthe fal

‘therapy determination shouldbe taken into account + A o Zi contraindicated or not avaiable, (4 G) remains a therapy option, taking nto account increased

Cani: adverse mens And wore ot yteataly erated n younger pants tie hoy A

1 ps wan onkopedia.com/delonkopediaiguidehnesichronischeAymphatsche-eukaemie-cU @@guldeinemtmiindexhm PeerView.com

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6. Targeted Options, Including BTKi-BCL2i Combinations, Are

Recommended in US Guidelines (NCCN)'

Recommendations for first-line therapy

Patients without del(17p)/TP53m Patients with del(17p)/TP53m

Preferred regimens a
+ Acalabrutinib + obinutuzumab (category 1) Preferred regimens

+ Acalabrutinib + obinutuzumab
+ Venetoclax + obinutuzumab (category 1) :
Duo Casse 1) Venetoclax + obinutuzumab

+ Zanubrutinib

Other recommended (BTK-based only)
+ Ibrutinib (category 1)

+ Ibrutinib + CD20 mAb or venetoclax
(category 2B)

Other recommended (BTK-based only)
* Ibrutinib

+ Ibrutinib + venetoclax

1. NCCN Cinial Practice Guideines in Oncology. Chronic Lymphocytic LeukemiaSmallLymphocysc Lymphoma Version 3.2024, mn
tps vn non orgproessionalsiphysician_gl/patc pa. PeerView.com

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7. Despite These Advances, Real-World Data
Suggest More Work Needs to Be Done

However, in 2023

Real-world assessment of first-line use of
modern CLL therapy in the US‘

+ N =6,328 CLL patients receiving treatment

between 2020 and 2023
+ Overall BCL2i and BTKi represented the majority
of first-line treatment choices

Where will FD BTKi/BCL2i combinations play a role?

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

Nearly 20% continue to receive
chemotherapy-based treatment

Similar trends reported in the EU23

Drug Utilization in First Line: 2020 to June 2023

Drug Class 2020, n (%) 2021, n (%)
BTKi 1,065 (55.8) 1,069 (56.6)
BCL2i 278 (14.6) 305 (16.1)
Anti-CD20 186 (9.8) 107 (5.7)

Chemotherapy 377 (19.8) 409 (21.6)

1. Hou JZ eta ASH 2023, Abstract 130.2. Chatzhonstantnou T et al, ASH 2021. Abstract 2635.3, YsebaertL.

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2022, n (%) Jan-June 2023, n (%)

984 (58.2) 473 (56.3)
317 (18.7) 166 (19.8)
67 (4) 44 (6.2)
322 (19) 156 (18.6)

ISPOREU 2025. Abstract HSD114. PeerView.com

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8. Our Goals for Today

Augment your understanding of the evidence supporting different
BTKi/BCL2i combinations in TN CLL

Equip you with the skills you need to develop personalized
treatment plans that include fixed-duration targeted combinations

Provide you with guidance on how to address practical aspects of
care with finite therapy in CLL, including dosing and safety
considerations

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9. Current Experience With Finite BTKi
Combinations and Questions for the
Road Ahead

Dr. Lydia Scarfo, MD E 5
Assistant Professor, Internal Medicine

Strategic Research Program on CLL
Universita Vita Salute San Raffaele and
IRCCS Ospedale San Raffaele

Milano, Italy

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10. Clinical Consult: A Patient With Symptomatic CLL

Gabriela, a 60-year-old patient with symptomatic CLL

Presents with Laboratory Other findings

+ Bsymptoms + WBC: 95 x 109/L + Unmutated IGHV

+ Splenomegaly + ANC 2.5x9/L, ALC 91 x 10%L + No del(17p)/TP53m
+ PSof1 + Hb: 9.8 g/dL

+ Progressive lymphadenopathy (10 cm)» PLT: 72 x 109/L

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11. Clinical Consult: A Patient With Symptomatic CLL

Gabriela, a 60-year-old patient with symptomatic CLL

Presents with Laboratory Other findings

+ Bsymptoms + WBC: 95 x 109%/L + Unmutated IGHV

+ Splenomegaly + ANC 2.5 x %/L, ALC 91 x 10%L + No del(17p)/TP53m
+ PSof1 + Hb: 9.8 g/dL

+ Progressive lymphadenopathy (10 cm)» PLT: 72 x 109/L

For discussion
> Would FD therapy be preferred for this patient (vs continuous treatment)?
> What are the goals of therapy when finite treatment is chosen?

> What is the experience in the EU with FD BTKi-venetoclax?
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12. When Compared With FCR, Use of BTKi
Prolonged PFS Regardless of IGHV Status

In the E1912 trial, after a median fe
to FCR in patients

IR (84 events/354 cases)

FCR (74 events/175 cases)

PFS Probability

HR = 0.37 (95% CI, 0.27-0.51)

w-up of 6 years, IR led to superior PFS relati
ith both IGHV-mutated and IGHV-unmutated CLL"

PFS IGHV Unmutated

IR (56 events/210 cases)

HR = 0.27 (85% Cl, 0.18-0.41)

5-year rates: 75%, 33%

IGHV Mutated

IR (14 events/70 cases)

(42 events71 cases) FOR (15 events/44 cases)

02 | HR = 0.27 (95% Ci, 0.11-0.62)
P= 001

5.year rates: 83%, 68%

P< 0001 P< 0001
S-year rates: 78%, 51% A
T 2 5 8 5 6 7 9 + 2
Time, y
Wo at Rok Wo at Rok

IC Oo FR 71 &
IR HS Ji 6 24 M9 NO 7 IR 20 20 1

1. Shanafelt T et al. Blood. 2022:140:112:10.

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7 9 1 2 3 4 8 8 7
Time, y
No. at Riek
o FR 4 Ars

SR D 6 & © % 0 1% 1

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13. GAIA/CLL13: Further Insights on FD Doublets and Triplets’

Infections PFS According to Treatment Arm
tic ii i lan PFS vs | JenG: NR vs 59.4 mo; HR = 0.47; P <.001
2 m infections CIT grade 3-5 infections Medien PFS ve CIT: prs INR ve 50.4 mo: pei. Be
5 10, 132
7° 122 4
2,12 108 E
350 E
=2 80 E
22° i
go
s* AAA + à
w 0

Time to Event (PFS), mo

em Venr Weng: vend PFS by MRD Level at Month 15, Pooled VenG/VenG!

+ After a median observation time of 50.7 mo, ¿A RO <108

VenG and VenGI showed superior PFS vs CIT gos

and VenR ae een

jo ROA ca

+ Patients with unmutated IGHV had longer PFS 30

with VenGl vs VenG AA

1. Fürstenau M et al. ASH 2023. Abstract 635. Time to Event Prstomenth OL DeerView.com

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14. CLL14: 6-Year Follow-Up Shows
Efficacy of Frontline VenG vs GCIb!

100
Median PFS, mo — 6-yPFS,%
A Von 762 $34 90
1 Sch 364 217 # go
so g
& 70
id £ 60
x j
¢ 3 50
go 2
5 40
He 8
30
Sn Ven
5 x0 20
E
2 10
10 sci o
0 12 24 36 48 60 72 84
0 2 À % 4 0 72 84 Nour Time to PFS From Randomization, mo
Vend cet « A o ss © » 2
Time to Event (PFS) From Randomization, mo Vers vor wo Fe 8 7 ¢
Seb ice 5 2 % 2 2
VenG 216 189 17 160 139 112 7 3 Sct CE 5 8 i
Gob 216 1 10 101 67 8038 HR
eee 038 (95% C1, 023-081): P< 001
Got 16HVm
an 033 (65% C1,029047),P<.001
1. AbSawaf O et al EHA 2023. Abstract 5145. PeerView.com

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15. CLL14: VenG Achieved High uMRD and Improved PFS13

VenG vs GCIb as Initial Tx in Patients
With CLL and Comorbidities (N = 432)=
MRD assessment via clonoSEQ assay

UMRD (<10“) by ASO-PCR 3 mo

After EOT!

80 ra wVenG
70 "Sch
60 ES

50
40
30
20
10

o

Patients, %

PB BM

Comparison done by Cochran-Mante-Haenszol tests stratified by Binet stage and geographic
Vi Fiore Ket a! N Engl Mod. 2019.3802225-2236. 2. A Sawal O et Lancet Oncol 2020.21 1168-1200. 3. ALSawal O tal. Nat Commun. 2023:14:2147.

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In a landmark analysis from EOT, patients with uMRD had
longer PFS vs L-MRD or H-MRD (HR = 0.10)

VenG

MRO 210% and <10:

MRD <104

MRD 210% and <10+

Cumulative PFS, %
Besssa3ss

MRO 2104

0 12 2 E ry ©

Time to Event (PFS) From Last Treatment Exposure, mo

© 86 79 n 48 2
56 54 51 38 30 3
23 2 20 7 13 1
2 4 " 9 7 o

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16. CLL14: No New Safety Signals,
No Difference in Rate of SPMs!

Most Frequent Grade 23 Adverse Events

Gcib No statistically significant
(Ge) * difference in the cumulative
During ‘After During After fi cidence of SPMs between
Treatment | Treatment | Treatment | Treatment [NE VenG and GCIb
‘Thrombocytopenia 142 05 15 o 2
Anemia 75 19 61 05 3
Febrile neutropenia 42 09 33 05 E Gray's test P=.071
Leukopenia 24 0 47 0
Pneumonia 38 33 37 14 0 12 24 36 48 60 72 84
e Time to Event (SPM), mo
ee 9 o 98 05 mora
Vene 212 106 100 1 m
Tce 04 o 33 o Goo 24 O2 OH 476 11 16 10 15
1.ALSawal Oot al. EHA 2023. Abstract $145. PeerView.com

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17. Rationale for BTKi/BCL2i Combinations

Distinct and Complimentary Mechanisms of Action for Ibrutinib and Venetoclax in CLL'4

Lymph node i
Ibrutinib mobilizes CLL cells out of | Ibrutinib accelerates apoptotic cell
e lymph nodes and other protective | killing by sensitizing CLL cells to
? € lymphoid niches and inhibits + BCL2 inhibition
Stromal Y «— Y, y proliferation ; Pal
= 5 Ibrutinib netoclax
Ibrutinib “et
pon Ibrutinib + venetoclax eliminates
Peripheral resting and dividing
blood CLL cell populations > en =
esting CLL cells
ce _, 0e 485 Apoptotic CLL cells
ee LA] X Dead CLL cells
1 LuP etal ood Cancer J 20211139.2. Dang el Loken. 2017:3:2075-204. 3. Harman ES et. Cn Cancer Res. 2018214642461. 7
4. Covantes-GomezF ta. Cin Cancor Ros. 2095.21 37083715. PeerView.com

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18. What Is the Evidence and Experience
With Ibrutinib-Venetoclax

Combinations?

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19. Major Trials Assessing
Ibrutinib + Venetoclax FD Combinations

» Phase 2 CAPTIVATE

« Phase 3 GLOW

+ Phase 3 FLAIR

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20. CAPTIVATE Tested FD and MRD-Guided
Ibrutinib + Venetoclax Regimens in TN CLL‘

F y

im 42 cycles ibrutinib + Upon PD, 1

i venetoclax patients could |
reinitiate

1 ibrutinib-based |

{ therapy

x 1

12 cycles ibrutinib +

MRD OU los bra

lead-in

confirmed

==

1. Ghia Pet at ASH 2023, Abstract 633. PeerView.com

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21. CAPTIVATE: FD I + V Continues to Show
Robust Activity Against TN CLL’

PFS in All Treated Patients and by Del(17p), TP53m, or Complex Karyotype (CK)
100
With median time on study of

61.2 mo, 5-y PFS was 67%

PFS was promising across most
high-risk features; numerically

lower in those with
del(17p)/TP53m

With dot 7p), TPS,
ck

A ren patas 189 won,
a} TPS o CK msn) un
ans sat) Tom. ot K mes

5-y OS rates were 290%,
regardless of genomic features

PFS, %
oS 88888388

© 6 42 18 24 30 96 42 4B Sa 60 65 72
tet Time, mo

mau Pan 5 © Sms x x
Mason mines een!

o

Dot 7)p/TP59m E

4121-59) 129 73 (64-80)
x E] 87 (97-72) 102 72 (61.20)
Deigp. fi 41 6085) 2 79.6787)
Dotes as 23 anal by conve
ta

ritonal CpG-stimuated cytogenetics." Excluding patients with deK17pYTPS3m or complex karyotype.
1. ASCO 2024. Abstract 7008.

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22. Is BTKi Retreatment an Option After FD Therapy?!

+ Of 61 patients with CLL PD after completion of FD | + Ven, 32 (52%) initiated retreatment with
single-agent | (n = 25) or | + Ven (n = 7}

Study Entry Baseline Characteristic:

Retreated Patients Best Response in Evaluable Patients to Datec

Single-Agent — Ibrutinib+ AllRetreated MER =PR BCR
Ibrutin Venet Patients
5 > : En
5600971) 63(49S0) 59(0971) 71%
15(60) 6 (86) 21 (66) & 60
Rai stage IV 4(16) 2(2) 6(19) Eso
High-risk genomic features $ 40
Unmutated IGHV 20 (80) 5(71) 25 (78) 5»
del(17p)mutated TPS3 5 (20) sm) 1061)
deiltigy 6 (24) 4 (14) 7 (22) 20
‘Complex karyotype® 2.66) 2(29) 11634) 10
Bulking LN disease o
nn 10 (40) 109) 11 (34)

Single-Agent Ibrutinib Ibrutinib + Venetoclax
(n= 22) (n=7)

Por protocol, only patients wäh PO >2 yoar ater completion of treatment were eligible to reiiate 1 + Ven. Four patients exted the study during | + Ven retreatment

‘and completed reveatment of study. Three patients who iniated single-agent| retreatment had not et undergone response assessment. Wahout de(17P) per

Dohner hierarchy. «Defined as 23 abnormalties by conventional CpG-stmulated cytogenetics fi
1. Wierda W et al ASCO 2024. Abstract 7009. PeerView.com

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23. GLOW: After Additional Follow-Up, Continued PFS and OS
Benefits With FD Ibrutinib + Venetoclax

Prior results led to EMA approval of | + Ven for adults previously untreated CLL'
updated findings recently reported after up to 5 years of follow-up?

mr IT
L+ Ven: 97.5

PFS, %
8

OS, %
05385833888

20 JEnd of End of
10 | GCib 1+Ven

0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 3% 42 48 60

Time From Randomization, mo Time From Randomization, mo

No. at Risk No. at Risk

Le Ven 105 99 92 99 88 83 80 75 68 55 11 LeVen 106 100 95 of of 93 91 89 87 74 19
Gob” 105 101 95 61 50 43 33 24 20 15 2 Gob” 105 103 103 100 93 90 86 79 70 57 17

| + Ven reduced the risk of progression or death by 74% vs GClb | | | + Ven reduced the risk of death by 55% vs GCIb
HR (95% Cl): 0.256 (0.172-0.382); P< .0001 + HR (95% Cl): 0.453 (0.261-0.785); P = .0038

1. Kater A etal. NEJM Evid, 202221, 2. Moreno C ot al. ASH 2023. Abstract 634, PeerView.com

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24. GLOW: Review of Study Deaths’

1+V (n = 106) GCib (n =105)
essen fon Det On Treatment | Pest Randomized | Gn treatment | PostRandomized
Infection-related 1 3 1 13
en 0 1 a Z
Cardiac 2 0 0 4
Sudden/unknown 2 3 0 4
Progressive disease 0 1 0 2
Vascular disorders ‘| 2 0 3

Other 0 2 1 4

Total 7 12 2 7

Total per arm 19 39

At 57 mo of follow-up, there were 19 deaths in | + V vs 39 in GCIb

+ 3 deaths in | + V and 13 in GCIb were due to post-treatment infections

+ 2 deaths in | + V and 7 in GCIb were due to secondary primary malignancies
1. Moreno C otal. ASH 2023. Abstract 634, PeerView.com

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25. Characterizing the Initial Safety Experience
With BTKi/BCL2i FD Combinations

Phase 3 GLOW' CAPTIVATE?
Median age: 71 y Median age: 60 y

mGCIb mi+V Selected grade 23 AEs
+ Neutropenia (33%)
2 (1.9%) patients in the
1+ V arm discontinued + Hypertension (6%)
ibrutinib because of AF
+ Infections (8%)
Any-grade AF: 4%

-10 10 30 50 70 + 1 sudden death during ibrutinib lead-in
out of 159 total patients treated

Infections (grade 23)

When ibrutinib + venetoclax are used in combination,

debulking with lea brutinib (3 cycles) reduced the risk of TLS®

1. Kater A etal. NEJM Evidence, 2022:1. 2. Tam CS ot al. Blood. 2022:139:3278-3289. 3, Wierda W etal. J Cin Oncol, 2021:39:3859-865. PeerView.com

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26. FLAIR: Improved PFS and OS With MRD-Directed
Ibrutinib + Venetoclax Over FCR in Untreated CLL"

Using MRD to direct duration of | + V maximizes outcome with a PFS of 97.2% at 3 years? ]

Primary Analysis of PFS in FCR vs | + V OS in FCR vs | + V
100 100 x5
% lev 0 itv
PS ae FOR
Median follow-up: 43 mo
70 1 Median followup: 43.7 mo ie °
eS FoR eo
Pe ci En 1#V___FCR
Eos 8 10] Sarsy.% 98 93
pe 1+v FOR go | say.“ 9 873
20 |Prsasy® 972 768 D] Deathstodate 9 25
fo [PFSat4y.% 35 CH HR (95% Cl): 0.31 (0.15-0.67); P <.005
0 | (95% ci: 013007024) < 0001 a
ie a a e e 0 2 a % 8 © 7
Time From Randomization, mo OS Events,n Time From Randomization, mo
PFS Events, n rev 0 0 4 5 9 9 9
ev 0 1 5 7 2 2 2B FOR 0 10 16 17 24 25 2
FOR O0 18 41 SS 71 74 7

PB MRO was assessed at 12 months and subsequent every 6 months and negative, was repeated at 3 months and 6 months in PB and BM.
4. Häimen Petal ASH 2023, Abstract 631

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27. CLL17 Is Testing Time-Limited Targeted Combinations
Versus Continuous BTKi Therapy in TN CLL’

Patients with
previously
untreated CLL,
including fit and
unfit patients and
patients with
del(17p)/TP53m

(N = ~862)

+ Primary endpoint: PFS
+ Key secondary endpoints: response, MRD, and OS

1. ps cinicatias govlet2showNCTO4608318, PeerView.com

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28. Consult Continued: Is Gabriela a Candidate for
Treatment With a BTKi-BCL2i Regimen?

Gabriela, a 60-year-old patient with symptomatic CLL

Presents with Laboratory Other findings

+ Bsymptoms + WBC: 95 x 109/L + Unmutated IGHV

+ Splenomegaly + ANC 2.5x9/L, ALC 91 x 10%L + No del(17p}TP53m
+ PSof1 + Hb: 9.8 g/dL

+ Progressive lymphadenopathy (10 cm)» PLT: 72 x 109/L

For discussion

> If FD ibrutinib + venetoclax is being considered, what are the logistical and AE
considerations (eg, toxicity mitigation)?

> What is the role of MRD assessment and potential of retreatment?
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29. Clinical Consult: Take-Homes for Gabriela’s Case

Gabriela, a 60-year-old patient with symptomatic CLL

Presents with Laboratory Other findings

+ Bsymptoms + WBC: 95 x 109/L + Unmutated IGHV

+ Splenomegaly + ANC 2.5 x 9%/L, ALC 91 x 10%L + No del(17p)/TP53m
+ PSof1 + Hb: 9.8 g/dL

+ Progressive lymphadenopathy (10 cm)» PLT: 72 x 109/L

Recommendations
= This is a young, fit patient with unmutated IGHV and no TP53 abnormalities

No relevant cardiovascular comorbidities and at high risk for TLS due to the increased ALC and >5 cm
lymph nodes

er We would consider this patient suitable for a FD regimen

e In Europe | + V would be a suitable choice, and | would prefer this over VenG considering the unmutated
IGHV and high tumor burden

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30. FD BTKi-Venetoclax in Del(17p) CLL From SEQUOIA Arm D!

ORR
100%

In 65 response-evaluable patients with
del(17p) and/or TP53 mutation, ORR was
100% and the CR+ CRi rate was 48%!

Patients, %

Median study follow-up:
31.6 (0.4-50.5) months

Zanubrutinib +
venetoclax (n=65)

1. Ghia Pet al EHA 2024, Abstract $160. PeerView.com

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31. Concluding Thoughts on the Experience
With FD Targeted Combinations in CLL
+ FD regimens have become practice-changing options for the
management of TN patients with CLL

+ BTKi-BCL2i combinations show deep responses with prolonged disease
control, even in patients with unfavorable disease features
(ie, uIGHV)

+ Ibrutinib-based retreatment demonstrates promising responses in
patients needing subsequent therapy

+ Whether a FD schedule or an MRD-adapted strategy is the optimal
approach, these approaches still need to be addressed in ad hoc
clinical trials

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32. The Road Ahead With Emerging
Time-Limited BTKi Combinations: Treatment
Planning, Safety, and Care Implications

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

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33. Clinical Consult: An Older Patient
With TN CLL and Comorbidities

Stephan is a 74-year-old patient with symptomatic CLL
(diagnosed with asymptomatic CLL 5 years earlier)

Presents with Laboratory Other findings
B symptoms + WBC: 250 x 10%L + Unmutated IGHV
History of HTN + Hb: 9.0 g/dL + No del(17p/TP53m

Early-stage COPD Apia
ee PLT: 70 x 10%/L

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34. Clinical Consult: An Older Patient
With TN CLL and Comorbidities

Stephan is a 74-year-old patient with symptomatic CLL
(diagnosed with asymptomatic CLL 5 years earlier)

Presents with Laboratory Other findings
+ Bsymptoms + WBC: 250 x 10%L + Unmutated IGHV
+ History of HTN + Hb: 9.0 g/dL + No del(17p)/TP53m

Early-stage COPD Mein
ee PLT: 70 x 109L

For discussion
+ Is this patient a candidate for time-limited therapy?

> If so, what would be the preferred combination partner for venetoclax +
obinutuzumab or ibrutinib?

2 Is there a future role for a second-generation BTKi and venetoclax combination?
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35. Second-Generation BTKi: Foundational
and Head-to-Head Evidence

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36. 6-Year ELEVATE-TN Findings Continue to Support
Acalabrutinib + Obinutuzumab in TN CLL

Estimated 72-mo PFS rates! a Aro gine)
+ 78% (A+ G)
+ 62% (A) x Fes
+ 17% (GCIb) MEET
Ele
ES ee
pa (= 177)
9 ne eh HR = 0.14; Reason
+ A vs GCIb: HR = 0.24: EEEETIITETZITITTTIEIZIITLIITIITZ)
5 Time,
P<.0001 AE
+ A+GvsA:HR=0.58; ESO
P=.0229
San duo AS ARE a on” Pe Date on sat prank est PeerView.com

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37. Longer Follow-Up From SEQUOIA
Also Supports Upfront Zanubrutinib vs CIT

Median PFS in the overall
population’

+ Zanubrutinib: NR

+ BR: 42.2 mo

+ HR=0.30; P< .001

Estimated 42-mo PFS rates
with zanubrutinib and BR
were 82.4% and 50.0%,
respectively

1. Muni Total. EHA 2023, Abstract P639

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PFS, Cohort 1, Overall Population

wo Zombruinib
©
so
n
Zo
3%»
E PFS, mo (95%
% „lar 422 (38.4498)
D 2 zane NENE)
E Plmexe 020021043)
er L Median follow-up: 43.7 mo
o
ENENREEEEEEEEENEEEET
Time, mo
ot ik

A
Zansraing 241 238 234 230 228 224 219 214 208 205 201 200 10 191 93 30 2

258 218 212 201 192 107 100 174 103 17 141 139 913 82 50 18

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38. What Are the Implications of Selectivity
for Off-Target Effects and Safety?1%

a Zanabeutinie Potential off-target effects include
4 > >

Ibrutinib

Covalent BTKi

Bleeding Cardiac toxicity

Head-to-head trials confirmed the hypothesis
that more selective BTKi have fewer off-target
effects, which contributes to less toxicity
versus ibrutinib?

4. Kaptoin A et al ASH 2018. Abstract 1871. 2. Bose Petal, Export Opn Drug Motab Toxico! 2016:12:1381-1392. 3. Herman SEM e al. Clin Cancer Ros
2017°25:2631-2641. 4, Owen C at al Curr Oncol 2019:26:6253-0240, 5. Mato A etal, Lancet. 2021.397:892.901. 6. Brandnuber 8 et al. Clin Lymphoma Myeloma
Leuk 2018:18:5216,

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39. ELEVATE-RR: Lower Incidence of Key AEs
With Acalabrutinib vs Ibrutinib!

After Median Follow-Up of 40.9 Months

All-Grade AF/Flutter, HTN, and Bleeding Lower cumulative incidences of
60 + AF flutter (HR = 0.52)
+ Hypertension (HR = 0.34)
50 + Bleeding (HR = 0.63)
= 40 + Diarrhea (HR = 0.61)
2 Koyascandany + Arthralgia (HR = 0.61)
3.” ‘endpoint = a
a Treatment discontinuations
20 because of AEs
‘a + 14.7% with acalabrutinib
+ 21.3% with ibrutinib
o +
AF/Flutter HTN Bleeding
sAcalabrutinib sm Ibrutinib
1. Byrd JC eta. J Glin Oncol. 2021:39:3441-3482. PeerView.com

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40. ALPINE: Safety Analysis Showed Lower Rates of AF/Flutter
With Zanubrutinib Compared With Ibrutinib!

After Median Follow-Up of 39.0 Months

20 s Treatment discontinuation because of AEs
sZanubrutinib = Ibrutinib a ua
_ + 19.8% with zanubrutinib
+ 26.2% with ibrutinib
50
z 444
g 40 43.8
=
£ 30
&
20 25.6 | 247
6 16.4
6.8
0 r
AF/Flutter HTN Bleeding
1. Brown J et al. ASH 2023. Abstract 202. PeerView.com

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41. Finite Therapy
With Second-Generation BTKi and

Venetoclax Combinations

42. SEQUOIA Arm D: MRD-Guided Zanubrutinib + Venetoclax

Treatment Regimen and Response Assessment Schedule 100
90
ct 0 cr cm on oc cm cacas cam 80
e 70
sa ORR: 97.2
5 2 (95% Cl, 85.5-99.9)
& 30

Investigator Assessment (n = 36)
SD =PRL "PR Ñ"CRICRi

+ Zanubrutinib + venetoclax achieved a high response rate in the very high-risk del(17p)/TP53m
CLL/SLL patient population!

+ Responses appeared to deepen in patients treated with the combination for longer periods, as
indicated by achievement of CR/CRi and undetectable MRD

+ No reported clinical TLS, no dose reduction due to AEs, and relatively low incidences of
neutropenia, diarrhea, and nausea

1. Tedeschi A et al. ASH 2021. Abstract 642. PeerView.com

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43. Experience to Date With Time-Limited Zanubrutinib +
Obinutuzumab + Venetoclax (BOVen) in TN CLL"
39 patients were enrolled in a phase 2 study

testing BOVen in a population enriched for
high-risk features

+ TP53m (del[17p] or mut): 13% HN
+ Unmutated IGHV: 72% E
ó
Take-Homes gh
+ Median follow-up of 25.8 mo LE
+ Primary endpoint met: 89% of patients 2
had uMRD after 10 mo 2
+ Common AEs: thrombocytopenia (59%), ES
fatigue (54%), neutropenia (51%), and x Er
bruising (51%) E Sim
+ Grade 3 neutropenia occurred in 18% Ej ee re
of patients Date UE ee DE DE TEE EEE
1. Soumera JD eta Lancet Haomai.20218:79800 == PeerView.com

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44. BOVen Induced Early MRD-Negative
Responses as Measured by Flow

Further Assessment of MRD‘

+ uMRD responses appeared early
+ 81% achieved this threshold at 8 mo
+ AMRD400 identified as a potential
biomarker
— To identify patients who reach early
BM uMRD and
— Define a cohort of patients with
high-risk biology at increased risk
for MRD recurrence after
treatment discontinuation

1. Soumerai JD et a. Lancet Moomatol 2021:8:0879-0890.

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UMRD, %

35/37

3m (95%)

39/37
(89%)

90

PB BM

First uMRD in PB Best uMRD

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45. BOVen Safety Summary!

Selected AEs in Patients Treated With BOVen (N = 39)

Thrombocytopenia 23 (59)
Fatigue 21 (54)
Neutropenia 20 (51)
Bruising 20 (51)

+ The most common AE at grade 3 or worse was neutropenia (7 [18%])
+ One death occurred in a patient with intracranial hemorrhage on day 1 of cycle 1 after initiating intravenous
heparin for pulmonary emboli

1. Soumerai JD et al Lancet Hoematol 2021,8:879.0800. PeerView.com

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46. Evidence on Time-Limited Acalabrutinib Doublets‘?

Mri MPR Mor
(P1041) A PHASE U STUDY OF TIME-LIMITED TREATMENT WITH ACALABRUTIMI PLUS OBINUTUZUMAB IN PATIENTS. x 100
{WITH TREATMENT AAIVE CHRONIC LYMPHOCYTIC LEUKEMIA
pl 6. Croc rpg kena and etd are Cae 30
a Burger, Extra im Wanda Lopes, Gaya a Ma Yar Manes Samar! za Mare 3 a
Baza? Hag Karr, Nn at Warn Ward once Frag" 3
a
2“
ime-limited acalabrutinib + G induced deep remissions, 5 2
with 67% of patients achieving a CR! =
o
SM 14m 24M
(672) À PHASE 2 STUDY OF MINIMAL RESIDUAL DISEASE (MAD) ADAPTED, TIME-LIMITED ACALABRUTIN AND + Time limited acalabrutinib + G was
‘OBINUTUZUMAB FOR THE INITIAL TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): MRD well tolerated and resulted in deep
‘OUTCOMES remissions, allowing for time-limited
Tol: 6 Crone encyclo andre des - Cina BTKi treatment (n = 55)
LUncaey Rocker! M. Lia Palo! Lor Leste”, Prey sam! Any Detach? Davis omo, Mark Bine Goyer. Aaron |”
5 GP Tol run an Ome! oa i Gun on en + 40% achieved U-MRD with 13
Tayara Feiner? Andre Go. Coleen inche. Dana Tyzna Kate Do. Vitoria Fac, Jamia Bas!
Care Haze! Syney Ree, Lauren Noga’. Cain Maloney’, Monica Shah Sara Coun. Gabby Magu, Ezabeth cycles cf treaimentyand 86% of
McCarty. Krups Pate, Ges Sales" Anew Zlonet Aron À Mats, Meghan Trempaon! these patients maintained uMRD
for 3 cycles post-completion

1. Burger J etal. EHA 2024. Abstract P1841. 2. Rooker Let al, EHA 2024. Abstract P672. PeerView.com

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47. 68 Patients Were Enrolled

Acalabrutinib Triplets in TN CLL

Response Assessments: C4D1 capt

Acalabrutinib

Venetoclax

c16D1

BM uMRD CR: can
discontinue therapy?

BM MRD+ CR or PR:
‘continue therapy"

Zeyclos — 4 cycles Beycles

Cycle length = 28 days

Acalabrutinib and obinutuzumab at standard doses
Venetoclax 20 mg C4D1, 50 mg C4D1, then standard ramp-up to 400-mg dose

PJP and HSV/VZV PPX mandatory

MRD at C16 and C25 assessed by multicolor flow cytometry (104)

PB MRD monitored every 3 months; tums postive, can resume AV.
1. Ryan Get al. ASH 2022. Abstract 344

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BM)

C25D1

Acalabrutinib

Venetoclax

a Phase 2 Study Testing AVO in a Population Enriched for High-Risk Features’

Primary Endpoint Assessment
(rate of iwCLL CR with uMR

BM uMRD: can
discontinue therapy?

MRD+: continue
therapy?

Acalabrutinib

Venetoclax

‘Continued until progression
‘or unacceptable toxicity

Standard BTKi Dosing

and Lead-In Period When

Second-Generation
Agents Are Used With
Venetoclax

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48. Time-Limited Acalabrutinib + Venetoclax
+ Obinutuzumab (AVO) Is Active in TN CLL12

+ BMuMRD in 86% of patients after 15 months
of treatment

+ Depth and durability of response so far are
similar in IGHV-unmutated and TP53-aberrant
patients

+ Responses are durable, with 93% PFS in all
patients at a median follow-up of nearly 3 years

1. Davids MS etal. Lancot Oncol 2021:22:1391-1402.2. Ryan C et al. ASH 2022. Abstract 344,

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Patients, %

no Uy Ye $6, Day 1 Cycle 16, Day 1
ceda PBMRD Status BMMRD Status

TP53 All TPS3 All TPS3
Patients Aberrant Patients Aberrant Patients Aberrant

"CR =PR =uMRD =dMRD "No available

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49. NGS (ClonoSeq) Demonstrates
Durably High Rates of Undetectable PB MRD With AVO!

[meo 2104
[O mo <10and 21050r indeterminate 105
[i mrp <10% and 210% or indeterminate 10%

+ Rate of uMRD < 10° at C16: 59%
+ Rate of uMRD < 10° at C25: 61%

Rate, %

No apparent difference in NGS-based PB

uMRD rates in patients with or without
TP53-aberrant disease

1 Cycle 025

1. Ryan Cet al. ASH 2022. Abstract 344 PeerView.com

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50. Time-Limited AVO Safety Summary!

Hematologic Toxicities
"Grade 1 mGrade2 mGrade 3 mGrade 4 Grade 3/4: 37%

Neutropenia
Thrombocytopenia

Anemia

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

p: 35 months (range,

Dose reductions

+ Patients with any dose reduction:
n=14 (21%)

+ Acalabrutinib only: n = 3

+ Venetoclax only: n =

+ Both drugs: n = 5

‘AEs of special interest
+ Grade 3 non-COVID infections: 5.8% (pneumonia [n = 3], colitis [n = 1])
+ COVID-19 infections: 9% (grade 2 [n = 4), grade 3 [n = 1], grade 5 [n= 1])
+ AF: 3% (grade 2 [n= 1], grade 3 [n = 1]); no ventricular arrhythmias

+ No febrile neutropenia or opportunistic infections

+ _ No major bleeding events

1.Ryan C etal. ASH 2022. Abstract 34. PeerView.com

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51. AMPLIFY (ACE-CL-311): Acalabrutinib + Venetoclax +
Obinutuzumab vs CIT in TN CLL Without Del(17p)/TP53m'

Key eligibility criteria

+ Previously untreated CLL
+ Without del(17p) or TP53m
+ ECOG PS <2

Acalabruti

1. ps -cinicaias gouct2/shouNCTO3836261

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inib + venetoclax (AV)
Up to 1 year

Acalabrutinib + venetoclax +

obinutuzumab (AVO)
Up to 1 year

FCR or BR

Primary endpoint

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

Key secondary endpoints

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

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

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52. Phase 3 CLL16 Trial: VenG vs AVO in High-Risk CLL’

Study is designed to test the

= Stratification + Fitand unfit

efficacy of a BTKi triplet vs + Delt17p) | Patients with previously | patients

A A A rp n treated CLL

FD VenG in patients with high-risk and TPS3 Ge + Only CKT/

status (N =178) del(17py

features as bas TP53m

Treatment Schedule
VEN 400 mg PO day (ct 622.12 628)
— 161000 mg (1d, 8, 16.<241)

Primary endpoint: PFS Acalabrutinib maintenance
in patients with MRD+

1. hip cinicaltials goviet2/showiNCTOS197182. PeerView.com

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53. MAJIC Phase 3 Study Will Test Acalabrutinib + Venetoclax
Combination in an All-Comer CLL/SLL Population!

Key eligibility criteria

+ “760 patients to be + TN CLUSLL requiring treatment per 2018 iwCLL guidelines

recruited

+ 40 sites around the word | * ECOG PS 02 o o
+ Antithrombotic agents permitted except for warfarin or equivalent vitamin K antagonists
All treatment ends Follow-up
at 24 mo at 5 years

MRD

36 60

Primary endpoint: PFS
(event-driven analysis)
VenG arm

Ven cont
(12 mo)

1. Davids MS et al, ASH 2021. Abstract 1853, PeerView.com

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54. What Have We Learned
About Resistance Mechanisms to Finite
Therapy With Targeted Agents?

55. Learning About Resistance From the Monotherapy

Experience V With BTKi and BCL2i in

CLL

ELEVATE-RR

ALPINE
Zanubrutinib arm Ibrutinib arm

No mutations
= C481 only

= C481 + PLCG2
©1528 only

= C481 +1528
a C4B1+ A428
Only PLCGZ

Mo oa ¡CUL 2023 Aosta 169.2 Brn Jet ak ASH 202. Abstract 100.3, Bombay ta. lod, 200.198 773777
4. Chong et al. J Gin Invest. 2023;133:0170168

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=
Ext

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56. Learning About Resistance From CLL141

n=25 Ven GCib n = 8s
2 a 0 0 1 2 3 4 5 6 (analyzed patients)
arm |
BIRC3
BRAF Newly Mutated Patients
EGR2 No acquired mutations in
FBXW7 BCL2, BIM, BAX, BCL-XL,
port or MCL1 detected
RPS15
SF3B1
VenG TP53 GClb
1. Tausch E et al. EHA 2021. Abstract $144, PeerView.com

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57. Will FD BTKi-BCL2i Mitigate “Downstream” Resistance?

(Co Current study: no acquired somatic mutations found

+ CAPTIVATE: After BTK A
first-line treatment with E É H
FD ibrutinib + Previous studies. somatic mutations in 56%-83% of 3
venetoclax, no BTK, pene Foe — —
BCL2, and PLCG2 ‘Arion Acid Number

mutations detected!

( ‘Current study: no acquired somatic mutations found
+ Assessment in 25 of | PLCG2 o EE Cee
29 patients with i Hi od
progressive disease Previous studios: somatic mutetionis ln 10-39%

parents win PD attr continuous bruto

Amino Acid Number

1. Jain N tal. in Cancer Res. 2024:30:498-505. PeerView.com

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58. Consult Revisited: Is There a Role
for Finite Therapy With Newer Combinations?

Stephan is a 74-year-old patient with symptomatic CLL
(diagnosed with asymptomatic CLL 5 years earlier)

Presents with Laboratory Other findings
+ Bsymptoms + WBC: 250 x 10%L + Unmutated IGHV
+ History of HTN + Hb: 9.0 g/dL + No del(17p)/TP53m

Early-stage COPD a (rie
UNE PLT: 70 x 109L

For discussion

> Does the evidence to date support the consideration of finite therapy with newer BTKi +
venetoclax combinations for Stephan's case?

> How can we prepare for second-generation BTKi-Ven combinations?
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59. Clinical Consult: Take-Homes for Stephan’s Case

Stephan is a 74-year-old patient with symptomatic CLL
(diagnosed with asymptomatic CLL 5 years earlier)

Presents with Laboratory Other findings
+ Bsymptoms + WBC: 250 x 10%L + Unmutated IGHV
+ History of HTN + Hb: 9.0 g/dL + No del(17p)/TP53m

Early-stage COPD a fire
ae PLT: 70 x 10%/L

Recommendations
æ Continuous BTKi would be a convenient option
# While combinations can be considered, discuss goals of treatment and preferences with
the patient
æ In the near future, a time-limited treatment with a more selective BTKi + Ven may be
available as a good option for a patient like this

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60. Concluding Thoughts on Emerging
BTKi-BCL2i Combinations

+ Acalabrutinib and zanubrutinib are more selective BTKi and are proven to be
safer than ibrutinib in head-to-head studies

+ AV and ZV (+ anti-CD20) are now in development and look promising

+ Once approved, more selective BTKi + venetoclax-based regimens may allow us
to extend the benefits of all oral finite therapy to a broader range of CLL patients,
including those with significant comorbidities

+ At present, known resistance mechanisms to targeted agent monotherapy have
not been detected, suggesting that it may be feasible to retreat with these
regimens in the future

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61. Audience Q&A © |

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