Redefining Frontlines in CLL: Key Questions on the Role of CIT, BTKi Standards, and Innovative BTKi Combinations

Chair, Nicole Lamanna, MD, discusses chronic lymphocytic leukemia in this CME activity titled “Redefining Frontlines in CLL: Key Questions on the Role of CIT, BTKi Standards, and Innovative BTKi Combinations.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/49Mazi3. CME credit will be available until June 11, 2025.

1. Redefining Frontlines in CLL
Key Questions on the Role of CIT, BTKi
Standards, and Innovative BTKi Combinations

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

Copyright © 2000-2024, PeerView

2. PeerView.com/UNN827

Our Goals for Today

Increase your understanding of various barriers to optimal CLL care,
including limitations associated with the use of chemoimmunotherapy

Augment your knowledge of evidence supporting finite therapy with
BTKi/BCL2i platforms

Sharpen your skills for developing personalized treatment plans with
continuous BTKi and emerging BTKi/BCL2i platforms

Enhance your ability to address dosing and safety considerations with
BTKi as single agents or as part of novel FD combinations

3. Where Does CIT Fit
in Modern Care?

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 information, including faculty disclosures.

2000-2024, PeerView

4. Historically, CIT Was a Backbone of CLL Management

Long-term evidence from FCR300 illustrates potential outcomes with CIT in CLL1

Patients Without Event, MN Patients Without Event, nn
“os: 131/300 ¡GAN mund das
* PES: 86300 Missing: 34786
# 100 ye IGHY unmutate: 10126
E j ®
¿ HE 4
us gen $
qe 33 = Irv mans À
5 o ¿E in À
2» rs SE S Ë
5 Be Epa IGHV unmutated
Fo of o
E 6 2» à 0 5 % u 2 à 0 5 0 % à à
Time, y Time, y Time, y
Mo, at isk No, a Risk
Lo iw iow
E za 0 KW O uno # % oo
os Xo mm ms 0
ion tu
vs 5 SO 8 7 3 0 OM mm O
Mr OS % 2% 9 Masog” 8 8 SM 3% 4 0
1. Thompson PA et al. Blood. 2023:142:1784-1788. PeerView.com

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5. What Is the Potential for SPMs With CIT?1
Evidence From FCR300

Causes of Death in the Full Cohort and According to IGHV Mutation Status

canton ee en
as TES ETS Sr
RS 5% aa En
= a zu BER

“The relationship between nonhematologic cancers and FCR is uncertain,

but therapy-related myeloid neoplasms such as MDS or AML are likely related to chemotherapy”

1. Thompson PA et al. Blood. 2023:142:1784-1788,

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6. What Is the Potential for SPMs With CIT?
Earlier, Retrospective Evidence

Study assessing 234 patients with CLL receiving
FCR-based regimens in the frontline setting’

4 risk of second cancers 2.38x higher vs general population

Rate of therapy-related AML/MDS 5.1%

Rate of RT 9%

Rate of solid tumors No increase

y survival Shorter (median 4.5 years) in those
with second cancer after FCR

1. Benjamini O etal, Leuk Lymphoma, 2015:56:1643-1650. PeerView.com

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7. Safety Considerations With CIT in the Real-World Setting
Include Infusion Reactions, Neutropenia, and Infections

Chart review of patients with CLL receiving
obinutuzumab/chlorambucil (2010-2017)

Adverse Reactions Based on Age and CIRS Score

Age at Treatment, y ciRS
Total
>75 5 ps > <8 m

Infusion-related reaction 29 43.28) 14 (48.28) 15(39.47) 47 1497.84) 15(60) 32
Neutropenia 4161.19) 18(6207) 23(60.53) 90 24(64.86) 17(5667) 49
Anemia 25 (37.31) 14 (48.28) 11(2895) 11-15 (40.54) 10(3333) 54
Thrombocytopenia 42 (62.69) 19(65.52) 23(6053) 68 2084.05) 22(73.33) 40
Infections 28 (41.79) 10 (34.48) 18(47.37) 2916 (43.24) 12(40) 79

+ OnsquareP vale N

1. Bourrer N et al. BMC Cancer. 2022:22:148. PeerView.com

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8. When Compared With FCR, Use of BTKi Platforms
Prolonged PFS Regardless of IGHV Status

In the E1912 trial, after a median follow-up of 6 years, IR led to superior PFS relative
to FCR in patients with both IGHV-mutated and IGHV-unmutated CLL"

PFS

IR (84 events/354 cases)

FCR (74 events/175 cases)

PFS Probability

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

P< 0001

5-year rates: 78%, 51%

T 2 3 4 à
Time, y

Wo at Riek
FoR NS US u 4
IR HS 1 6 24 10

1. Shanafelt Total. Blood. 2022:140:112-120.

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a
mo

IGHV Unmutated

IGHV Mutated

IR (14 events/70 cases)

IR (56 events/210 cases)

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

HR = 0.27 (95% Cl, 0.18-0.41)

02 02 .27 (95% CI, 0.11-0.62)
P< 0001 1
9 | year rates: 75%, 33% a | Syear rate: 83%, 68%
7 o 7 2 3 4 8 68 1 0 1 2 3 4 5 6 7
Time, y Time, y
No. at Risk oat isk
ano mn A w n vw + 0
TOR mm wm Ww om & GR 7 6 & © © 0 1 1

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9. Real-World Evidence Confirms Lack of Efficacy
of CIT in CLL With del(17p)!

10

Events _Censored_Median. y (95% CI)
TANTRA 25 4 102(NRMR)
Skip) posiive 4 2 207 (08.05)
08

206
A
& del(17p) negative
Zo.
5 del(17p) positive
a eee

02

o

o 2 4 6 8 10 2 14
Time From FCR, y

No, at Risk
Goli7p)nogave 79 68 53 2% 16 a 1 o
ol17p) postive 6 3 0 03 2 1 1 0 o

1. Olvera AC et al. nt J Hemotol.2023;117:388-397. PeerView.com

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10. In Current Guidelines, CIT Has a Limited Role in CLL
Without del(17p)/TP53 Mutations

First-Line Therapy

Useful in Certain Circumstances
+ Consider for IGHV-mutated CLL in patients aged <65 y

Preferred Regimens Other Recommended Regimens without significant comorbidities
Acalabrutinib + obinutuzumab Ibrutinib (category 1) = FCR (Mludarabine, cyclophosphamide, rituximab)
(category 1) + Ibrutinib + obinutuzumab Consider when BTKI and venetociax are not available or

+ Venetociax + obinutuzumab (category 28) contraindicated or rapid disease debulking needed

(category 1) + Ibrutinib + rituximab (category 28) — Bendamustine + anti-CD20 mAb
+ Zanubrutinib (category 1) + Ibrutnib + venetoctax (category 28) = Obinutuzumab + chlorambucil
— HDMP + anti-CD20 mAb (category 2B; category 3

for patients <65 y without significant comorbidities)

No Role for CIT in del(17p)/TP53 CLL

First-Line Therapy

Sn Useful in Certain Circumstances

referred Reina Other Recommended Regimene * Consider en BT and ventcia ar not aval or
2 eslora baume | une Containdcated or raid ease daba m
Rae + Ibrutinib + venetoclax (category 28) = HOMP + anti-CD20 mAb

Obinutuzumab

1. NCCN Cinial Practice Guideines in Oncology. Chronic Lymphocytic LeukemiaíSmalLymphocytc Lymphoma Version 3.2024, eer
its: ww nccn org/professionals/physician_gls/pdíc pat. PeerView.com

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11. Despite Limitations of CIT, Real-World Data
Suggest Its Use Persists in the Modern Era

However, in 2023

Real-world assessment of first-line use of
modern CLL therapy in the United States!

+ N=6,328 patients with CLL 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% continued to receive
chemotherapy-based treatment

Similar trends were reported in the
European Union23

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. Chatzonstantnou T ot al, ASH 2021. Abstract 2635.3, Ysebaert Letal. ISPOREU 2023, Abstract HSO114,

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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)

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12. The Role of BTKi Platforms
in 1L Care

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 information, including faculty disclosures.

2000-2024, PeerView

13. Treatment Choices for an Older Patient With TN CLL

Chris is an 80-year-old man
with confirmed symptomatic CLL
and a PS of 2

Comorbidities
+ COPD and CAD

Testing shows
+ del(17p)/TP53 (confirmed on NGS)
+ Unmutated IGHV

Questions to consider
What is the best choice: continuous
BTKi or a FD platform?
Does the presence of del(17p) help
inform treatment choices?
If you use continuous BTKi, how would
you choose among covalent options?

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14. Treatment Choices for an Older Patient With TN CLL

Chris is an 80-year-old man
with confirmed symptomatic CLL
and a PS of 2

Comorbidities
+ COPD and CAD

Testing shows
+ del(17p)/TP53 (confirmed on NGS)
+ Unmutated IGHV

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Questions to consider

What is the best choice: continuous
BTKi or a FD platform?

Does the presence of del(17p) help
inform treatment choices?

If you use continuous BTKi, how would
you choose among covalent options?

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15. Covalent and Non-Covalent BTKi Now Represent
Core Treatment Options for TN and R/R CLL

Agent Target Status in CLL/SLL
ea]

Ibrutinib’ Are
Acalabrutinib? BTK (covalent)

Approved

eS

Zanubrutinib’ Anproved
Venetoclax* BCL2 Approved

Approved in December 2023 (for patients receiving
22 prior LOT, including a BTKi and a BCL2i)

a wt

Pirtobrutinib' ee ei Phase 3 BRUIN CLL-321
(noc salen) Phase 3 BRUIN CLL-313

Nemtebrutinib® Phase 3 (BELLWAVE-008)

1, Imre (main) Pas remain. np ww arcs JEAN EM DOUTD ZE) Ba
2. Calquence (acalaruin) Praserbing Information. ts wer accossdata da goviénspsatca_docs/abel2017/210259s000 pe

4. Vencioxia (venetociax) Proserbing Information. ips wu accossdata Ida govidugsatida_docs/abel”2018/20857350091 po

5. Jayprea (probuin) Proscring Infomation. ps wn accossdata da govidugsatida docs/abo/2023/2 1608000 s000Corecod_ ét. —
8. Woyach J tal. ASH 2022. Abstract 3114, PeerView.com

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16. Covalent BTKi Are Recommended as Frontline Therapy
for CLL With del(17p)/TP53 Mutations

First-Line Therapy

Useful in Certain Circumstances
Preferred Regimens

Sonar mien BTI and venecia ee not
ald 2 inma Other Recommended Regimens avale corrido ai aso
M

E debulking needed
+ Zanubrutinib Eu vorn a0 22) — HDMP + anti-CD20 mAb

= Obinutuzumab

CLL14: PFS for VenG
100 pps. in Unfit Patients With 7P53 Mutation?

However, to date,
del(17p)/TP53 mutations

are associated with less
favorable outcomes with
FD venG

Cumulative Survival

re à D % & & E E
Time to Event (PFS) From Randomization, mo

1. NCCN Cinial Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Sma Lymphocyte Lymphoma. Version 3.2024, u
its swww.ncen.orgiprotessionalsiphysician_s/plc pal. 2. ALSawal O eta. Nature. 2023:18:14:2147. PeerView.com

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17. 6-Year ELEVATE-TN Findings Continue to Support
Acalabrutinib + Obinutuzumab in TN CLL

Estimated 72-mo PFS rates!

A+G (n= 179)
78% (A+ G)
62% (A) A(n=119)
17% (GCIb) Protease 0.14 0.10020)
Be
A

A + G vs GClb: HR = 0.14;
P<.0001

Avs GClb: HR = 0.24; o
tERRETTEFEFTTEPTTTETITIITETIITIIT.

P<.0001 Time, mo

Geib (n = 177

apes A ZA O. res 1701610416160 17156 19015) 12151 15 144 ar 140 138120130127 128139110 90 SA 30 25 10 2 0
A+G vs A: HR = 0.58; 170107160158 19155153 15 149148142 14 137135139130 129 12411 11511310300 95 85 58 37 22 7 2 0
P=.0229 Gow 177169 15615 190125 10100 60 82 67 68 60 49 dû a 20 00 29 2 2 21 21 18 1 8 8 3 1 0 0
HR based on stated Cox proportona hazards model» value bated on sated log-rank test o
1. Shaman Jot al. ASH 2023 Abstract 636. PeerView.com

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

Median PFS in the PFS, Cohort 1, Overall Population
overall population!

+ Zanubrutinib: NR

+ BR: 42.2 mo

+ HR=0.30; P< .001

Zanubrutnib

PFS Probability, %
08888883888

® re
Zandra NE (NE)
Estimated 42-mo PFS pron 9089 Median follow-up: 43.7 mo
rates with zanubrutinib TE TE TE TEE TE TE TE TE TDR wT
and BR were 82.4% and aia Time, mo
5 ; or me ate 212 201 te Hr 00 nme oe 0
50.0%, respectively Yanna 241 208 ZU 200 223 220 209 24 208 205 201 200 100 11 0D 2D 4 3 0
1. Muni Tet al. EHA 2023. Abstract PESO. PeerView.com

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19. Evidence From Major Trials Also Supports
Second-Generation BTKi in del(17p)/TP53 CLL

Acalabrutinib Zanubrutinib

No. with
del(17p)/TP53

Median PFS, mo

ELEVATE-TN!

73

Estimated 72-mo PFS rates
78% (A+ G)
62% (A)
17% (GCIb)

SEQUOIA?

110

NR (cohort 2/arm C)

1. Sharman Jet al, ASH 2023. Abstract 696.2, Muni T et a, EHA 2029. Abstract P639

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20. BTKi Selectivity Has Implications
for Safety and Treatment Selection’*

Potential off-target effects include

Zanubrutinib

Head-to-head trials confirmed the

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

1, Kapoin Ao al ASH 2018. Abstract 1871, 2. Bosa P tal. Export Opin Drug Metab Toxico 2016:121381-1392. 3 Hernan SEM otal. Cin Concer Ros
2017 23.2831-2841. 4. Owen C Lal Cur Oncol 2019:26:0233:9240.6, Mato Aa al, Lancet 202139789201. 6, Brandhuber BJ ei a. Cin Lymphoma Myeloma 7
Leuk 2018:18:5216, PeerView.com

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21. ELEVATE-RR: Lower Incidences of Key AEs
With Acalabrutinib vs Ibrutinib!

After a Median Follow-Up of 40.9 Months

70 All-Grade AF/Flutter, HTN, and Bleeding Lower cumulative incidences of

pa mAcalabrutinib = Ibrutinib AF/flutter (HR = 0.52)
Hypertension (HR = 0.34)

so Bleeding (HR = 0.6

40

30 Key secondary

Patients, %

Diarrhea (HR = 0.61)

Arthralgia (HR = 0.61)

endpoint Treatment discontinuations
20 because of AEs
+ 14.7% with acalabrutinib
10 cl + 21.3% with ibrutinib
of > -
AF/Flutter Bleeding

1. Bytd JC eL al. J Clo Oncol. 2021:39:3441-3482

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

After a Median Follow-Up of 39 Months

70 Treatment discontinuation because of AEs
= Zanubrutinid = Ibrutinib 5
© 1 with zanubrutinib
with ibrutinib
50
x 444
go 43.8
E
£ 30
&
20 25.6 | 247
do 16.4
6.8
o
AF/Flutter HTN Bleeding
1. Brown J tal. ASH 2023. Abstract 202. PeerView.com

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23. Finite Therapy
With BTKi/BCL2i Platforms

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 information, including faculty disclosures.

Copyright © 2000-2024, PeerView

24. Rationale for BTKi/BCL2i Combinations

Distinct and Complimentary Mechanisms of Action for Ibrutinib and Venetoclax in CLL14

Lymph node i
Ibrutinib mobilizes CLL cells out of | Ibrutinib accelerates apoptotic cell
lymph nodes and other protective | kiling by sensitizing CLL cells to
N © Iymphoid niches and inhibits | BCL2 inhibition
Stromal FT y proliferation h Pl
= % Ibrutinib netoclax
Ibrutinib wee
EA Ibrutinib + venetoclax eliminates
Peripheral resting and dividing
blood CLL cell populations > = a hire =
esting CLL cells
ce _, 0e AB} Apoptotic CLL cells
ee .o X Dead CLL cells
1 LuP tal ood Concer J 2021:11:9. 2. Dang al Loken. 2017:3:2075-2084. . Harman ES ot. Cn Cancer Res. 2015214642461. |
4. Carvantes Gomez Fetal. Cin Cancer Ros, 2018213705:3715. PeerView.com

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25. GLOW: After Additional Follow-Up, Continued PFS and OS

Bene’

s With FD Ibrutinib + Venetoclax

Prior results led to EMA approval of | + V for adults with previously untreated CLL";
updated findings were recently reported after up to 5 years of follow-up?

100
El
80
70
* 60
g 50
Es
30
20

10 ] scib
o

o 6
No. at Risk
IV 106

rr

[End of End of

[37

12 18 24 30 36 42 48
Time From Randomization, mo

99 92 90 88 8 80 75 68

Gol 105 101 95 61 50 43 33 24 20

1+ V reduced the risk of progression or death by 74% vs GClb

+ HR (95% Cl): 0.

so
E
a
»
a
“2
go
a
a
A]
:
oe eee ee we
Tine From Randomization, mo

Lev 108 100 95
Gem 105 103 103

94 of 93 91 89 87 74 19
100 93 90 86 79 70 S7 17
1+ V reduced the risk of death by 55% vs GCIb

+ HR (95% Cl): 0.453 (0.261-0.785); P = .0(

1. Kate A tal. NEJM Evi. 2022:1. 2. Moreno C ot al. ASH 2023. Abstract 694,

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26. CAPTIVATE: FD | + V Continues to Show
Robust Activity Against TN CLL"

+ With a median time on 5-Year Follow-Up From FD Cohort

study of 56 months,
54-month PFS and OS 90
rates were 70% and 80
97%, respectively 70

All treated patients

54-mo PFS Rate, % (95% Cl

& 60
PFS was promising «5 so] _ Alltreated patients (N= 159) 70 (62-77)
across most high-risk & 40 Unmutated IGHV (n = 40) 68 (50-80)
features but numerically 30 dol(14q) (n= 11% 64 (90-86)
lower in those with 20 Complex karyotype (n = 31)° 60 (41-75)
del(17p)/TP53 mutation 10 del(17p)/TP53 mutation (n = 27) 45 (25-64)
o
0 6 12 18 24 30 3 42 48 54 60
No, at Risk Time, mo
Alltveated patients 159 153 162144 143 12 10 115 13 99 01

Defned as 23 abnormalities by conventional CpG-stimulated cytogenatics* Excluding patients wih de 17pJTPS3 mutaon or complex karytype. A
1. Ghia Pet al. ASH 2023, Abstract 65. PeerView.com

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27. 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
i OS in FCR vs 1+ V
ö in FOR vs 1+V 100 ev
9 14 = FOR
so 70 | — Median follow-up: 43 mo
70 | Median followup: 43.7 mo
a) go
FoR © lev FOR
Ea E so] Say 98 93
es Y ea so | OSatdy.% 09 ers
»|Prsasy® 97268 D] ice 9 =
fo [PFSot4y.% 935 648 a] "RE5%00:03110.150.87): P<006
9 | tres cn: 0.13 0.07.028; P < 0001 e
0 À % 4% 0 7 0 2 a % 8 © 7
Time From Randomization, mo O8Gvents,n Time From Randomization, mo
Ivo o 4 5 9 9 9
En a FR 0 10 16 17 24 25 25
FR 0 18 41 71 74 7

PB MRD was assessed at 12 months and then 6 monthly and i negative, was repeated at 3 mo and 6 mo In PB and BM.
4. Häimen Petal ASH 2023, Abstract 631

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28. Finite Therapy
With Second-Generation BTKi
and Venetoclax Platforms

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

Treatment Regimen and Response Assessment Schedule

Gt ch Cr cm cr cr cr cacas cae

100
90
80

Zanubrutni 160 mg twice daly f en
Venetoclax ramp-up. daily for 12-14 cy: 2 ‘ORR: 97.2
em). ER Els
MSN assessment 2 40
Mens eat & 30
ee 20
wor lo © © © © © oo oo eo 19
Er nn Investigator Assessment (n = 36)
nou mp —____.

=SD PRL =PR @CRICRI

Zanubrutinib + venetoclax achieved a high response rate in the very high-risk
del(17p)/TP53-mutated 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 inci
neutropenia, diarrhea, and nausea

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

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30. 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

+ TP53 mutation (del[17p] or mutated): 13% N
+ Unmutated IGHV: 72%

Take-Homes

Median follow-up of 25.8 mo
+ Primary endpoint met: 89% of patients

had uMRD after 10 mo 2
+ Common AEs: thrombocytopenia (59%), 2
fatigue (54%), neutropenia (51%), and x ET
bruising (51%) E ane
+ Grade 3 neutropenia occurred in 18% El rer
of patients TTT TT SERE BEBE JE HEBE BEBE ES
1. Soumerai JD et al. Lancet Moometol.2021:2:0879-0890. = PeerView.com

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31. 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 al. Lancet Hoomaol, 2021:8:0879-0890.

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UMRD, %

35/37

am (95%)

33/37
(89%)

90

6mo PB BM

First uMRD in PB Best uMRD

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

68 patients were enrolled in a phase 2 study testing ey CYcle16.Day1 Cycle 16, Day 1
AVO in a population enriched for elecrtena — PEMRO Status BM MRD Status

high-risk features!

+ TP53 mutation (del[17p] or mutated): 60%

+ Complex karyotype (23 abnormalities): 24%
+ Unmutated IGHV: 74%

Patients, %

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

+ Depth and durability of response so far are

similar in IGHV-unmutated and TP53-aberrant AU TPSZ Al TP53 All TPS3

patients Patients Aberrant Patients Aberrant Patients Aberrant
+ Responses are durable, with 93% PFS in all "CR =PR =uMRD =#dMRD "Not available

patients at a median follow-up of nearly 3 y

1.Daviós MS et al. Lancot Oncol. 2021:22:1391-1402. 2. Ryan C et al. ASH 2022. Abstract 344. PeerView.com

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33. NGS (ClonoSeq) Demonstrates Durably High Rates
of Undetectable PB MRD With AVO'

MRD 2104

MRO <10+and 210 0r
indeterminate 105

Rate, %

MRD <10%and 210% or
indeterminate 10°

016 Cycle

1. Ryan Cet al. ASH 2022. Abstract 344

PeerView.com/UNN827

c25

Rate of uMRD <10° at C16: 59%
Rate of uMRD <105 at C25: 61%

No apparent difference in NGS-based
PB uMRD rates in patients with or
Without TP53-aberrant disease

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34. AMPLIFY (ACE-CL-311): Acalabrutinib + Venetoclax +
Obinutuzumab vs CIT in TN CLL Without del(17p)/TP53mut!

A Acalabrutinib + venetoclax (AV)
+ Previously Up to 1 year
untreated CLL

+ Without Acalabrutinib + venetoclax + obinutuzumab (AVO)

del(17p) or Up to 1 year
TP53 mutation

+ ECOG PS <2 FCR or BR
Up to 6 cycles

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

+ Key secondary endpoints: PFS (IRC assessed) of AVO vs FCR/BR and PFS
(INV assessed) of AV vs FCR/BR

1. ps incas gouct/shou/NCTO2836261. PeerView.com

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

Key eligibility criteria

+ +780 patients to be + TN CLUSLL requiring treatment per 2018 iwCLL guidelines

recruited

+ 40 sites around the world | * ECOG PS 0-2 o . .
+ Antithrombotic agents permitted except for warfarin or equivalent vitamin K antagonists
All treatment ends Follow-up
at 24 mo at 5 years

Start 2 6 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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36. Phase 3 CLL16 Trial Will Compare
Venetoclax/Obinutuzumab With AVO in High-Risk CLL"

Study is designed to test the

Stratification + Fitand unfit

i i tri Patients
efficacy of a BTKi triplet versus + del(17p) and een patients
an FD venetoclax platform in TPS3 status untreated CLL + Only CKT/
+ Age (N= 178) del(17py

patients with high-risk features TP53 mutated

Treatment Schedule

Ven 400 mg PO dally (C1 422.012 628)
— 6 1.000 mg Iv (C1 41,8, 15,626.41)

Acalabrutinib +
VenG

mm ee we m Maintenance

. ; Acalabrutinib
6 24 cy 2) para mth MRO" ter je 18607" Primary endpoint: PFS maintenance in patients
with MRD+
Months
ee 67 12 14 24
1. ips www clinicaltials govicZishowiNCTO5197182. PeerView.com

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37. CLL17 Is Testing Time-Limited Venetoclax Platforms
vs Continuous BTKi Therapy in TN CLL"

Patients with

previously Ibrutinib until intolerance or PD (n = 294)
untreated CLL,

including fit and

unfit patients Venetoclax + obinutuzumab

(6x venG, 6x venetoclax) (n = 294)

and patients with
del(17p)/TP53
mutation

Venetoclax + ibrutinib
(3x ibrutinib, 12x venetoclax + ibrutinib) (n = 294)

(N ~862)

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

1. tpsIcinicalals goviet2/show NCTO4608318, PeerView.com

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38. Preparing for BTKi/BCL2i Platforms:
Dosing and Safety Considerations

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 information, including faculty disclosures.

2000-2024, PeerView

39. Practical Points for a Patient Preparing for BTKi/BCL2i

Michelle is a 73-year-old woman with TN
CLL and a PS of 2

Comorbidities

+ Diabetes, HTN

+ GERD (taking omeprazole)
Testing shows

+ Unmutated IGHV

PeerView.com/UNN827

Questions to consider

Assuming FD BTKi/BCL2i is an option,
what are the dosing considerations?

Does BTKi safety management change
when combined with venetoclax?

Will debulking with BTKi prior to
venetoclax be used regardless of which
BTKi is considered?

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40. Practical Points for a Patient Preparing for BTKi/BCL2i

Michelle is a 73-year-old woman with TN Questions to consider
CLL and a PS of 2

Assuming FD BTKi/BCL2i is an option,
what are the dosing considerations?

Comorbidities

+ Diabetes, HTN >
aoe Does BTKi safety management change

+ GERD (taking omeprazole) when combined with venetoclax?

Testing shows Will debulking with BTKi prior to

5 venetoclax be used regardless of which
Unmutated, (Oey BTKi is considered?

Standard BTKi doses have been uset
debulking as a component of treatment

let's explore the data PeerView.com

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41. Review Standard Dosing and Drug Interactions
With BTKi When Formulating Treatment Plans

Ibrutinib.
420 mg once daily

Acalabrutinib?
100 mg every 12 hours

Zanubrutinib
160 mg orally twice daily
or 320 mg orally once daily

Pirtobrutinib?
200 mg orally once daily

Coadministration With!

Strong CYP3A4
Inhibitor

Moderate CYP3A4
Inhibitors

Moderate or Strong
CYP3A4 Inducers

+ Reduce to 140 mg

once daily 280 mg
+ For short-term use ‘once daily e
(<7 d), interrupt ibrutinib
Avoid use; if necessary,
100 mg à
Avoid use 9 increase to 200 mg
‘once dally twice daily
80 mg 80 mg
once daily twice daily ES
Avoid use; if

Avoid use; if unavoidable,
reduce dose by 50 mg

unavoidable, increase the
dose to 300 mg if starting
dose is 200 mg"

Agents

No dosage adjustment
recommended

No dosage adjustment
recommended

No dosage adjustment
recommended

No dosage adjustment
recommended

1.Wels TMetal y

50 mg or 100 mg once daly, Increase tho dose by 50 mg,
Pharm Prac 282228 1411-1439. 2 Sharma Sat al ASH 2021. Abstract 4365, 3. Jaypica(pitobrtin) Prescribing Information

ntps:iwwv.accessdata fda govirugsatida_docslabeV2023/2160590rig!s000Corected_ pc.

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42. Team Principles of Safety Management With BTKi!*-5

| Selected Toxicities With BTKi | Toxicities With BTKi

Eee

Arthralgia

+ Do not give concomitantly with warfarin

+ New-onset AF: non-warfarin anticoagulation +
monitoring

BTK + Hypertension: manage with antihypertensives

Inhibitors

Q Infection

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

+ Monitor patients for signs of bleeding

+ Monitor for infections and secondary malignancies

{testy À LomanraN Hematig Am Soc Hamail Ed Program 20201336245 2 NCCN Cal Pacs Guides Once, Ovni Lumen
eukoralSmal D Lymohoma, Version 3 2024. tos hw cen orgipotessionalsiphysican_lsipdc pal. 3. Calquenca (acalabrutn) Prescribing

Innen, hips rn secossata ca gov ocsabelZ01772 102286000019 4 Bruins caba) Presi namen

ow scons i SLR Eat ona aan Perg man >

nips: accessdata. {da ovidrugsatida_docs/abelí2023/2 160590rIg s000Correcied PeerView.com

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43. Unique Safety Aspects With Second-Generation BTKi!*

Selected Toxicities With BTKi
2

Arthralgia

+ Acalabrutinib: manage headache with
acetaminophen + caffeine

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

BTK
Inhibitors

Infection

Sequencing to secon
strategy in settin:

generation BTKi is a useful
of ibrutinib intoleranc

1. Upsky À Lamanna N. Homatoogy Am Soc Hematol Educ Program. 2020:1:36-345. 2 NCCN Cinial Practica Guideänes in Oncology. 6-Cal Lymphomas.
Versen 52024 pe au nee or prolessonalsphyacian, palco po. 3. Calquenco (calaruin) Prescrbin infomation.

Pos ww ccosedata 1d govidrugsatia_docsfabal2017/210250s000%i pal 4, Brisa (zanubruin) Prescribing Infomation. ñ

ps: accessdata.(da govidrugsatida_docs/abel202/213217801010 paf. PeerView.com

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44. What Is the Safety Experience
With BTKi/BCL2i Platforms?

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

Phase 3 GLOW'
Median age: 71 y

=GClb wi+V

Infections (grade 23) 2 (1.9%) patients in the

1+ V arm discontinued
ibrutinib because of AF

CAPTIVATE?
Median 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

1. Kator A et al. NEJM Evidence, 2022:1.2. Tam CS et al. Blood. 2022:139:3278-3280. 3. Werda W eta. J Cin Oncol. 2021;39:3853-3865,

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46. GLOW: Review of Study Deaths’

1+V (n= 106) | GCib (n =105)

Br | On Treatment | PostRandomized | On Treatment | Post Randomized
Infection related 1 3 1 13
Sela : 1 o 7
Cardiac 2 0 0 4
Sudden/unknown 2 3 0 4
Progressive disease 0 1 0 2
Vascular disorders 1 2 0 3
Other 0 2 À 4
Total LA 12 2 37
Total per arm 19 39

At 57 months of follow-up, there were 19 deaths in the | + V arm versus 39 in the GCIb arm
+ 3deaths in | + V and 13 in GCIb were due to post-treatment infections

+ 2 deaths in | + V and 7 in GClb were due to secondary primary malignancies

1.Moreno G et al. ASH 2023. Abstract 634. PeerView.com

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47. Standard BTKi Dosing and Lead-In Period When
Second-Generation Agents Are Used With Venetoclax'

Primary Endpoint Assessment

(rate of WELL CR with uMRD in BM)
Response Assessments: C4D1 caos crept 2501
| EM UMRD: can
discontinue thera
al EM uMRD CR: can a NY
E discontinua therapy?
= 3 Acalabrutinib H Acalabrutinib MRD+: continue
h /enetociax theray
EN Nena BM MRD+ CRorPR: Vonetociax | or
ht 1 1 | [continue therapy" |
it H H H H H Acalabrutinib
1 cycle. H H H i if Venetoclax
++ + + + [q (lag KK —
Zoyclos — 4eycles sorcier Heyden ‘Continued untl progression

‘or unacceptable toxicity

+ Cycle length = 28 days
IE) - Acalabrutinib and obinutuzumab at standard doses
+ Venetociax 20 mg C4D1, 50 mg C4D1, then standard ramp-up to 400-mg dose
+ PJP and HSVIVZV PPX mandatory
+ MRD at C16 and C25 assessed by multicolor flow cytometry (104)

PR MRO montored every months: tums postive, can resume AV. >
A Ryan Get a ASH 2022 Abarat 344 PeerView.com

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48. 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, %

jp: 35 months (rang

Dose reductions

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

+ Acalabrutinib only: n = 3

+ Venetociax only: n = 6

+ 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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49. BOVen Safety Summary!

Selected AE: Patients Treated

With BOVen (N = 39) n (2)

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 IV heparin for pulmonary emboli

1. Soumerai JO et al. Lancet Hoomato,2021;8:0879-2890. PeerView.com

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50. Final Take-Homes on the Practicalities of BTKi/BCL2i

PeerView.com/UNN827

Based on ongoing studies and the recent approval of ibrutinib/venetoclax in the European
Union, the approval of a BTKi/venetoclax platform in the United States is anticipated in
the near future

There are toxicities that will need to be monitored, and adjustments of therapy should
be done accordingly (particularly for older patients with comorbidities)

+ These combinations have demonstrated excellent efficacy so far

Ongoing studies testing MRD-guided approaches with FD BTKilvenetoclax platforms may
potentially be used to optimize duration of treatment

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