Preliminary Efficacy and Safety of the Bruton
Tyrosine Kinase Degrader BGB-16673 in Patients
With Relapsed or Refractory CLL/SLL: Results Fromthe Phase 1 BGB-16673-101 StudyRicardo D. Parrondo,1 Meghan C. Thompson,2 Anna Maria Frustaci, 3 John N. Allan,4 Paolo Ghia,5,6Igori Vinogradov, 7 Constantine S. Tam, 8 Judith Trotman,9 Michael Choi, 10 Xiangmei Chen,11Kunthel By,12 Shannon Fabre, 12 Jason C. Paik,12 Amit Agarwal,12 John F. Seymour13
1Mayo Clinic - Jacksonville, Jacksonville, FL, USA; 2Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3ASST Grande Ospedale Metropolitano Niguarda, Milano,Italy; 4Weill Cornell Medicine, New York, NY, USA; 5Università Vita-Salute San Raffaele, Milano, Italy; 6IRCCS Ospedale San Raffaele, Milano, Italy; 7The Institute of Oncology,
ARENSIA EXPLORATORY Medicine, Düsseldorf, Germany; 8Alfred Hospital and Monash University, Melbourne, VIC, Australia; 9Concord Repatriation General Hospital,
University of Sydney, Concord, NSW, Australia; 10Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; 11BeiGene (Shanghai) Co, Ltd, Shanghai,China; 12BeiGene USA, Inc, San Mateo, CA, USA; 13Peter MacCallum Cancer Centre, Royal Melbourne Hospital and University of Melbourne, Melbourne, VIC, Australia

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

Disclosures• Ricardo D. Parrondo: Bristol Myers Squibb, GSK (Research funding); Sanofi Aventis (Honoraria)

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BGB-16673: A Chimeric Degradation Activating Compound (CDAC)
••

•

•
•

Ternary complex formation

Many patients with CLL/SLL experience disease progression after BTK
inhibitors1-3

BGB-16673
E3ligase

BGB-16673, a CDAC, is a bivalent molecule comprising a BTK-binding
moiety + linker + E3 ligase binder that induces BTK degradation via
polyubiquitination4

Polyubiquitination

In preclinical models, BGB-16673 degraded both wild-type and mutant
BTK resistant to covalent and noncovalent BTK inhibitors,a leading totumor suppression4,5

E3ligase

BTK

Target degradation

BGB-16673 led to substantial reductions in BTK protein levels inperipheral blood and tumor tissue in the first-in-human study6Here, the updated safety and efficacy results are presented from patientswith R/R CLL/SLL in the ongoing CaDAnCe-101 study

BTKBTK

E3ligase

Proteasomea Cov alent BTK inhibitor–resistant mutations including C481S, C481F, C481Y , L528W, and T474I; non-cov alent BTK inhibitor–resistant mutations

including V416L, M437R, T474I, and L528W. CDAC, chimeric degradation activ ating compound; ub, ubiquitin.
1. Tam CS, et al. Blood Cancer J. 2023;13(1):141-413; 2. Woy ach JA, et al. N Engl J Med. 2014;370:2286-2294; 3. Wang E, et al. N Engl J Med.
2022;386:735-743; 4. Feng X, et al. EHA 2023. Abstract P1239; 5. Wang H, et al. EHA 2023. Abstract P1219; 6. Sey mour JF, et al. ASH 2023;
Abstract 4401.

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Study Design• CaDAnCe-101 (BGB-16673-101, NCT05006716) is a phase 1/2, open-label, dose-escalation anddose-expansion study evaluating BGB-16673 in adults with R/R B-cell malignancies
Key eligibility criteria for
CLL/SLL• Meets iw CLL 2018 criteria fortreatment• ≥2 prior therapies, including
cBTKi if approved for disease• ECOG PS 0-2 & adequate
end-organ functionKey study objectives for part 1• Prim ary: safetyc andtolerability, MTD, and RP2D
• Secondary: PK, PD,and preliminary antitumor
activity dPart 1: Monotherapy dose findingaPart 1a: Dose escalationb
Selected R/R B-cellmalignancies

600 m g

500 m g
(MZL, FL, MCL,
CLL/SLL, WM,
350 m gDLBCL, RT)
200 m gn≤72
100 m gOral50 mg(28-day cycle, QD)

Part 1b: Safety expansion

Part 1c: Additional safety expansion

Selected R/R B-cellmalignancies

Selected R/R B-cellmalignancies(MZL, MCL, CLL/SLL, WM)
n≤120(MZL, WM, RT, DLBCL, FL)n≤40≤20 patients at doses cleared in part 1a:dose escalation and recommended for
additional evaluation by the SMC

After part 2 opened, ≤40 patients in ≤3
dose levels as recommended by the SMC

Determination of
BGB-16673 RP2D

Phase 2
Cohort 1:
Post-BTK inhibitor,
R/R CLL/SLL

Cohort 2:
Post-BTK inhibitor,
R/R MCL

Cohort 3:
Post-BTK inhibitor,
R/R WM

Cohort 4:
Post-BTK inhibitor,
R/R MZL

Cohort 5:
R/R FL

Cohort 6:
R/R non-GCB
DLBCLCohort 7:Post-BTK inhibitor,R/R RTa Data f rom grey portions of f igure are not included in this presentation. b Bay esian optimal interv al design with 6 dose lev els (50-600 mg orally QD). c Saf ety was assessed according to CTCAE v 5.0 in all patients andiwCLL hematologic toxicity criteria in patients with CLL; DLTs were assessed during the f irst 4 weeks. d Response was assessed per iwCLL 2018 criteria af ter 12 weeks f or patients with CLL. 1
GCB, germinal center B-cell; RT, Richter transf ormation. 1. Hallek M, et al. Blood. 2018;131:2745-2760.

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Patient Disposition•

As of February 14, 2024, 49 patients with R/R CLL/SLL enrolled in Part 1A/1B and received BGB-16673•Forty patients (82%) remained on treatment

Enrolled (N=49)

Treated (n=49)
50 mg (n=1)
100 mg (n=5)
200 mg (n=16)
350 mg (n=15)
500 mg (n=12)

Off study treatment (n=9)• Disease progression (n=4)• Adverse event (n=4)• Investigator decision (n=1)a
On study treatment (n=40)

Median follow-up (range):
4.60 months (0.3-19.8)

a Patient had ongoing low-grade arthralgia that did not otherwise meet the criteria f or discontinuation.

5Patient Characteristics• Patients had a median of 4 (range, 2-10) prior lines of therapy• Of patients with available data, high-risk characteristics were prevalent, such as:̶Unmutated IGHV locus (82%)̶Del(17p) or TP53 mutation (60%)̶Complex karyotype (47%)
Total (N=49)
70 (50-91)
31 (63)Age, median (range), years
Male sex, n (%)
ECOG PS, n (%)
119 (39)
21 (2)
CLL/SLL risk characteristics at study entry, n/N (%)
Binet stage C
23/46 (50)
Unmutated IGHV
32/39 (82)del(17p) or TP53 mutation
28/47 (60)Complex karyotype (≥3 abnormalities)
15/32 (47)cBTK, cov alent BTK; ncBTK, noncov alent BTK.

Total (N=49)

Mutation status, n/N (%)
BTK mutation present
PLCG2 mutation present
No. of prior lines of therapy, median (range)
Prior therapy, n (%)
Chemotherapy
cBTK inhibitor
ncBTK inhibitor
BCL2 inhibitorcBTK + BCL2 inhibitors
cBTK + ncBTK + BCL2 inhibitors
Discontinued BTK inhibitor due to PD, n/N (%)

15/47 (32)
6/47 (13)
4 (2-10)38 (78)45 (92)11 (22)42 (86)37 (76)
11 (22)40/45 (89)6Overall Safety Summary• One DLT was reported (200-mg dose;
grade 3 maculopapular rash)a

Patients, n (%)

Total(N=49)

Any TEAE

47 (96)• None of the 3 TEAEs that led to death
were considered related to treatmentby the investigator

Any treatment-related

30 (61)

Grade ≥327 (55)Treatment-related grade ≥3Serious
Treatment-related serious
Leading to deathb
Treatment-related leading to death
Leading to treatment discontinuationc
Treatment-related leading to treatment discontinuation

Leading to treatment modification

13 (27)21 (43)6 (12)3 (6)06 (12)1 (2)18 (37)

Dose interruption

18 (37)

Dose reduction

3 (6)a DLTs w ere only assessed during the first 4 w eeks of Part 1a. b (1) Septic shock (350 mg); (2) aspergillosis (350 mg); (3) pneumonia (200 mg) in the context of PD. c (1) Aspergillosis andcerebral aspergillosis (350 mg); (2) general physical health deterioration (350 mg) in the context of PD; (3) septic shock (350 mg); (4) pneumonia (200 mg) in the context of PD; (5) subdural
hemorrhage (350 mg); (6) thyroid carcinoma (200 mg).

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Most Frequent Adverse Events
Total (N=49)a
Patients, n (%)
Fatigue
Contusion
AnemiaDiarrhea
Neutropenia/neutrophil count decreased
Pneumonia
COVID-19
CoughDyspnea
Amylase increasedb
Lipase increasedb
Pyrexia
Thrombocytopenia/platelet count decreased
Arthralgia
Decreased appetite
NauseaAll GradeGrade ≥316 (33)
14 (29)11 (22)11 (22)11 (22)8 (16)
7 (14)
7 (14)
7 (14)
6 (12)
6 (12)
6 (12)
6 (12)
5 (10)
5 (10)
5 (10)

1 (2)
0
1 (2)
0
10 (20)6 (12)
0000
1 (2)
00000

No cases of atrial fibrillation or grade ≥3 hypertension were reporteda All grade TEAEs

in ≥10% of patients. b All events w ere lab findings and w ere transient, mostly occurring during the first 1-3 cycles of treatment, w ith no clinical pancreatitis.

8Overall Response Rate•The ORR was 72% (31/43) in response-evaluable patients with CLL/SLL•The ORR for the 200-mg group was 88%, with 2 patients achieving CR
50 mg
(n=1)

100 mg(n=5)

200 mg(n=16)

350 mg(n=14)

500 mg(n=7)

Total(N=43)

CR

002 (13)002 (5)PR

1 (100)4 (80)

10 (63)6 (43)

1 (14)

22 (51)PR-L

002 (13)

2 (14)

3 (43)

7 (16)SD0

1 (20)

1 (6)

2 (14)

3 (43)

7 (16)PD
Discontinued prior to first assessment

0000

1 (6)
01 (7)
3 (21)

00

2 (5)
3 (7)

ORR, n (%) b

1 (100)4 (80)

14 (88)c8 (57)

4 (57)

31 (72)Disease control rate, n (%) d

1 (100)5 (100)15 (94)10 (71)7 (100)38 (88)

Follow-up time, median, months

19.8

7.2

6.3

3.9

3.3

4.6e

2.9(2.9-2.9)

4.2(2.8-6.2)

2.8(2.6-4.1)

2.8(2.6-5.6)

2.8(2.6-2.8)

2.8(2.6-6.2)

Best overall response, n (%) aTime to first response, median (range), months f

a Percentages may not sum to 100 due to rounding. b Proportion of patients who achiev ed a best ov erall response of PR-L or better. c One additional patient reported response af ter the February 14, 2024 data cut,indicating a 94% ORR (15/16 patients) in the 200-mg dose group. d Proportion of patients who achiev ed a best ov erall response of SD or better. e Study f ollow-up enrolled set N=49. f Time to f irst qualif ying response inpatients with a best ov erall response better than SD. PR -L, partial response with ly mphocy tosis.

9Overall Response Rate• The ORR was similar in patients who had:̶Previously received cBTK + BCL2 inhibitors (70%)̶Del(17p) or TP53 mutation (68%)̶Complex karyotype (67%)• Responses have been observed in patients with C481S, T474I, and/or L528S BTK mutations, as well as
patients with PLCG2 mutations

cBTK, cov alent BTK.

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Treatment Duration and Response

BTK mutation status listed or was absent (-) or unknown (U).
PR-L, partial response with ly mphocy tosis.

11Conclusions••

In results from this ongoing first-in-human study, the novel BTK degrader BGB-16673 showed a generally
well tolerated safety profile in this heavily pretreated CLL population̶

One DLT was reported and MTD was not reached̶No atrial fibrillation or grade ≥3 hypertension has been reported so far

There was promising antitumor activity, including in patients with BTK inhibitor–resistant mutations and thosepreviously exposed to cBTK inhibitors, ncBTK inhibitors, and BCL2 inhibitors̶

ORR was 72% (31/43) with an 88% ORR in the 200-mg group, including 2 CRs a̶

Median time to first response was 2.8 months
̶Responses may continue to evolve as the study continues beyond the median 4.6-month follow-up•A phase 2 cohort of patients with CLL/SLL exposed to both a cBTK inhibitor and BCL2 inhibitor is nowenrolling•

These data support promising clinical activity of BGB-16673 in treatment of patients with CLL/SLLa One additional patient reported response af ter the February 14, 2024 data cut, indicating a 94% ORR (15/16 patients) in the 200-mg dose group.

cBTK, cov alent BTK; ncBTK, noncov alent BTK.

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CaDAnCe-101 Study Sites (Recruiting)• Enrollment for the CaDAnCe-101 study part 1c and phase 2 is ongoing at 90 of 115 planned study sites acrossthe US, Canada, UK, France, Georgia, Germany, Italy, Moldova, Spain, Sweden, Turkey, Australia, SouthKorea, and Brazil

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Acknowledgments

The authors thank the patients and their families, investigators,
co-investigators, and the study teams at each of the participating centers.
We would also like to thank Jenish Patel, Qi Wu, Pengfei Cheng, Stephanie Conto, Anahita Mohammedy,Yosephine Lumintang, Diana Neyra, Yelena Hua, and Ana Carolina Fernandez, for their contributions to data
analysis and operational support.
This study was sponsored by BeiGene, Ltd. Medical writing support was provided by
Shanen Perumal, PhD, of Nucleus Global, an Inizio company, and supported by BeiGene14

Thank you15