Preliminary Efficacy and Safety of the Bruton Tyrosine Kinase Degrader BGB-16673 in Patients
With Relapsed or Refractory Indolent NHL: Results From the Phase 1 BGB-16673-101 StudyP1119

Chan Yoon Cheah,1-3 John F. Seymour,4 Masa Lasica,5 Herbert Eradat,6 Anna Maria Frustaci,7 John N. Allan,8 Victor T.G. Lin,9 Judith Trotman,10 Ranjana Advani,11 Xiangmei Chen,12 Kunthel By,13 Shannon Fabre,13 Jason C. Paik,13 Amit Agarwal,13 Constantine S. Tam14Sir Charles Gairdner Hospital and PathWest Laboratory Medicine, Nedlands, WA, Australia; 2Medical School, University of Western Australia, Crawley, WA, Australia; 3Linear Clinical Research, Nedlands, WA, Australia; 4Peter MacCallum Cancer Centre, Royal Melbourne Hospital, and University of Melbourne, Melbourne, VIC, Australia; 5St. Vincent’s Hospital Melbourne,Fitzroy, VIC, Australia; 6David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 7ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy; 8Weill Cornell Medicine, New York, NY, USA; 9Mary Bird Perkins Cancer Center, Baton Rouge, LA, USA; 10Concord Repatriation General Hospital, University of Sydney, Concord, NSW, Australia; 11Stanford Cancer Institute,Stanford, CA, USA; 12BeiGene (Shanghai) Co, Ltd, Shanghai, China; 13BeiGene USA, Inc, San Mateo, CA, USA; 14Alfred Hospital and Monash University, Melbourne, VIC, Australia
1• Bruton tyrosine kinase (BTK) inhibitors have become the standard of care for treating patients with•••••some B-cell malignancies, including CLL/SLL, Waldenström macroglobulinemia (WM), mantle celllymphoma, marginal zone lymphoma (MZL), and follicular lymphoma (FL)1
Many patients experience disease progression, which is sometimes caused by resistance mutations
within BTK that arise during treatment with both covalent and noncovalent BTK inhibitors2,3
BGB-16673, a chimeric degradation activating compound (CDAC), is a bivalent molecule comprising aBTK-binding moiety + linker + E3 ligase binder that induces BTK degradation via polyubiquitination(Figure 1)4
In preclinical models, BGB-16673 degraded both wild-type and mutant forms of BTK regardlessof whether the mutation is associated with covalent (C481S, C481F, C481Y, L528W, and T474I) ornoncovalent (V416L, M437R, T474I, and L528W) inhibitors, leading to tumor suppression4,5
BGB-16673 treatment led to substantial reductions in BTK protein levels in peripheral blood andtumor tissue in the first-in-human phase 1 study, even at the lowest dose6
Here, updated safety and efficacy results are presented in patients with FL, MZL, and WM in theongoing CaDAnCe-101 study

RESULTS• As of February 14, 2024, a total of 25 patients with FL (n=7), MZL (n=5), and WM (n=13) had received•BGB-16673, and 16 (64%) remained on treatment (Figure 3); median follow-up time was 5.85 months
Patients were heavily pretreated, with a median of 4 (range, 2-11) prior lines of therapy (Table 1)

Enrolled (N=25)

Off study treatment (n=9)• Disease progression (n=7)b• Investigator decision (n=1)• Patient withdrawal (n=1)

Dose per day until disease progression or unacceptable toxicity. Includes 1 patient who discontinued treatment due to an AE in the context of diseaseprogression.
ab

Parameter
Age, median (range), years

BGB-16673

All with FL/MZL/WM(N=25)
72.0 (56-88)

Male15 (60)

Female10 (40)ECOG performance status, n (%)

Polyubiquitination
E3ligase

Attributes and Potential Advantages ofBGB-16673
sustained target binding
Can interrupt formation of oncogenic protein
complexes (scaffolding)Potential to overcome resistance mutations(eg, BTK C481S, C481F, C481Y, L528W, and V416L)•Target degradation•BTK

dose‑expansion study evaluating BGB‑16673 in adults with relapsed/refractory (R/R) B‑cellmalignancies (Figure 2)
Patients in this analysis had FL, MZL or WM and were treated in cohorts at 100 mg, 200 mg, or350 mg per day until disease progression or unacceptable toxicity

Figure 2. CaDAnCe-101 Study Design

114 (56)

21 (4)WM

13 (52)FL

7 (28)MZL

5 (20)
4 (2-11)

Prior covalent BTK inhibitor, n (%)

16 (64)

Prior noncovalent BTK inhibitor, n (%)

4 (16)
14/17 (82)

Prior BCL2 inhibitor, n (%)

6 (24)BTK mutation present, n/N (%)

2/14 (14)Ann Arbor stage III/IV at study entry (FL/MZL), n/N (%)

9/12 (75)

5 (20)

Upper respiratory tract infection

6 (24)1 (4)Amylase increased

6 (24)

0Fatigue

6 (24)

0

Lipase increasedb

5 (20)

1 (4)Anemia4 (16)

2 (8)Diarrhea

4 (16)

0Dizziness

3 (12)

0Dyspnea

3 (12)1 (4)Headache3 (12)

0Petechiae

3 (12)

0Part 1a: Dose escalationa
Selected R/R B-cellmalignancies
600 mg(MZL, FL, MCL,500 mg
CLL/SLL, WM,DLBCL, RT)
350 mgn≤72
200 mgOral dosing

Part 1b: Safety expansion

Part 1c: Additional safety expansion

Selected R/R B-cellmalignancies

Selected R/R B-cellmalignancies(MZL, WM, RT, DLBCL, FL)n≤40(MZL, MCL, CLL/SLL, WM)
n≤120(28-day cycle, QD)•••

Up to 20 patients enrolled at dosesthat are cleared in Part 1a: dose
escalation and recommended for
additional evaluation by the safety
monitoring committee••Low risk

3/13 (23)Intermediate risk

5/13 (38)High risk

4/13 (31)patient with history of hypertension not on antihypertensives)
One patient with MZL had a TEAE of pleural effusion in the context of PD that led to treatment
discontinuation (Table 2)
One patient with WM experienced a TEAE of septic shock in the context of PD that led to death,
which was not considered treatment related by the investigator
The most common TEAEs across dose groups were contusion (32%), fatigue, neutropenia/neutrophil
count decreased, amylase increased, and upper respiratory tract infection (each 24%) (Table 3)
The most common grade ≥3 TEAEs were neutropenia/neutrophil count decreased (n=5, 20%) andanemia (n=2, 8%)
Five patients experienced grade ≥3 infections (1 in the context of PD and 1 possibly in the context of PD)
No patients experienced a dose-limiting toxicity (DLT) during the DLT window (first 4 weeks of Part 1a)

After part 2 is opened, up to 40
patients enrolled in up to 3 doselevels as recommended by thesafety monitoring committee

Any TEAE––WM(n=12)

Treatment-related leading to death

Phase 2
Cohort 2:

Post-BTK inhibitor,
R/R MCL

Cohort 3:

Post-BTK inhibitor,
R/R WM

Cohort 4:

Post-BTK inhibitor,
R/R MZL

Leading to treatment discontinuationb
Cohort 5:
R/R FL

Cohort 6:

R/R non-GCB
DLBCLCohort 7:

Treatment-related leading to treatment discontinuation

Post-BTK inhibitor,
R/R RT

Bayesian optimal interval design with 6 dose levels (50-600 mg orally QD). b Safety was assessed according to CTCAE v5.0 in all patients; DLTs wereassessed during the first 4 weeks. c Response was assessed per Lugano 2014 criteria after 12 weeks in patients with FL and MZL and per IWWM-6
criteria after 4 weeks in patients with WM.8,9
cBTKi, covalent Bruton tyrosine kinase inhibitor; GCB, germinal center B-cell; RT, Richter transformation.

Leading to treatment modificationaa– The ORR was 57% in patients with FL, 60% in patients with MZL, and 92% in patientswith WM• These data support further investigation of the clinical activity of BGB-16673 in patients withNHL; dose finding and additional safety expansion (Part 1c) are ongoing and enrollment
continues in the CaDAnCe-101 study

Figure 5. Percent Change From Baseline in IgM for Patients With WM
25

1 (14)

0VGPR

2 (17)00PR

9 (75)

3 (43)

3 (60)SD

1 (8)

2 (29)

1 (20)PD

01 (14)

1 (20)

Disease control rate, n (%)a12 (100)

6 (86)

4 (80)

ORR, n (%)b

11 (92)4 (57)

3 (60)

0.95 (0.9-3.7)

2.71 (2.6-3.3)

2.83 (2.8-2.9)

5913172125

29

33

3749

61

73

Visit, week

Study Status• Enrollment for CaDAnCe-101 Part 1c and Phase 2 is ongoing at 90 of 110 planned study sites acrossthe US, Canada, Brazil, the UK, France, Germany, Italy, Spain, Sweden, Moldova, Turkey, Georgia,
South Korea and Australia (Figure 6)

Figure 6. CaDAnCe-101 Study Sites

Prior therapyacBTKincBTKi BCL2i BTKmutb

UWMNFLU

FL

N

MZLN

MZL

N

MZL

N

MZLYc

WM

UWM

UWM

YdWM

UWM

NWM

NFL

N

FL

N

FL

N

FL

1 (4)

U

MZL

0U

WM

UWM

UWM

All with FL/MZL/WM(N=25)
24 (96)6 (24)
8 (32)01 (4)0REFERENCES
1.
2.
3.
4.
5.

CR
VGPR
PR
MR
SD
PD
NE
Ongoing treatment
Death

1325Dose Level (mg)37Treatment duration, weeks
100

200496173

350

Gray shading = patient had the indicated prior therapy; b BTK mutation status was classified as present (Y), absent (N), or unknown (U).
cMutated L528F, L528W, C481S. d Mutated C481Y and C481S.
BCL2i, B-cell lymphoma 2 inhibitor; BTKi, covalent Bruton tyrosine kinase inhibitor; MR, minor response; mut, mutation; ncBTKi, noncovalent Bruton
tyrosine kinase inhibitor, VGPR, very good PR.
aTam CS, et al. Blood Cancer J. 2023;13:141-413.
Woyach JA, et al. N Engl J Med. 2014;370:2286-2294.
Wang E, et al. N Engl J Med. 2022;386:735-743.
Feng X, et al. EHA 2023. Abstract P1239.
Wang H, et al. EHA 2023. Abstract P1219.

6.
7.
8.
9.

Seymour JF, et al. ASH 2023. Abstract 4401.
Chirnomas D, et al. Nature Rev Clin Onc. 2023;20:265-278.
Cheson BD, et al. J Clin Oncol. 2014;32:3059-3067.
Owen RG, et al. Br J Haematol. 2022;160:171-176.

DISCLOSURES

05 (20)

Septic shock (WM, 200 mg) in the context of possible disease progression. b Pleural effusion (MZL, 200 mg) in the context of disease progression.

BLFigure 4. Treatment Duration and Response Assessment

WM0-75

Proportion of patients with a best overall response of SD or higher. b Proportion of patients who achieved a best overall response better than SD.
cTime to first qualifying response in patients with a best overall response better than SD.
VGPR, very good PR.

U

Dose reduction

-50a

WM

5 (20)-25

BL, baseline; IgM, Immunoglobulin M.

MZL
(n=5)

0U

Dose interruption

FL(n=7)

CRTime to first response, median (range), monthsc

0-100Best overall response, n (%)

WM

13 (52)

Leading to deathapatients with NHL, the ORR was 75%

Table 4. Responses by Histology in Evaluable Patients

NGrade ≥3

Treatment-related serious

Determination ofBGB-16673 RP2D– In the high-risk heavily pretreated (median of 4 prior lines of therapy) population of• All patients with WM had a numerical reduction from baseline in IgM (Figure 5)

FL18 (72)

Seriouspatients with NHL, including those with BTK inhibitor–resistant diseasepreviously received a covalent BTK inhibitor (n=12; 11 WM, 1 MZL) and a noncovalent BTK inhibitor(n=3; 1 FL, 2 WM) (Table 4, Figure 4)
Disease control rate was 100% (12/12) in WM, 86% (6/7) in FL, and 80% (4/5) in MZLBoth patients with detected BTK mutations responded (WM; 200 mg; 1 PR, 1 VGPR)

N

Any treatment-related
Treatment-related grade ≥3• BGB-16673 had durable antitumor activity with a short time to response in heavily pretreated• In response-evaluable patients, the ORR was 75%– The ORR was 57% (4/7) in FL, 60% (3/5) in MZL, and 92% (11/12) in WM, including patients who hadTable 2. Overall Safety SummaryPatients, n (%)– Discontinuations due to TEAEs were low (1 of 25 patients)– No atrial fibrillation has been reported so farAntitumor Activity• No cases of atrial fibrillation and 1 case of grade ≥3 hypertension were reported (an 88 year old•

Part 1: Monotherapy dose finding

Post-BTK inhibitor,
R/R CLL/SLL

6 (24)

Must include prior anti-CD20 in patients with FL, WM, and MZL in the US and EU, and cBTKi in patients with WM in the US and EU, and in patients withMZL in the US. b One patient had prior treatment with noncovalent BTK inhibitor without prior covalent BTK inhibitor. c One patient had unknown risk.

• CaDAnCe-101 (BGB‑16673‑101, NCT05006716) is a phase 1/2, open‑label, dose‑escalation, andCohort 1:

Neutropenia/neutrophil count decreaseda

aMETHODS

50 mg

0There were no cases of febrile neutropenia. b All events were lab findings and were transient, mostly occurring during the first 1-3 cycles of treatment,with no clinical pancreatitis. A total of 6 patients reported TEAEs of increased amylase or lipase.

Safety100 mg

8 (32)

IWWM stage (WM), n/N (%)c

CDAC, chimeric degradation activating compound; Ub, ubiquitin.

Key study objectives forPart 1• Primary: safety b andtolerability, define MTD
and RP2D• Secondary: characterizePK, pharmacodynamics,
and preliminary antitumor
activityc

10 (40)Discontinued BTK inhibitor due to PD, n/N (%)bProteasome

Key eligibility criteria• Received ≥2 prior therapies(≥1 prior therapy for RT)• Received a cBTKi if
approved for their disease• ECOG PS 0-2• Adequate end-organfunction• No current or history ofcentral nervous system
involvement by B-cellmalignancy

0No. of prior lines of therapy, median (range)aE3ligase•Contusion

Disease type, n (%)• Catalytic pharmacology that does not require

BTKGrade ≥3

BGB-16673 appears to have a safe and tolerable profile, with no DLTs in patients with MZL,WM, or FL

aSex, n (%)

BTKAll GradebOn study treatment (n=16)
100 mg (n=4)
200 mg (n=7)
350 mg (n=5)

Ternary complex formation

E3
ligasePatients, n (%)

Figure 3. Patient Disposition
Treated (n=25)a
100 mg (n=5)
200 mg (n=12)
350 mg (n=8)• Updated data from this ongoing, first-in-human study show that the novel BTK degrader

All With FL/MZL/WM(N=25)

Table 1. Demographic and Baseline Characteristics

Figure 1. BGB-16673: A BTK-Targeted CDAC7

CONCLUSIONS

Table 3. Most Common TEAEs (All Grade ≥10%)

IgM change from baseline, %INTRODUCTION

85

CYC: Consultancy, honoraria, and membership on an entity's board of directors or advisory committees: Roche, Janssen, MSD, Gilead, Ascentage Pharma, AstraZeneca,
Lilly. JFS: Honoraria, membership on an entity's board of directors or advisory committees, research funding and speakers bureau: AbbVie, AstraZeneca, Janssen,BMS, BeiGene, Gilead, Genor Bio, Roche; Consultancy: TG Therapeutics; Research funding: Roche. ML: Travel, accommodations, expenses: Celgene. HE: Researchfunding, honoraria, or consulting fees: AbbVie, Genentech, Kite, Gilead Sciences, Takeda, Acerta, AstraZeneca, BeiGene and Juno. AMF: Consulting or advisory role:
AbbVie, BeiGene, AstraZeneca, Janssen; Travel, accommodations, expenses: AbbVie, BeiGene. JNA: Research funding: BeiGene, Celgene/BMS, Genentech, Janssen,Pharmacyclics, Regeneron; Consultancy: AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, BeiGene, Genentech, Janssen, Lilly, NeoGenomics,Pharmacyclics; Speakers bureau: AbbVie, BeiGene, Janssen, Pharmacyclics; Other: Merck. VTGL: Research funding: BeiGene, Pfizer, Merck, AstraZeneca, GSK, AVEO,LOXO@Lilly, Regeneron, Genentech. JT: Research funding: BeiGene, Janssen, Pharmacyclics, Roche, Celgene/BMS, Selectar; Consulting or advisory role: BeiGene.
RA: Writing support: BeiGene; Consulting fees: Roche/Genentech, Merck, ADC Therapeutics, BeiGene; Travel support: Roche; Advisory board: Merck.
XC, KB, JCP, AA: Employment and may hold stock: BeiGene. SF: Current employment and current equity holder in publicly traded company: BeiGene; ended
employment in the past 24 months: BMS. CST: Research funding: Janssen, AbbVie, BeiGene; Honoraria: Janssen, AbbVie, BeiGene, Loxo, AstraZeneca.

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, and Shanen Perumal, PhD, of Nucleus Global, an Inizio company, and supported by BeiGene.

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