Preliminary Safety and Antileukemic Activity of Sonrotoclax (BGB-11417), a Potent and Selective
BCL2 Inhibitor, in Treatment-Naive Patients With Acute Myeloid Leukemia

P538

Jake Shortt,1 Shuh Ying Tan,2 Sophie Leitch,3 James Mao-Chun Liang,4 Chun Yew Fong,5 Sundra Ramanathan,6 Qiubai Li,7 Pau Montesinos,8 Courtney DiNardo,9 Jinhua Zhong,10 Wai Y. Chan,11 Rui Li,10 Oleg Zernovak,11 Amit Agarwal,11 Andrew H. Wei12
Monash Health and Monash University, Clayton, VIC, Australia; 2St Vincent's Hospital, Melbourne, VIC, Australia; 3Te Whatu Ora, Health New Zealand, Waitemata, Auckland, New Zealand; 4Middlemore Hospital, Auckland, New Zealand; 5Austin Health, Melbourne, VIC, Australia; 6St George Hospital, Kogarah, NSW, Australia; 7Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China; 8Hospital Universitari I Politècnic La Fe, Valencia, Spain; 9MD Anderson Cancer Center, Houston, TX, USA; 10BeiGene (Shanghai) Co, Ltd, Shanghai, China; 11BeiGene USA, Inc, San Mateo, CA, USA; 12Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia
1

Table 1. Baseline Patient Characteristics• Acute myeloid leukemia (AML) is the most common acute form of leukemia in adults and has an aggressive
disease course• The B-cell lymphoma 2 (BCL2) inhibitor venetoclax + azacitidine has improved outcomes in treatment-naive (TN)

Sonro
40 mg
× 10 d(n=9)

1,2

Eligibility criteria• ECOG PS 0-2• Not receiving warfarin; moderate orstrong CYP3A4 inhibitor or inducer
within 5 half-lives
DLT observation window
Hematologic DLTFirst dose

Sonro
320 mg× 21 d(n=4)

20.6(0.3-34.0)

1.5(1.1-1.9)

14.1(1.4-27.6)

0.9(0.5-1.6)

13.6(5.1-24.4)

7.6(7.6-7.6)

11.8(8.8-12.6)

10.5(0.3-34.0)

Age, median (range), years

72.0(64-91)

77.0(67-85)

71.5(68-75)78.0(70-87)

73.5(71-78)70.0(65-80)68.0(68-68)76.0(72-81)75.0(64-91)

Male sex, n (%)

6 (67)

5 (45)

1 (50)

6 (75)

3 (75)

7 (78)

1 (100)3 (75)

32 (67)

Part 3
Efficacy
expansionc

3-6
patients

10 patients

20 patients(TN AML)

Sonrotoclax dose: TN AML

|

40 mg
80 mg

|

D28

Part 2
Safetyexpansionc

10 days
10 days

160 mg
160 mgIntermediate doses
80 mg 14 days
160 mg

D42a

10 days
28 days

320 mg
320 mg21 days
28 days

14 days

320 mg

14 daysOr cycle 2 initiation. b As a precautionary measure for TLS monitoring, patients were hospitalized during the ramp-up period. c Safety monitoring committee reviews available data to determine dose
escalation in part 1, dose expansion to part 2, and the final RP2D to start part 3.
CYP3A4, cytochrome P450 3A4; HMA, hypomethylating agent; non-APL, nonacute promyelocytic leukemia.

• As of March 31, 2024, a total of 48 patients with TN AML were enrolled and had received sonrotoclax + azacitidine
treatment and 18 (38%) remain on treatment (Figure 2)• In all patients with TN AML, the median study follow-up was 10.5 (range, 0.3-34.0) months and the median age was
75 years (Table 1)• The median number of treatment cycles was 7, with the longest average cycle duration (median, 35.1 days) in the
azacitidine + sonrotoclax 160 mg x 28 day cohort (Table 2)• The median dose intensity relative to the assigned dose of sonrotoclax was >80% except in the azacitidine + sonrotoclax
160 mg x 28 day and 320 mg x 21 day cohorts

Figure 2. Patient Disposition

160 mg x 10 d: n=8160 mg x 14 d: n=4
160 mg x 28 d: n=9

320 mg x 14 d: n=1
320 mg x 21 d: n=4

Off treatment (n=30; 63%)
• Relapseb (n=11)• Adverse event (n=8)• Patient withdrawal (n=5)• Investigator decision (n=2)• Disease progressionc (n=1)• Proceeding to transplant, patient in CR (n=1)• Start of new anticancer therapyd (n=1)• Treatment failuree (n=1)

Data cutoff: March 31, 2024. The efficacy-evaluable population included patients who (1) completed ≥1 treatment cycle (initiated the second cycle) or 42 days, whichever is earlier, or discontinued
treatment during the first cycle or (2) had ≥1 response assessment. Two patients have yet to complete cycle 1 and were excluded from the efficacy-evaluable population. b Hematologic relapse (after CR/
CRi) defined as bone marrow blasts ≥5%, reappearance of blasts in the blood, or development of extramedullary disease. c Defined as evidence for an increase in bone marrow blast percentage and/or
increase in absolute blast counts in the blood, both per ELN2017 response criteria. d Patient switched therapy while in CRi. e Defined as no CR or CRi after 6 cycles of sonrotoclax + azacitidine according
to ELN2017.
CRi, CR with incomplete hematologic recovery; ELN, European LeukemiaNet.
aSerious TEAEs

37 (77)thrombocytopenia (n=2) occurred in 2 patients

5 (10)• Sonrotoclax + azacitidine demonstrated antileukemic activity in TN unfit patients

TEAEs leading to discontinuation
Aza

8 (17)Sonro

8 (17)

with AML in all dose cohorts– The ORR was 78%, of which CR/CRh was achieved in 63% of patients and CR
in 54% of patients

11 (100)

2 (100)6 (75)

2 (50)

6 (67)

1 (100)3 (75)

36 (75)Aza

14 (29)• The study stopping criteria has not been met in any of the dose cohorts

Secondary

4 (44)

00

2 (25)

2 (50)

3 (33)

0

1 (25)

12 (25)Sonro

12 (25)• Safety expansion of x 14-day dosing is ongoing in 80 mg, 160 mg, and 320 mg
cohorts to determine the recommended phase 2 dose

TEAEs leading to interruption

Favorable0

3 (27)0

1 (13)0

1 (11)

0

1 (25)

6 (13)

Intermediate

4 (44)

5 (45)

0

3 (38)

2 (50)

3 (33)

0

3 (75)

20 (42)Adverse5 (56)

3 (27)

2 (100)3 (38)

2 (50)

4 (44)

1 (100)020 (42)7 (78)

9 (82)

2 (100)7 (88)

3 (75)

5 (56)

1 (100)2 (50)

36 (75)−7 or del(7q)1 (11)

2 (18)

0

2 (25)

1 (25)

2 (22)

00

8 (17)−5 or del(5q)2 (22)

2 (18)0

1 (13)0

1 (11)

1 (100)0

7 (15)NPM1

0

3 (27)0

1 (13)00

0

1 (25)

5 (10)TP53 aneuploidy

1 (11)1 (9)0

2 (25)0

1 (11)00

5 (10)−17/abn(17p); TP53
abnormality0

2 (18)0

1 (13)

0

0

0

0

3 (6)

IDH1/IDH2-R172b

1 (11)

1 (9)

0

0

1 (25)

0

0

0

3 (6)

FLT3-ITD high AR

1 (11)

1 (9)

0

0

0

0

0

0

2 (4)

FLT3-ITD low AR

0

1 (9)

0

1 (13)

0

0

0

0

2 (4)

FLT3-TKD

0

0

0

0

1 (25)

0

0

0

1 (2)

Aza

10 (21)Sonro

14 (29)

Sonro
80 mg
× 10 d(n=11)Sonro
80 mg
× 14 d(n=2)

Figure 3. TEAEs in ≥20% (All Grades) or ≥10% (Grade ≥3)
NeutropeniaaThrombocytopenia

52

Nausea52

Average cycle duration,
median (range), days
Relative dose intensity(sonro), median (range), %4.0(1.0-25.0)
32.0(13.0-44.5)

15.0(1.0-34.0)
31.1(8.0-46.9)

80.2
91.0
(42.6-105.9) (38.8-100)

2.0(2.0-2.0)

42

Hypokalemia

25

13

Diarrhea

33

Pyrexia29

Vomiting
COVID-19

17

Injection site reactionc

21

Sepsisd

19

Pneumonia 2

15

White blood cell count decreased 2

Sonro
160 mg× 14 d(n=4)

Sonro
320 mg× 14 d(n=1)

Sonro
320 mg× 21 d(n=4)

All TNAML(N=48)

8.5(1.0-28.0)

1.0(1.0-2.0)

95.9(21.6-109.4)

100(96.1-100)

5.0(1.0-16.0)
35.1(2.0-73.0)
63.3(29.5-100)

7.0(7.0-7.0)

8.5(7.0-12.0)

32.9
32.4
(32.9-32.9) (25.4-37.7)

7.0(1.0-34.0)
31.8(2.0-73.0)

85.6
66.4
91.7
(85.6-85.6) (39.3-94.0) (21.6-109.4)
50.1(50.1-50.1)

40

15.2
4.3
4.3
8.7
2.2
10.9
Patients with TN AML
Efficacy-evaluable population(N=46)

Grade 1/2
Grade ≥3

10

ORR included CR, CRi, MLFS, and PR.
CR, complete response; CRi, CR with incomplete hematologic recovery; MLFS, morphologic leukemia-free state; ND, not done; ORR, overall response rate; PD, progressive disease; PR, partial response;
SD, stable disease.

a

10

20

30

40

50

60

70

b

80

90

c

Figure 5. MRD
100

Antileukemic Activity•••

CR/CRh was achieved in 63% of patients by a median time to CR/CRh of 1.3 months (Table 4)
At a median follow-up of 19.8 months, the median duration of response was 15.1 months for CR
The median duration of response was 16.9 months for both CR/CRh and CR/CR with incomplete hematologic recovery(CRi, median follow-up 19.8 months)
The ORR was 78% in patients with TN unfit AML (Figure 4)
Minimal residual disease–negative status was achieved by 37% of all TN patients with unfit AML in the efficacyevaluable population (Figure 5)

–
–

Sonro
80 mg
× 10 d(n=11)Sonro
80 mg
× 14 d(n=2)

Sonro
160 mg× 10 d(n=8)

Sonro
160 mg× 14 d(n=2)

Sonro
160 mg× 28 d(n=9)

Sonro
320 mg× 14 d(n=1)

Sonro
320 mg× 21 d(n=4)

All TNAML(N=46)

4 (44)

1 (100)3 (75)

25 (54)

MRD positive

37

NE/ND

60%
60
35

40%
40
20%
20
0
0%

Table 4. Summary of Disease Responses
Sonro
40 mg
× 10 d(n=9)

MRD negative

80
80%

a

77.6
86.9
(50.5-87.4) (37.2-101.2)

28
Patients with TN AML
Efficacy-evaluable population(N=46)MRD, minimal residual disease; ND, not done; NE, not evaluable.

Aza

aza, azacitidine; sonro, sonrotoclax.

CR, n (%)

• An overall summary of TEAEs in patients with TN AML is shown in Table 3• The most common any-grade TEAEs were neutropenia (including neutrophil count decreased), thrombocytopenia(including platelet count decreased), constipation, and nausea (Figure 3)– Neutropenia and thrombocytopenia were the most common grade ≥3 TEAEs and grade ≥3 infections and infestations
occurred in 24 patients (50%)• The most common TEAE class leading to treatment discontinuation was infections and infestations (azacitidine, n=5;
sonrotoclax, n=5)
• The most common TEAE leading to dose reduction was neutropenia (n=9, sonrotoclax reduction; n=11, azacitidine
reduction)• Five patients had a TEAE leading to death, none were considered related to sonrotoclax or azacitidine treatment, and the
30-day mortality rate was 2%– Two TEAEs leading to death were considered related to disease (bronchopulmonary aspergillosis [80 mg x 10 day]and neutropenic sepsis [160 mg x 10 day])– Three TEAEs leading to death were not considered related to disease (pulmonary sepsis without preceding confirmed
pneumonia [40 mg x 10 day], hospital acquired pneumonia [80 mg x 10 day], and metastatic squamous cell carcinoma[80 mg x 10 day])Three DLTs occurred in 2 patients in the azacitidine + sonrotoclax 80 mg x 10 day cohort (neutropenia [n=1; grade 4]
and thrombocytopenia [n=2; grade 4])
Laboratory TLS occurred in 1 patient in the azacitidine + sonrotoclax 160 mg x 10 day cohort (hyperuricemia andhyperphosphatemia; cycle 2) and resolved in 4 days with concomitant allopurinol

ND

0

Patients, %Sonro
160 mg× 28 d
(n=9)

PD

2
4

SD

60
60%

20
20%

25

PR

54.3

38

Febrile neutropenia

MLFS

80
80%

Neutropenia includes the terms neutropenia and neutrophil count decreased. Thrombocytopenia includes the terms thrombocytopenia and platelet count decreased. All injection site reactions wererelated to azacitidine. d Sepsis is a grouped term excluding fungal sepsis.

22.8
34.4
25.0
(16.5-29.0) (22.0-44.9) (14.0-27.0)100(100-100)

6

CR
CRi

60

Constipation
Anemia

100
100%
77

8

b

0

Aza
No. of cycles,
median (range)

2

a

Sonro
160 mg× 10 d
(n=8)

ORRa
78%

 EAEs leading to death were pneumonia, neutropenic sepsis, bronchopulmonary aspergillosis, pulmonary sepsis, and metastatic squamous cell carcinoma; none were considered related to aza or sonro.
Taza, azacitidine; sonro, sonrotoclax.

Table 2. Treatment Exposure in TN Unfit AML
Sonro
40 mg
× 10 d(n=9)

Figure 4. Response Ratesa

Missing data for 2 patients (n=1, 160 mg x 10 day cohort; n=1, 160 mg x 28 day cohort). b No patients had IDH2-R172 abnormality.
AR, allelic ratio; aza, azacitidine; ITD, internal tandem duplication; sonro, sonrotoclax; TKD, tyrosine kinase domain.

••– Across dose cohorts, 3 DLTs of grade 4 neutropenia (n=1) and grade 4

TEAEs leading to reduction

Relative dose intensity (aza),
72.9
69.6
99.8
85.1
100.2
94.1
median (range), %(39.4-101.2) (37.2-100.4) (98.5-101.1) (57.2-100.2) (99.9-101.0) (44.3-100.2)

Safetypopulation/
all enrolled(n=48)On active
treatment(n=18; 38%)44 (92)

TEAEs leading to deatha

SafetyEfficacy evaluable
populationa(n=46)

Grade ≥3

patients with TN unfit AML

5 (56)RESULTS

40 mg x 10 d: n=980 mg x 10 d: n=1180 mg x 14 d: n=2

48 (100)aa

Patients with TN AML(N= 48)

Any TEAEs• Sonrotoclax + azacitidine combination treatment was generally well tolerated in

De novo

Positive genetic
abnormality, n (%)

Part 1Dose
escalation

All TN AML(N=48)

Patients, n (%)

All TNAML(N=48)

9.5(0.5-29.4)

Sonrotoclax (10, 14, 21, or 28 days in 28-day cycle with 4-day
ramp-up in cycle 1 starting at 1/8th of the target doseb)+
2
Azacitidine (75 mg/m for 7 days SC or IV)• AML (non-APL):• TN unfit for intensive
chemotherapy• No prior BCL2 inhibitor or
azacitidine exposure

|

Sonro
320 mg× 14 d(n=1)

AML risk stratification, n (%)aFigure 1. BGB-11417-103 Study Design

Nonhematologic DLT

Sonro
160 mg× 28 d(n=9)

AML type, n (%)-expansion study evaluating sonrotoclax ± azacitidine in patients with AML, MDS, or MDS/myeloproliferative
neoplasms (Figure 1)
The primary and key secondary endpoints were safety per CTCAE v5.0 and CR + CR with partial hematologic recovery(CRh) rate per the 2017 European LeukemiaNet criteria and partial hematology recovery criteria for AML
An exploratory objective was minimal residual disease (MRD) status, assessed by multiparameter flow cytometry(patients were MRD negative if 1 sample was below the cutoff [≤1 residual leukemic blasts per 1,000 leukocytes or 10-3]
at any time on the study)
Sonrotoclax was administered orally once daily for a limited duration with an initial 4-day ramp-up to mitigate potential
risk of tumor lysis syndrome (TLS), and azacitidine (75 mg/m2 for 7 days/cycle) was administered subcutaneously
or intravenously

|

Sonro
160 mg× 14 d(n=4)

Study follow-up, median(range), months• BGB-11417-103 (NCT04771130; EudraCT: 2021-003285-12) is an ongoing, global, multicenter, dose-finding and

•

Sonro
160 mg× 10 d(n=8)

Aza

METHODS
•
•

Sonro
80 mg
× 14 d(n=2)

Patients, %•••patients with AML unfit for intensive chemotherapy compared with azacitidine alone3; however, relapse is common andprognosis is suboptimal4,5
Sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, is more selective and a more pharmacologically potent inhibitorof BCL2 than venetoclax, with a shorter half-life and no accumulation6
In ongoing phase 1 studies, sonrotoclax has been well tolerated, with preliminary antitumor activity in B-cell malignancies,
AML/myelodysplastic syndromes (MDS), and multiple myeloma7-9Here, we present the preliminary safety and antileukemic activity of sonrotoclax + azacitidine in TN patients with unfit AML
in BGB-11417-103, a phase 1b/2 study

Sonro
80 mg
× 10 d(n=11)

CONCLUSIONS

Table 3. TEAE Summary

Patients, %INTRODUCTION

4 (44)

8 (73)

0Time to CR, median(range), months

1.3(1.3-1.8)

1.8(0.9-6.5)-

Duration of CR, median(95% CI), monthsb

NR(6.8-NE)

17.0(0.6-NE)

5 (56)

8 (73)

Time to CR/CRh, median(range), months

1.3(1.3-5.6)

Duration of CR/CRh,median (95% CI), monthsb

4 (50)

1 (50)

1.7(1.0-4.0)

0.8(0.8-0.8)

3.0(1.1-7.9)

2.1(2.1-2.1)

4.1(2.1-11.1)

1.8(0.8-11.1)-

NR(8.7-NE)NR(NE-NE)

8.0(4.4-NE)NR(NE-NE)

3.7(3.5-NE)

15.1(6.8-NE)0

5 (63)

1 (50)

5 (56)

1 (100)4 (100)29 (63)

1.4(0.9-4.4)-

1.2(1.0-4.0)

0.8(0.8-0.8)

1.2(1.1-4.9)

2.1(2.1-2.1)

4.1(2.1-9.7)

1.3(0.8-9.7)

NR(6.8-NE)

17.9(0.6-NE)-NR(8.7-NE)NR(NE-NE)

8.7(4.4-NE)NR(NE-NE)

3.8(3.5-NE)

16.9(7.5-NE)

6 (67)

8 (73)

0

6 (75)

1 (50)

6 (67)

1 (100)4 (100)32 (70)Time to CR/CRi, median(range), months

1.3(1.1-5.6)

1.4(0.9-4.4)-

1.1(1.0-4.0)

0.8(0.8-0.8)

1.5(1.1-4.9)

2.1(2.1-2.1)

1.8(1.7-2.1)

1.3(0.8-5.6)

Duration of CR/CRi,
median (95% CI), monthsb

NR(6.8-NE)

17.9(0.6-NE)-NR(6.7-NE)NR(NE-NE)

7.0(4.0-NE)NR(NE-NE)NR(3.8-NE)

16.9(6.8-NE)

CR/CRh, n (%)

CR/CRi, n (%)

Responses were determined using the 2017 European LeukemiaNet criteria and partial hematology recovery criteria for AML. b Medians were estimated using the Kaplan-Meier method, with 95% CIs
estimated using the Brookmeyer and Crowley method with log-log transformation.
aza, azacitidine; CRh, CR with partial hematologic recovery; CRi, CR with incomplete hematologic recovery; NE, not estimable, NR, not reached; sonro, sonrotoclax.

a

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1.

Shimony S, et al. Am J Hematol. 2023;98(3):502-526.

6.

Hu N, et al. AACR 2020. Abstract 3077.

2.

Yi M, et al. J Hematol Oncol. 2020;13(1):72.

7.

Li C, et al. ASCO 2023. Abstract 7558.

3.

DiNardo CD, et al. N Engl J Med. 2020;383(7):617-629.

8.

Shortt J, et al. ASH 2022. Abstract 1443.

4.

Thol F, Ganser A. Curr Treat Options Oncol. 2020:21(8):66.

9.

Quach H, et al. ASH 2023. Abstract 1011.

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Greiner J, et al. Int J Mol Sci. 2022:23(6):3304.

DISCLOSURES
JS: Consulting/advisory: BMS, Astellas, Otsuka; Research funding: Astex; Speaker’s bureau: Novartis, Mundipharma. SL: Consulting or advisory role: BeiGene.
JM-CL: Travel, accommodations, or expenses: Janssen. CYF: Consulting or advisory role: AbbVie, Novotech, Adaptive, Amgen, Servier, Pfizer, Otsuka, Celgene, Jazz,
Astellas; Research funding: Astellas, Jazz; Speakers bureau: AbbVie, Amgen, Pfizer; Travel, accommodations, or expenses: Gilead/Kite. PM: Consultancy: Astellas, Agios,
Tolero Pharmaceutical, Glycomimetics, Forma Therapeutics, BMS/Celgene, Daiichi Sankyo; Research funding: AbbVie, Astellas, BMS/Celgene, Daiichi Sankyo, Janssen,
Karyopharm, Novartis, Pfizer, Teva; Speakers bureau: AbbVie, Astellas, BMS/Celegene, Daiichi Sankyo, Incyte, Janssen, Novartis, Pfizer, Sanofi, Servier, Teva.
CD: Honoraria: Daiichi Sankyo, Astellas, Gilead, Loxo; Consulting or advisory role: GSK, Rigel, AbbVie, GenMab, AstraZeneca, Servier, Schrodinger; Research funding:
AbbVie, BMS, Loxo, Astex, Schrodinger, BeiGene, Foghorn. WYC: Employment: BeiGene; Stock or other ownership: BeiGene, BMS. AHW: Consultancy: Servier, BeiGene,
AbbVie, Novartis; Research funding: Novartis, AbbVie, Servier, Janssen, BMS, Syndax, Astex, AstraZeneca, Amgen; Honoraria: Novartis, AstraZeneca, Astellas, Janssen,
Amgen, Roche, Pfizer, AbbVie, Servier, Gilead, BMS, Shoreline, Macrogenics, Agios; Patents and royalties: Servier; Speaker’s bureau: AbbVie, Novartis, BMS, Servier,
Astellas; Travel, accommodations, or expenses: Novartis, Servier. JZ, RL, OZ, AA: Current employment and current equity holder in publicly traded company: BeiGene.
SYT, SR, QL: Nothing to disclose.

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 supported by BeiGene. Medical writing was provided by Kendall Foote, PhD, of Nucleus Global, an Inizio company, and supported by BeiGene.

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