Combination Treatment With Novel BCL2 Inhibitor Sonrotoclax (BGB-11417) and Zanubrutinib InducesHigh Rate of Complete Remission for Patients With Relapsed/Refractory Mantle Cell Lymphoma

P1112

Constantine S. Tam,1 Stephen Opat,2 Marc Hoffmann,3 Jacob Soumerai,4 Masa Lasica,5 Narendranath Epperla,6 Jing-Zhou Hou,7 Ramón García-Sanz,8 Johannes Schetelig,9 Robert Weinkove,10,11 Yiqian Fang,12 Sheel Patel,13 Wei Ding,13 Haiyi Guo,14 Raul Cordoba15
Alfred Hospital and Monash University, Melbourne, VIC, Australia; 2Lymphoma Research Group, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; 3University of Kansas Cancer Center, Fairway, KS, USA; 4Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA; 5St Vincent’s Hospital Melbourne, Fitzroy, VIC, Australia; 6The James Cancer Hospital and Solove Research Instituteat Ohio State University, Columbus, OH, USA; 7University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 8Hospital Universitario de Salamanca, Salamanca, Spain; 9Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany; 10Te Rerenga Ora Blood and Cancer Centre, Te Whatu Ora Health New Zealand Capital Coast & Hutt Valley, Wellington, New Zealand; 11Cancer Immunotherapy Programme, Malaghan Institute of Medical Research,Wellington, New Zealand; 12BeiGene (Beijing) Co, Ltd, Beijing, China; 13BeiGene USA, Inc, San Mateo, CA, USA; 14BeiGene (Shanghai) Co, Ltd, Shanghai, China; 15Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
1treatments was 1 (Table 1)• Mantle cell lymphoma (MCL) is an incurable and commonly aggressive disease1• Despite high response rates with frontline therapy, many patients experience relapsed/2 patients discontinued due to toxicity

refractory (R/R) disease and require novel therapies to improve clinical outcomes

Table 1. Baseline Patient Characteristics• Combining BCL2 and BTK inhibition with venetoclax + ibrutinib has shown efficacy in patientswith R/R MCL; however, this treatment was associated with high rates of toxicity and a need for asafer and potent combination still remains2

Characteristic• Sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, is a more selective andpharmacologically potent inhibitor of BCL2 than venetoclax with a shorter half-life and noaccumulation3• Zanubrutinib is a next-generation BTK inhibitor approved in multiple (5) indications, including
R/R MCL4• Zanubrutinib was designed to provide complete and sustained BTK occupancy for efficacy

Sonro 80 mg+ zanu(n=6)

Contusion

Sonro 160 mg Sonro 320 mg Sonro 640 mg+ zanu
+ zanu+ zanu
(n=13)(n=16)(n=5)

All(N=40)

Neutropeniaa

Study follow-up, median(range), months

27.5(3.9-29.6)

16.0(1.0-25.7)

12.5(0.4-18.8)

3.5(2.2-8.6)

12.5(0.4-29.6)

Diarrhea

Age, median (range), years

60.0(46-84)

69.0(45-81)

69.0(45-85)

71.0(68-80)

68.5(45-85)

Thrombocytopeniab

Male sex, n (%)

5 (83)

11 (85)7 (44)

3 (60)

26 (65)

5,6• Here, safety and efficacy data are presented for patients with R/R MCL treated with sonrotoclax+ zanubrutinib in the ongoing BGB-11417-101 study0

3 (50)

8 (62)

4 (25)

3 (60)

18 (45)

12 (33)5 (38)

12 (75)

2 (40)

21 (53)

METHODS• BGB-11417-101 (NCT04277637) is a first-in-human, phase 1, open‑label, multicenter,

dose-escalation and -expansion study in patients with B-cell malignancies (Figure 1)

LDi <10 and ≥5 cm

3 (50)

4 (31)

3 (19)

2 (40)

12 (30)LDi ≥10 cm

1 (17)

2 (15)

3 (19)

06 (15)• Eligible patients had R/R MCL (disease that relapsed after or was refractory to ≥1 prior systemictherapy) and required treatment in the opinion of the investigator• The primary objectives of the study were to assess safety/tolerability, evaluate the ramp-up<30%

3 (50)

4 (31)

6 (38)

013 (33)≥30%

2 (33)

2 (15)

4 (25)

2 (40)

10 (25)• Responses were assessed per Lugano 2014 criteria7• Zanubrutinib was administered orally (320 mg QD or 160 mg BID) 8 to 12 weeks prior to

1 (1-1)1 (1-4)

1 (1-3)

1 (1-1)1 (1-4)

sonrotoclax treatment

16 (100)

10 (77)

11 (69)5 (100)32 (80)• Sonrotoclax was administered orally, QD, following a daily or weekly ramp-up schedule to202 (15)1 (6)

03 (8)

mitigate potential risk of TLS≥301 (8)4 (25)

05 (13)Figure 1. BGB-11417-101 Study Design

Prior BTK inhibitor, n (%)

003 (19)

03 (8)

Sonrotoclax + zanubrutinib dose findinga(weekly/daily ramp -up)

Sonrotoclax + zanubrutinib expansion

BTK inhibitor as last priortherapy, n (%)

003 (19)

03 (8)

R/R CLL/SLL, R/R MCL,TN CLL/SLL

R/R CLL/SLL, R/R MCL,TN CLL/SLL

Prior BTK inhibitor duration,
median (range), months−−

4.8(0.3-25.0)−4.8(0.3-25.0)

320 mg
160 mg

160 mg and 320 mg
selected for expansion

320 mg
160 mg

80 mg
40 mg

Prior cellular therapies(transplant or CAR-T), n (%)• As of February 4, 2024, a total of 40 patients with R/R MCL had received sonrotoclax +zanubrutinib and 27 remained on study treatment (Figure 2)– Ten patients (25%) discontinued sonrotoclax + zanubrutinib due to PD (n=5), patient
withdrawal (n=1), and AEs (n=4), only 1 of which was treatment related (pneumonia)– Four patients discontinued zanubrutinib, 3 (160 mg, n=2; 320 mg, n=1) due to PD during
lead-in; one patient discontinued from zanubrutinib only due to diarrhea• The sonrotoclax 160- and 320-mg dose levels were chosen for expansion cohorts
Figure 2. Patient Disposition

WM
sonrotoclax
EHA 2024
Abstract P1110

R/R MCL n=40

Median follow-up: 12.5 months(range, 0.4 -29.6 months)
80 mg: n=6160 mg: n=13320 mg: n=16640 mg: n=5On treatment
n=2780 mg: n=5160 mg: n=6320 mg: n=12640 mg: n=411 (28)80 mg
160 mg13320 mg

Grade 1/213640 mg
Zanubrutinib lead-inGrade ≥3135101520253035

Neutropenia combines preferred terms neutrophil count decreased and neutropenia. b Thrombocytopenia combines preferred terms
platelet count decreased and thrombocytopenia.

a• With a median study follow-up of 12.5 months, ORRs were 73% and 92% in the 160- and 320-mg
cohorts, respectively, and CR rates were 46% and 83%, respectively (Figure 4)• Of 3 response-evaluable patients with prior BTK inhibitor treatment, 2 responded: 1 achieved PR
and 1 achieved CR (Figure 5)**

Figure 4. Response Ratesa
ORRb73%•• Toxicity was generally the same among all tested dose levels with no new safety signals

ORRb92%ORRb
81%

CRPRSDPD*100

Ongoing treatment
Death
Reached sonrotoclax
target dose(28%) (Figure 3)80• The most common grade ≥3 TEAE was neutropenia (18%)– Neutropenia was manageable, with no dose reductions and only 1 dose hold due to a046

concurrent COVID-19 infection; 6 patients used G-CSF with a median treatment durationof 3.5 days

Table 2. TEAE SummaryPatients, n (%)

Sonrotoclax +obinutuzumab± zanubrutinib
n=25(CLL cohorts)

Off treatment
n=13

Sonro 80 mg+ zanu
(n=6)
4 (67)

Sonro 160 mg Sonro 320 mg Sonro 640 mg+ zanu+ zanu+ zanu
(n=13)(n=16)(n=5)
13 (100)

15 (94)5 (100)All(N=40)

60

40

4 (67)

6 (46)

7 (44)

1 (20)

18 (45)

Serious TEAEs

3 (50)

4 (31)

2 (13)

09 (23)

83

27

CR
PR

Leading to death

1 (17)

1 (8)

1 (6)

03 (8)

Leading to zanu
discontinuation

1 (17)

3 (23)

2 (13)06 (15)b

Leading to zanu dose
reduction

1 (17)1 (8)002 (5)Treated with sonro, n (%)

6 (100)11 (85)13 (81)5 (100)35 (88)

Leading to sonro
discontinuation

03 (23)2 (13)

05 (13)dLeading to sonro dose
reduction

00000

Leading to death01 (8)

00

1 (3)e1920a

Pleural effusion (due to PD), abdominal sepsis, and pneumonia. b Lymph node pain (due to PD), diarrhea, MDS, abdominal sepsis, pneumonia,
and bruising. c COVID-19 (temporary). d Diarrhea, abdominal sepsis, MDS, pneumonia and lymph node pain secondary to PD. e Pneumonia.
MDS, myelodysplastic syndrome; sonro, sonrotoclax; zanu, zanubrutinib.

Study follow-upd,
median (range),monthsPD

68138c0SD

918

Sonro 160 mg+ zanu
(n=11)

Sonro 320 mg+ zanu
(n=12)

Allc(N=32)

16.0(1.0 -25.7)

12.5(0.4 -18.8)

12.5(0.4 -29.6)

aResponses were assessed per Lugano 2014 criteria.
sonro, sonrotoclax; zanu, zanubrutinib.
a7 b46810121416182022242628303234363840

Time since first dose, months

REFERENCES

37 (93)

Grade ≥32

* Patient had prior treatment with BTK inhibitor.
aGray bar indicates duration of zanubrutinib lead-in.

63• No laboratory or clinical TLS was seen regardless of target dose
• Dose escalation was completed with no MTD reached

Any TEAE

R/R CLL/SLL
sonrotoclax +zanubrutinib
EHA 2024
Abstract S156

0DosePatients, %An overall summary of TEAEs in patients with R/R MCL is shown in Table 2N=348

n=200 (CLL and MCL cohorts)

6 (38)

5150CAR-T, chimeric antigen receptor T-cell; LDi, longest diameter; PS, performance status; sonro, sonrotoclax; zanu, zanubrutinib.

All patients dosed to date in BGB-11417 -101

n=123
(all NHL cohorts)

10Figure 5. Treatment Duration and Investigator-Assessed Responsesa• The most common any-grade TEAEs were contusion (30%), neutropenia (28%), and diarrhea

RESULTS

Sonrotoclax + zanubrutinib

3 (23)

responses in patients with R/R MCL, including an ORR of 92% andCR rate of 83% in the 320-mg cohort• The 320-mg dose was selected as RP2D for development in future
pivotal studies

13identified; sonrotoclax 160-mg and 320-mg dose levels were chosen for expansion cohorts

The safety monitoring committee reviewed dose-level cohort data before dose escalation.

Sonrotoclax
monotherapy

2 (33)• Sonrotoclax + zanubrutinib combination therapy demonstrated deep

20

CoughPatients, %640 mg

observed

23

Peripheral edema

No. of lines of priorsystemic therapy, n (%)– No atrial fibrillation or TLS (laboratory or clinical) events were
310FallNo. of lines of prior systemic
therapy, median (range)

18

HeadachePrior therapy

dosing schedule, define the MTD, and determine the RP2D of sonrotoclax in combination withzanubrutinib in patients with B-cell malignancies including R/R MCL

assessed dose of 640 mg

25

AnemiaKi67 proliferation index, n (%)

tolerated– The maximum tolerated dose was not reached up to the highest

10Fatigue

Tumor bulk, n (%)• Sonrotoclax in combination with zanubrutinib was generally well

30

COVID-19

ECOG PS

across multiple B-cell malignancies with fewer off-target AEs compared with other BTK inhibitors

aSonrotoclax + zanubrutinib(N=40)– Three patients received prior BTK inhibitor therapy and all had it as their last prior therapy;

1CONCLUSIONS

Figure 3. TEAEs in ≥5 Patients by Grade

Target dose, mg• Across dose cohorts, the median age was 68.5 years, and the median number of prior

INTRODUCTION

ORR was defined as PR or better. For all dose levels. For all patients as treated (N=40).
cd

1.
2.
3.
4.
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DISCLOSURESCST: Research funding: Janssen, AbbVie, BeiGene; Honoraria: Janssen, AbbVie, BeiGene, Loxo, AstraZeneca. SO: Consulting
fees: AbbVie, Antengene, AstraZeneca, BeiGene, BMS, CSL Behring, Gilead, Merck, Novartis, Janssen, Roche, Takeda; Researchfunding: AbbVie, AstraZeneca, BeiGene, BMS, Gilead, Janssen, Merck, Novartis, Pharmacyclics, Roche, Takeda; Honoraria: AbbVie,AstraZeneca, BeiGene, BMS, Gilead, Janssen, Merck, Novartis, Roche, Takeda; Membership on an Entity’s Board of Directors orAdvisory Committees: AbbVie, AstraZeneca, BeiGene, BMS, Gilead, Janssen, Merck, Novartis, Roche, Takeda (outside the submitted work).
MH: consultancy role with AbbVie, AstraZeneca, BeiGene, Eli Lilly, Janssen, Kite, Novartis, Pharmacyclics, and TG Therapeutics.
JS: Consultancy: AstraZeneca, BeiGene, Biogen, BMS, Roche, Seattle Genetics; Research Funding: Adaptive Biotechnologies,BeiGene, BostonGene, Genentech/Roche, GSK, Moderna, Takeda, TG Therapeutics. ML: Travel, accommodations, expenses: Celgene.
NE: Research Funding and Speakers Bureau: BeiGene; Speakers Bureau: Incyte; Consultancy, Membership on an entity's Board ofDirectors or advisory committees: Novartis, Merck, ADC Therapeutics, Lilly. JH: Consultancy: AbbVie, AstraZeneca, Genentech.
RGS: Consultancy: Janssen, BeiGene; Research Funding: Gilead, Takeda; Honoraria: Janssen, Takeda, BeiGene, Incyte, Astellas,Novartis, GSK; Patents and Royalties: IVS (Institutional Agreement); Speaker's Bureau: Janssen, BeiGene. JS: Nothing to disclose.
RW: Honoraria and/or Research Funding: Janssen, AbbVie, BeiGene, BioOra; Current equity holder in publicly-traded company:
Fisher & Paykel Healthcare. YF, SP, HG: Employment and may hold stock: BeiGene. WD: Research funding: BeiGene; Grants: Merck,AstraZeneca, DTRM Pharma, Octapharma, BeiGene; Advisory board: Kite Pharma; Employment: BeiGene. RC: Current Employment:
Fundacion Jiminez Diaz University Hospital; Consultancy: Roche, Takeda, AbbVie, Janssen, AstraZeneca, Lilly, BeiGene, BMS,Genmab, Incyte, Gilead; Speakers Bureau: Roche, Takeda, AbbVie, Janssen, AstraZeneca, Lilly, BeiGene, BMS, GenMab, Incyte, Gilead;
Membership on an entity's Board of Directors or advisory committees: EHA, SEHH.

ACKNOWLEDGMENTS
The authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participatingcenters. This study was sponsored by BeiGene, Ltd. Medical writing was provided by Shanen Perumal, PhD, of Nucleus Global, anInizio company, and supported by BeiGene.

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