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

P562

Pau Montesinos,1 Paul Cannell,2 Jake Shortt,3 Teng Fong Ng,4 David M. Swoboda,5 Sophie Leitch,6 Chun Yew Fong,7 Uwe Platzbecker,8 Andrew H. Wei,9 Si Cheng,10 Adam Greenbaum,11 Yu Liu,12 Kendra Sweet,11 Amit Agarwal,11 Courtney DiNardo13
Hospital Universitari I Politècnic La Fe, Valencia, Spain; 2Fiona Stanley Hospital, Murdoch, WA, Australia; 3Monash Health and Monash University, Clayton, VIC, Australia; 4Gold Coast University Hospital and Griffith University, Queensland, Australia; 5Tampa General Hospital, Tampa, FL, USA; 6Te Whatu Ora, Health New Zealand, Waitemata, Auckland, New Zealand;
7
Austin Health, Melbourne, VIC, Australia; 8Universitaetsklinikum Leipzig Aör, Leipzig, Germany; 9Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Melbourne, VIC, Australia; 10BeiGene (Shanghai) Co, Ltd, Shanghai, China; 11BeiGene USA, Inc, San Mateo, CA, USA; 12BeiGene (Beijing) Co, Ltd, Beijing, China; 13MD Anderson Cancer Center, Houston, TX, USA
1

INTRODUCTION

Sonro
40 mg
× 10 d(n=7)• Acute myeloid leukemia (AML) is the most common acute form of leukemia in adults and has

an aggressive disease course1,2
Although treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax has improved
outcomes in some patients with newly diagnosed AML,3 venetoclax is not approved inrelapsed/refractory (R/R) AML4
Sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, is more selective and a more
pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and noaccumulation5
Here, we present the preliminary safety and antileukemic activity of sonrotoclax + azacitidine
in R/R AML in BGB-11417-103, a phase 1b/2 study•• The most common TEAE class leading to treatment discontinuation was infections andTable 1. Baseline Patient Characteristics
Sonro
80 mg
× 10 d(n=6)

Sonro Sonro Sonro Sonro Sonro Sonro Sonro
All R/R
80 mg 160 mg 160 mg 160 mg 160 mg 320 mg 320 mg
AML
× 14 d × 10 d × 14 d × 21 d × 28 d × 14 d × 21 d
(N=51)
(n=6)
(n=4)
(n=2)
(n=8)
(n=3)
(n=6)
(n=9)
Aza
5.8
(4.6-7.1)

4.9
3.8
7.4
5.8
(1.2-21.8) (1.0-7.6) (2.6-12.2) (0.2-31.7)

70.0(54-78)

57.5(52-70)52.5(36-71)

54.0(27-67)

53.0(42-66)

57.0(29-69)66.5(44-74)70.0(67-73)60.0(27-80)3 (43)

3 (50)

2 (50)

5 (63)

2 (67)

4 (67)

6 (67)

3 (50)

1 (50)

29 (57)• BGB-11417-103 (NCT04771130; EudraCT: 2021-003285-12) is an ongoing, global, multicenter,

De novo

7 (100)4 (67)

2 (50)

7 (88)

1 (33)

6 (100)8 (89)

6 (100)1 (50)

42 (82)

Secondary0

2 (33)

2 (50)

1 (13)

2 (67)0

1 (11)0

1 (50)

9 (18)

Table 3. TEAE Summary•

HMA failure, n (%)

00

1 (25)

1 (13)

1 (33)

1 (17)

1 (11)

1 (17)

1 (50)

7 (14)

Patients, n (%)•

METHODS

Figure 1. BGB-11417-103 Study Design
Eligibility criteria

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 dosec)+
Azacitidine (75 mg/m 2 for 7 days SC or IV)• AML (non-APL):• R/R with no prior BCL2 inhibitoror azacitidine exposure• HMA-failurea with no prior BCL2
inhibitor exposure• ECOG PS 0-2• Not receiving warfarin; moderate orstrong CYP3A4 inhibitor or inducer
within 5 half-lives

Part 1Dose
escalation|

Hematologic DLT
Nonhematologic DLTFirst dose

≈10 patients≈20 patients(R/R AML)

Sonrotoclax dose: RR AML|

40 mg × 10 days
80 mg × 10 days|

D28

Part 3
Efficacy
expansion dPart 2
Safetyexpansion d

3-6
patients

DLT observation window|

Age, median (range), years

64.0(36-80)Male sex, n (%)
AML type, n (%)

dose-finding and -expansion study evaluating sonrotoclax ± azacitidine in patients with AML,
myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasms (Figure 1)
The primary and key secondary endpoints were safety per CTCAE v5.0 and CR + CR withpartial hematologic recovery (CRh) rate per the 2017 European LeukemiaNet criteria and partial
hematology recovery criteria for AML
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

•

15.4
19.9
(9.2-30.1) (1.5-31.7)

•

0.9
6.8
1.7
(0.7-2.1) (0.2-24.5) (1.5-1.7)•

Study follow-up, median(range), months•

infestations (azacitidine, n=4; sonrotoclax, n=4)
The most common TEAEs leading to dose reduction were neutropenia (sonrotoclax reduction,n=5) and neutrophil count decreased (azacitidine reduction, n=1)
Six patients had a TEAE leading to death; the 30-day mortality rate was 2%– Two of these TEAEs were considered related to sonrotoclax, azacitidine, and disease(neutropenic sepsis [160 mg x 28 day], pneumonia [320 mg x 14 day])– Two TEAEs leading to death were related to PD (pulmonary mucormycosis [160 mg x 14 day],bone marrow failure [160 mg x 28 day])– The TEAEs of aorto-bronchial fistula (160 mg x 28 day) and Klebsiella sepsis (160 mg x 10 day)leading to death were not related to treatment or disease
One DLT (grade 4 thrombocytopenia) occurred in the azacitidine + sonrotoclax 320 mg x 14 day cohort
No cases of laboratory or clinical TLS were reported

160 mg × 10 days
160 mg × 28 days

320 mg × 21 days
320 mg × 28 days

Intermediate doses
80 mg × 14 days
160 mg × 14 days
160 mg × 21 days

D42b

320 mg × 14 days

HMA failure received ≥1 cycle of HMA and had PD or no PR or better hematologic improvement after 4 cycles of >75% of planned dose. b Or cycle 2
initiation. c As a precautionary measure for TLS monitoring, patients were hospitalized during the ramp-up period. d 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.

••

AML risk stratification, n (%)
Favorable

1 (14)

1 (17)0

1 (13)

00

2 (22)00

5 (10)

Intermediate

3 (43)

1 (17)

2 (50)

4 (50)

0

2 (33)

2 (22)00

14 (27)Adverse3 (43)

4 (67)

2 (50)

3 (38)

3 (100)4 (67)

5 (56)

6 (100)2 (100)32 (63)

Positive genetic
abnormality, n (%)

6 (86)

5 (83)

2 (50)

7 (88)

2 (67)

5 (83)

7 (78)

5 (83)

2 (100)41 (80)NPM1

2 (29)TP53 aneuploidy

1 (17)00

0

2 (25)

1 (25)000

0

3 (33)

1 (17)

1 (17)0

1 (17)0
1 (50)

50 (98)Grade ≥3

45 (88)Serious TEAEs

37 (73)

TEAEs leading to deatha

6 (12)

1 (17)

0

0

0

0

0

0

0

2 (4)

−7 or del(7q)1 (14)

00

2 (25)0

1 (17)

2 (22)

00

6 (12)IDH1

0

2 (33)

0

2 (25)

00

1 (11)

1 (17)

0

IDH2 R172

1 (14)

1 (17)0

1 (13)0

1 (17)

2 (22)

0

FLT3-ITD high AR

0

0

0

0

0

0

0

FLT3-ITD low AR

0

1 (17)0

1 (13)0

1 (17)

FLT3-TKD

00

1 (25)

00−5 or del(5q)0

1 (17)0

1 (13)

0Aza

320 mg cohorts to determine the recommended phase 2 dose

Table 4. Summary of Disease Responsesa
Sonro
40 mg
× 10 d
(n=7)

Sonro

7 (14)

TEAEs leading to reduction
1 (2)

6 (12)Sonro

7 (14)0

6 (12)

TEAEs leading to interruption

1 (17)

1 (50)

2 (4)

Aza

3 (6)

0

0

0

3 (6)

Sonro

5 (10)0

1 (11)

0

0

2 (4)

1 (17)

0

0

0

3 (6)

• As of March 31, 2024, a total of 51 patients with R/R AML were enrolled and had received•••

sonrotoclax + azacitidine treatment and 4 (8%) remain on treatment (Figure 2)
In all patients with R/R AML, the median age was 60 years and the median number of prior lines oftherapy was 2 (Table 1)
The median number of treatment cycles was 2, with the longest average cycle duration(median, 42.3 days) in the azacitidine + sonrotoclax 320 mg x 21 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 21 day cohort

No. of lines of priorsystemic therapy,
median (range)

1.0 (1-2)0
1.0 (1-2)

1 (25)
1.5 (1-2)0

1 (33)

1 (17)

1 (11)

2.0 (1-2) 2.0 (1-2) 2.0 (1-6)

2 (33)

1.0 (1-3)

2.0 (1-3)

1 (50)
1.5 (1-2)

7 (14)
2.0 (1-6)

TEAEs leading to death were aorto-bronchial fistula, bone marrow failure, Klebsiella sepsis, neutropenic sepsis (related to aza and sonro), pneumonia (related toaza and sonro), and pulmonary mucormycosis.
aza, azacitidine; sonro, sonrotoclax.

AR, allelic ratio; aza, azacitidine; ITD, internal tandem duplication; sonro, sonrotoclax; TKD, tyrosine kinase domain.

Sonro
40 mg
× 10 d
(n=7)

Sonro
80 mg
× 10 d
(n=6)

Sonro
80 mg
× 14 d(n=4)

Sonro
160 mg× 10 d(n=8)

Sonro
160 mg× 14 d(n=3)

Sonro
160 mg× 21 d(n=6)

Sonro
160 mg× 28 d
(n=9)

Sonro
Sonro
320 mg 320 mg
× 21 d× 14 d(n=6)(n=2)

Figure 2. Patient Disposition
Patients with R/R AML(N=51)
40 mg x 10 d: n=780 mg x 10 d: n=680 mg x 14 d: n=4

160 mg x 10 d: n=8160 mg x 14 d: n=3
160 mg x 21 d: n=6

Efficacy evaluable
populationa(n=50)

160 mg x 28 d: n=9
320 mg x 14 d: n=6
320 mg x 21 d: n=2

Safetypopulation/
all enrolled(n=51)On active
treatment(n=4; 8%)

Off treatment (n=47; 92%)
• Disease progressionb (n=15)• Proceed to transplant (n=10)• Adverse event (n=6)• Patient withdrawal (n=6)• Investigator decision (n=4)• Relapsec (n=4)• Start of new anticancer therapy (n=1)• Other (n=1)

Data cutoff: March 31, 2024. a 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. b Defined as evidence for an increase inbone marrow blast percentage and/or increase in absolute blast counts in the blood, both per ELN2017 response criteria. c Hematologic relapse(after CR/CRi) defined as bone marrow blasts ≥5%, reappearance of blasts in the blood, or development of extramedullary disease.
CRi, CR with incomplete hematologic recovery; ELN, European LeukemiaNet.

No. of cycles,
median (range)

2.0
10.5
(2.0-15.0) (1.0-28.0)

1.0(1.0-1.0)

2.5(1.0-20.0)

1.0(1.0-2.0)

2.0(1.0-7.0)

2.0(1.0-4.0)

2.0(1.0-5.0)

3.5(1.0-6.0)

Average cycle
duration, median(range), days

34.5
(29.541.5)

32.7(21.040.9)

26.5(22.044.0)

35.0(5.048.7)

34.0(23.044.0)

36.8(25.053.0)

35.0(25.355.0)

40.7(26.546.0)

42.3(35.749.0)

35.0(5.055.0)

Relative dose
intensity (sonro),
median (range), %97.4(26.0100)81.1(57.0112.7)

100(100100)100(33.9100)

100(90.9100)79.6(54.9100)84.6(22.0156.0)

81.1(47.2100)82.1(64.3100)97.4(22.0156.0)

Relative dose
intensity (aza),
median (range), %100(52.3100.3)

87.4(45.8101.0)

100.2(99.8101.5)

99.8(73.0101.1)

100(85.2100.0)

99.5(64.9103.4)

100(69.9100.9)

99.8(60.5100.3)

92.7(84.3101.1)

99.9(45.8103.4)

429

Pyrexia2.0(1.0-28.0)

62 (33)

2 (22)00

12 (24)

Time to CR, median(range), months

3.2
4.1
0.8
3.2
(1.5-4.9) (3.7-4.6) (0.8-0.8) (1.9-4.4)-

1.4(0.9-1.9)

1.3(1.1-1.4)

-

-

1.9
(0.8-4.9)

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

7.7(2.3-NE)

18.0(1.9-NE)NR
20.5(NE-NE) (NE-NE)

-

0.1
NR
(NE-NE) (NE-NE)

-

-

13.1
(0.1-20.5)

CR/CRh, n (%)

5 (71)

4 (67)

1 (33)

3 (38)

0

2 (33)

3 (33)

2 (33)

1 (50)

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

2.4(1.2-3.5)

3.9(1.1-4.6)

0.8(0.8-0.8)

1.9(1.0-1.9)-

1.4(0.9-1.9)

1.1(0.8-1.4)

1.9(1.3-2.4)

7.7(7.7-7.7)

1.9(0.8-7.7)

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

8.6(4.0-NE)

18.0(1.9-NE)NR
20.5(NE-NE) (NE-NE)-

NR(NE-NE)NR(0.1-NE)

4.0
NR
13.1
(NE-NE) (NE-NE) (1.9-20.5)

CR/CRi, n (%)

4 (57)

4 (67)

1 (33)

3 (38)

0

2 (33)

3 (33)

3 (50)

1 (50)

21 (42)Time to CR/CRi, median(range), months

2.0(1.2-3.2)

3.0(1.1-4.1)0.8
1.0(0.8-0.8) (0.8-1.9)-

1.4(0.9-1.9)

1.1(0.8-1.4)

1.2(0.9-1.3)

7.7(7.7-7.7)

1.3(0.8-7.7)

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

8.6(4.0-NE)

18.0(1.9-NE)NR
20.5(NE-NE) (NE-NE)-

NR(NE-NE)NR(0.1-NE)

4.0(0.1-NE)NR
13.1(NE-NE) (1.9-20.5)

31

Hypokalemia
Diarrhea

24
18

60
60%

10

Grade 1/2

26

Grade ≥3

CR

12

40
40%

0
0%

20

ORRa
54%

CRi
MLFS

28

20
20%

SD
PD

12
6

NE/ND

Patients with R/R AML
Efficacy-evaluable population(N=50)ORR included CR, CRi, MLFS, and PR.
CRi, CR with incomplete hematologic recovery; MLFS, morphologic leukemia-free state; ND, not done; NE, not evaluable.
aConstipation

26

Sepsisc

REFERENCES

18
0

10

20

30
40
Patients, %50

60

aza, azacitidine; sonro, sonrotoclax.

Neutropenia includes the terms neutropenia and neutrophil count decreased. b Thrombocytopenia includes the terms thrombocytopenia and platelet
count decreased. c Sepsis is a grouped term excluding fungal sepsis.

Safety• An overall summary of TEAEs in patients with R/R AML is shown in Table 3• The most common any-grade TEAEs were neutropenia (including neutrophil count decreased),

Antileukemic Activity• CR/CRh was achieved in 42% of patients by a median time to CR/CRh of 1.9 months (Table 4)– The median duration of response was 13.1 months for CR (median follow-up, 20.8 months),

thrombocytopenia (including platelet count decreased), and nausea (Figure 3)– Neutropenia was the most common grade ≥3 TEAE and grade ≥3 infections and infestations
occurred in 24 patients (47%)

0

80
80%

37

Vomiting

1 (33)

Responses were determined using the 2017 European LeukemiaNet criteria and partial hematology recovery criteria for AML. b Medians were estimatedusing 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.

33

Febrile neutropenia

Aza

2 (25)45

43 (50)

100
100%

41

AnemiaAll R/R
AML(N=51)

2 (29)

59

NauseaTable 2. Treatment Exposure in R/R AML

CR, n (%)

Figure 4. Response Rates

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

Thrombocytopeniab 2

Sonro Sonro Sonro Sonro Sonro Sonro Sonro
All R/R
80 mg 160 mg 160 mg 160 mg 160 mg 320 mg 320 mg
AML
× 14 d × 10 d × 14 d × 21 d × 28 d × 14 d × 21 d
(N=50)
(n=6)
(n=3)
(n=2)
(n=8)
(n=3)
(n=6)
(n=9)

a

a

Neutropeniaa

Sonro
80 mg
× 10 d(n=6)

Aza

Patients, %RESULTS0with R/R AML in all dose cohorts– The ORR was 54%, of which CR was achieved by 24% and CR/CRh
by 42%, and the transplant rate was 20%• The study stopping criteria has not been met in any of the dose cohorts• Safety expansion of x 14-day dosing is ongoing in 80 mg, 160 mg, anda

Prior aza exposure, n (%)• Sonrotoclax + azacitidine demonstrated antileukemic activity in patients

7 (14)

Aza

Prior therapy

well tolerated in patients with R/R AML without prior BCL2 inhibitor
exposure– Across dose cohorts, 1 DLT of grade 4 thrombocytopenia occurred

TEAEs leading to discontinuation

4 (8)

1 (14)• Sonrotoclax + azacitidine combination treatment was generally

All R/R AML(N=51)

Any TEAEs

9 (18)−17/abn(17p); TP53
abnormality

CONCLUSIONSa•

CR/CRh (median follow-up, 3.5 months), and CR/CR with incomplete hematologic recovery(CRi; median follow-up, 3.5 months)
The ORR was 54% in patients with R/R AML (Figure 4)

70

1.
2.
3.

Shimony S, et al. Am J Hematol. 2023;98(3):502-526.
Yi M, et al. J Hematol Oncol. 2020;13(1):72.
Bazarbachi A. Bone Marrow Transplant. 2022;57(2):147-148.

4.
5.

Venetoclax. Prescribing information. AbbVie, Inc. 2022.
Hu N, et al. AACR 2020. Abstract 3077.

DISCLOSURES

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/Celgene, Daiichi Sankyo, Incyte, Janssen, Novartis, Pfizer, Sanofi, Servier, Teva. JS: Consulting/advisory: BMS, Astellas, Otsuka;
Research funding: Astex; Speakers bureau: Novartis, Mundipharma. TFN: Travel, accommodations, or expenses: Janssen, Novartis, Sobi. DMS: Consulting or advisory role: AbbVie, Astellas, Boston Gene,
BMS, Daiichi Sankyo, MorphoSys, Sellas; Speakers bureau: BMS, GSK, ThermoFisher, Servier. SL: Consulting or advisory role: BeiGene. 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. UP: Honoraria:
Novartis, BMS, Janssen, AbbVie, Curis, Geron, Jazz, Akeso, Gilead, Servier; Consulting or advisory role: AbbVie, BMS, Janssen, Novartis, GSK, Hemavant; Speakers bureau: Novartis, BMS, Janssen,
Jazz, Takeda, Sobi, Blueprint, AstraZeneca; Travel, accommodations, or expenses: AbbVie, Janssen. 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, Macrogenic, Agios; Patents androyalties: Servier; Speakers bureau: AbbVie, Novartis, BMS, Servier, Astellas; Travel, accommodations, or expenses: Novartis, Servier. AG: Employment: BeiGene, ICON (self), Adaptive Biotechnologies,
Notch Therapeutics (spouse); Stock or other ownership: BeiGene (self), Adaptive Biotechnologies (spouse). KS: Employment: BeiGene; Research funding: Incyte, Jazz; Consulting role: Nkarta, Jazz;
Honoraria and travel expenses: BMS; Expert testimony: Nelson and Mullins; Data safety monitoring board: Karyopharm; Stock or stock options: BeiGene. 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. SC, YL, AA: Current
employment and current equity holder in publicly traded company: BeiGene. PC: 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