Combination of Zanubrutinib + Venetoclax forTreatment-naive CLL/SLL With del(17p) and/or TP53:
Preliminary Results From SEQUOIA Arm DShuo Ma,1 Talha Munir,2 Masa Lasica,3 Mazyar Shadman,4,5 Alessandra Tedeschi,6Emmanuelle Ferrant,7 Ian W. Flinn,8 Wojciech Janowski,9 Monica Tani,10 Tadeusz Robak,11Jennifer R. Brown,12 Constantine S. Tam,13 Tian Tian,14 Emily Mantovani,14 Stephanie Agresti,14Linlin Xu,14 Aileen Cohen,14 Wojciech Jurczak,15 Paolo Ghia16,171Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 2Leeds Teaching Hospitals NHS Trust, Leeds, UK;
3St Vincent's Hospital Melbourne, Fitzroy, VIC, Australia; 4Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 5University of Washington, Seattle, WA, USA;

6ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; 7Département Hématologie, CHU de Lyon-Sud, Lyon-Sud, France; 8Tennessee Oncology/OneOncology, Nashville, TN, USA;

9Calvary Mater Newcastle Hospital, Waratah, NSW, Australia; 10Hematology Unit, Santa Maria delle Croci Hospital, Ravenna, Italy; 11Medical University of Łódź, Copernicus Memorial Hospital,Łódź, Poland; 12Dana-Farber Cancer Institute, Boston, MA, USA; 13Alfred Hospital and Monash University, Melbourne, VIC, Australia; 14BeiGene USA, Inc, San Mateo, CA, USA;

15Maria Sklodowska-Curie National Research Institute of Oncology, Kraków, Poland; 16IRCCS Ospedale San Raffaele, Milan, Italy; 17Università Vita-Salute San Raffaele, Milan, Italy

Presented at the EHA2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain

Disclosures for Paolo Ghia• AbbVie (honoraria, research funding); AstraZeneca (honoraria, research funding); BeiGene (honoraria);
Bristol Myers Squibb (honoraria, research funding); Janssen (honoraria, research funding); Galapagos (honoraria);
Lilly/Loxo (honoraria); MSD (honoraria); Roche (honoraria); Sanofi (honoraria)

2Introduction• Zanubrutinib is a highly potent and selective next-generation BTK inhibitor approved in TN and R/R CLL
as monotherapy1,2 that was designed to provide complete and sustained BTK occupancy, with fewer off-target
AEs and improved efficacy compared with other BTK inhibitors3,4• In Arm C of the phase 3 SEQUOIA trial, zanubrutinib monotherapy was well tolerated and achieved a high
ORR (95%) and 18-month PFS estimate (89%) in patients who had untreated CLL/SLL with del(17p)5, which wereconsistent with outcomes in patients without del(17p)6• Monotherapy with venetoclax, the first-generation BCL2 inhibitor, has also been shown to be well tolerated withdurable responses achieved in patients with del(17p) and/or TP53 mutation7, but data on venetoclax + ibrutinib
combination therapy in this high-risk population has been limited• Combination therapy with a BCL2 inhibitor in patients with high-risk CLL may provide deep responses and improveoutcomes in patients treated with zanubrutinib• Preliminary results in patients with del(17p) and/or TP53 mutation who received zanubrutinib + venetoclax
combination treatment in Arm D of the SEQUOIA trial are presented
1. Brukinsa. Prescribing information. BeiGene, Ltd; 2024; 2. Brukinsa. Summary of product characteristics. BeiGene, Ltd; 2021; 3. Guo Y, et al. J Med Chem. 2019;62(17):7923-7940;
4. Tam CS, et al. Expert Rev Clin Pharmacol. 2021;14(11):1329-1344; 5. Tam CS, et al. Haematologica. 2021;106(9):2354-2363; 6. Tam CS, et al. LancetOncol. 2022;23(8):1031-1043;
7. Stilgenbauer S, et al. J Clin Oncol. 2018;36(19):1973-1980.

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SEQUOIA Study Design – Arm D Cohort With del(17p) and/or TP53mut
Arm A and B
without del(17p)Open label
R 1:1

Key eligibility criteria• Untreated CLL/SLL• Met iwCLL criteria fortreatment• Measurable disease
by CT/MRI• For Arm D: central
confirmation ofdel(17p) by FISH
and/or local TP53mutation

Arm Cwith del(17p)

Arm D(N=114)

Zanubrutinib
Bendamustine + rituximab
Zanubrutinib

With del(17p)/TP53mut
n=66
Enrollment start date:Nov 2019
Without del(17p)n=48
Enrollment start date:
Jan 2022

a Reponses assessed per modified iwCLL criteria for CLL and Lugano criteria for SLL.

Endpoints for Arm D

Zanubrutinib + venetoclax• ORR (INV)a• PFS (INV)• uMRD4 rate(<10−4 sensitivity)• Safety per CTCAE4

SEQUOIA Arm D Treatment Regimen and Assessment Schedule• Zanubrutinib lead-in (3 cycles) followed by zanubrutinib + venetoclax (12-24 cycles dependent on uMRD earlyvenetoclax-stopping rules), then zanubrutinib monotherapy until disease progression, unacceptable toxicity,or meeting uMRD early zanubrutinib-stopping rules
Beyond C28, continue
zanubrutinib alone
until confirmed uMRD

C1C4C7C10C13C16C19C22C25C28+

Treatments

Zanubrutinib 160 mg twice daily for ≥27 cycles
Lead-in

Venetoclax ramp-up cycle, then 400 mg once daily for 12-24 cycles
Starting at C16, may discontinue venetoclax
for confirmed uMRD (PB & BM)

Assessments

TLS risk assessments
Hematology/physicalexamination/imaging
MRD: PB
BM biopsy & aspirate
for CRa
MRD: BM aspirateb
a BM biopsy and aspirate are required to confirm a suspected CR/CRi (BM collection timepoint not defined per protocol), starting after cycle 9 and then annually if needed.
b Patients with confirmed CR/CRi and 2 consecutive PB uMRD ≥12 weeks apart.

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uMRDa-guided Early Zanubrutinib- or Venetoclax-stopping Rules• Zanubrutinib or venetoclax can be stopped early if all of the following conditions are met:
•Response assessed as CR/CRi confirmed by a bone marrow biopsy•

uMRD4 achieved in 2 consecutive peripheral blood MRD tests conducted ≥12 weeks apart•uMRD4 achieved in 2 consecutive bone marrow aspirate MRD tests conducted ≥12 weeks apart•

Received• ≥12 cycles of venetoclax (to stop venetoclax early)• ≥27 cycles of zanubrutinib (to stop zanubrutinib early)

a uMRD was assessed by flow cytometry.
CRi, complete response with incomplete hematopoietic recovery.

Patient Disposition
Patients with del(17p) and/or TP53 mutationa (N=66)
Enrolled between November 2019 and June 2022
Median study follow-up: 31.6 (0.4-50.5) months

Off study prior to venetoclax
initiation (n=3)• Death (n=2)b• Withdrawal by patient (n=1)

Initiated zanubrutinib +venetoclax (n=63)

Off study (n=3)• Death (n=2)c• Lost to follow-up (n=1)

Data cutoff: January 31, 2024.
a Based on central assessment. b Due to AE. c Due to AE (n=1); due to PD (n=1).

Study follow-up (n=5)• Long-term survival follow-up (n=2)• Post-treatment efficacy follow-up (n=3)

On treatment (n=55)• Zanubrutinib + venetoclax (n=8)• Zanubrutinib monotherapy after
discontinuing venetoclax (n=47)

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Treatment Discontinuations
Patient, n (%)
Enrolled/dosed
Treated with zanubrutinib only
Discontinued from zanubrutinib
AEPD
Completed treatment (uMRD early stopping)
Withdrawal by patient
Discontinued from venetoclax
Completed treatment
24 cycles per protocol
uMRD early stopping
AEPD
Investigator decision

Zanubrutinib + venetoclax(n=66)
66 (100)
3 (5)​11 (17)​
5 (8)​
2 (3)​
3 (5)​1 (2)
55 (83)50 (76)49 (74)
1 (2)
2 (3)
2 (3)
1 (2)

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SEQUOIA Arm D Included a High-risk Cohort

LDi, longest diameter.

CharacteristicAge, median (range), years≥65 years, n (%)
Male sex, n (%)
White race, n (%)
ECOG performance status, n (%)
12SLL, n (%)
Bulky disease, n (%)
Any target lesion LDi ≥5 cm
Any target lesion LDi ≥10 cm
Genotype status, n (%)
del(17p) positive and/or TP53 mutateddel(17p) positive and TP53 mutateddel(17p) positive and TP53 wildtype
del(17p) negative and TP53 mutated
Unmutated IGHV
Complex karyotype, n (%)≥3 abnormalities≥5 abnormalitiesdel(17p) % of abnormal nuclei, median (range)

Zanubrutinib + venetoclax(n=66)
66 (26-87)
36 (55)34 (52)58 (88)32 (48)2 (3)3 (5)29 (44)5 (8)66 (100)
42 (64)17 (26)
7 (11)
56 (85)33 (50)24 (36)60.5 (1-98)

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Proportion of Patients at High Risk for TLS Decreased by 91%
After Zanubrutinib Lead-in
Baseline Before TreatmentBefore Venetoclax
Higha(3.0%)

Higha(34.8%)

Medium(71.2%)
Medium(60.6%)
Low(24.2%)
Low(4.5%)

Not Available(1.5%)

a Any lymph node with the largest diameter ≥10 cm or an absolute lymphocyte count ≥25 x 109/L and a lymph node with the largest diameter ≥5 cm by radiologic assessment.

TLS, tumor lysis syndrome.

Safety Summary
TEAEs in >10% of patients
COVID-19

52

Diarrhea

30

Nausea30

Contusion

29

Fatigue
Neutropenia

Treatment-emergent adverse events of special interest
3Infections

9Hemorrhage

23aArthralgia

15Epistaxis

11Median study follow-up:31.6 (0.4-50.5) months

Fall11

Grade 1/2

Petechiae

Grade ≥3

11010203040Patients, %50

a Neutropenia combines preferred terms neutrophil count decreased and neutropenia.

60

1552

Neutropenia

5Second primarymalignancies

5Hypertension 217556

17
88Anemia

62

Thrombocytopenia

62

Atrial fibrillation/flutter

2

Grade 1/2
Grade ≥3

2010

2030

4050Patients, %607080• Of all infections, 36 patients (55%) had COVID-19,2 (3%) of whom experienced a grade ≥3 event11

TEAEs Leading to Discontinuation and Death
Zanubrutinib + venetoclax(n=66)

Patients, n (%)
TEAE leading to zanubrutinib discontinuation
TEAE leading to venetoclax discontinuation
TEAE leading to death
PatientTEAE(s)1Motor vehicular accident,
intra-abdominal hemorrhage,
and intracranial hemorrhage

2
3
4
5

Pneumonitis
Lung carcinoma
Pneumonia
Pneumonia (S. aureus)
Septic shock (S. aureus)a Patient completed venetoclax treatment. b Patient did not start venetoclax.

5 (8)
2 (3)
3 (5)

Led tozanubrutinibdiscontinuation

Led tovenetoclax
Led to death
discontinuation

XX

X

X
XX
X

N/Aa
N/AbX

X

N/AbX
X
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In 65 Response-evaluable Patientsa with del(17p) and/or TP53 Mutation,ORRb,c was 100% and the CR+CRi rate was 48%
ORR
100%

10090
80

46Patients, %

70
60
50

24030

51

20
100CR
CRiPRPR-L

2Median study follow-up:
31.6 (0.4-50.5) months

Zanubrutinib +venetoclax (n=65)

a Received ≥1 dose of zanubrutinib with ≥1 post-baseline disease assessment. The 1 patient that was not response-evaluable died during cycle 1. b Responses assessed by investigator per modified

iwCLL criteria for CLL and Lugano criteria for SLL. c ORR was defined as PR-L or better.

13Rates of uMRD in PB Increased with Longer Treatment Duration• Best uMRD rate: 59% (39/66) in ≥1 PB sample; 37% (13/35) in ≥1 BM samplea
MRD rates in PB

a BM biopsy and aspirate were required to confirm a suspected CR/CRi and additional BM aspirate uMRD sample collection was dependent on PB uMRD status; BM collection timing varied by patient.
On treatment BM aspirate samples have been collected in 35 patients to date.

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Treatment Duration With Time to First uMRD

Treatment duration, weeks

With Median Study Follow-up of 31.6 Months, Median PFS was Not Reached

Estimated PFS
12-month95%

24-month

94%

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Conclusions• Preliminary results for treatment with zanubrutinib + venetoclax in patients with high-risk TN CLL/SLL
with del(17p) and/or TP53 mutation showed favorable safety and tolerability•Rates of atrial fibrillation/flutter and hypertension were low (2% and 9%, respectively)• Promising efficacy was seen in this high-risk population with deep and durable responses•An ORR of 100% and a high rate of uMRD were achieved•

With a median follow-up of 31.6 months, high 12- and 24-month PFS estimates were seen
(95% and 94%, respectively)• The study is ongoing and results in patients who meet MRD-guided early stopping rules will bereported as data mature• The ongoing phase 3 CELESTIAL-TNCLL trial (BGB-11417-301) is evaluating zanubrutinib in
combination with sonrotoclax, a next-generation and potent BCL2 inhibitor, as fixed duration therapy
in patients with TN CLL17

Acknowledgments• The authors thank the patients and their families, investigators, co-investigators,
and the study teams at each of the participating centers• This study was sponsored by BeiGene, Ltd• Medical writing was provided by Brittany Gifford, PharmD, of Nucleus Global,
an Inizio company, and supported by BeiGene

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