ANTI-TIM-3 ANTIBODY MBG453 IN COMBINATION WITH HYPOMETHYLATING AGENTS (HMAS) IN PATIENTS (PTS) WITH HIGH-RISK MYELODYSPLASTIC SYNDROME (HR-MDS) AND ACUTE MYELOID LEUKEMIA (AML): A PHASE 1 STUDY
Author(s): ,
Uma Borate
Affiliations:
Oregon Health & Science University,Portland,United States
,
Jordi Esteve
Affiliations:
Hospital Clínic,Barcelona,Spain
,
Kimmo Porkka
Affiliations:
Helsinki University Hospital Comprehensive Cancer Center,Helsinki,Finland
,
Steve Knapper
Affiliations:
Cardiff University,Cardiff,United Kingdom
,
Nobert Vey
Affiliations:
Institut Paoli-Calmettes,Marseilles,France
,
Sebastian Scholl
Affiliations:
University Hospital Jena,Jena,Germany
,
Guillermo Garcia-Manero
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Martin Wermke
Affiliations:
University Hospital Dresden,Dresden,Germany
,
Jeroen Janssen
Affiliations:
Amsterdam University Medical Centers, VUmc,Amsterdam,Netherlands
,
Elie Traer
Affiliations:
Oregon Health & Science University,Portland,United States
,
Chong Chyn Chua
Affiliations:
The Alfred Hospital and Monash University,Melbourne,Australia
,
Rupa Narayan
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Natalia Tovar
Affiliations:
Hospital Clínic,Barcelona,Spain
,
Mika Kontro
Affiliations:
Helsinki University Hospital Comprehensive Cancer Center,Helsinki,Finland
,
Oliver Ottmann
Affiliations:
Cardiff University,Cardiff,United Kingdom
,
Siyan Xu
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,United States
,
Haiying Sun
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
,
Purushotham Naidu
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
,
Tyler Longmire
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,United States
,
Sebastian Szpakowski
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,United States
,
Serena Liao
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,United States
,
Anisa Mohammed
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
,
Mikael L. Rinne
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,United States
,
Andrew Brunner
Affiliations:
Massachusetts General Hospital,Boston,United States
Andrew H. Wei
Affiliations:
The Alfred Hospital and Monash University,Melbourne,Australia
EHA Library. Borate U. 06/12/20; 295005; S185
Dr. Uma Borate
Dr. Uma Borate
Contributions
Abstract

Abstract: S185

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Novel treatments for MDS II

Background

MBG453 is a high-affinity, humanized, anti-TIM-3 IgG4 antibody being developed for treatment of MDS and AML. TIM-3, an immune checkpoint expressed on multiple immune cell types, has a complex role in regulating adaptive and innate immunity. TIM-3 is also expressed on leukemic stem cells (LSCs) and blasts, but not on normal hematopoietic stem cells, making it a promising target in MDS/AML. MBG453 enhances immune cell-mediated killing of AML cells in vitro and may target TIM-3 on both immune cells and LSCs.

Aims

A multicenter, open-label, phase 1b dose-escalation study to evaluate MBG453 combined with decitabine (Dec) or azacitidine (Aza) in pts with HR-MDS or AML (NCT03066648).

Methods
Pts with high or very high-risk MDS (per IPSS-R) and newly diagnosed (ND) or relapsed/refractory (R/R; after ≥1 prior therapy; MBG453+Dec arm only) AML were eligible if they were HMA naive and not candidates for intensive chemotherapy. Escalating doses of MBG453 were administered IV at 240 or 400mg Q2W (D8, D22) or 800mg Q4W (D8), combined with Dec (20mg/m2 IV D1–5) or Aza (75mg/m2 SC or IV D1–7) every 28 days. Primary objectives were safety/tolerability; secondary objectives included PK and preliminary efficacy (IWG response). 

Results
69 pts (median age 71y) with HR-MDS (n=19) or AML (n=50) received MBG453+Dec (data cutoff 27Nov2019) and 29 pts (median age 74y) with HR-MDS (n=13) or AML (n=16) received MBG453+Aza (data cutoff 14Jan2020). MTD was not reached for either combination. One DLT occurred with MBG453+Dec (at 240mg Q2W): a corticosteroid-responsive Gr 3 ALT elevation. No DLTs occurred with MBG453+Aza. Median (range) exposure duration was 4.9 (0.7–26.7) mo for MBG453+Dec with 15 pts ongoing, and 3.0 (0.1–9.2) mo for MBG453+Aza with 19 pts ongoing.

Both combinations were well tolerated. With MBG453+Dec and MBG453+Aza, respectively, most common Gr 3/4 treatment-emergent (TE) AEs were thrombocytopenia (41%; 52%), febrile neutropenia (46%; 21%), neutropenia (42%; 38%), and anemia (25%; 28%). For MBG453+Dec, only 4 pts (6%; 3 AML, 1 MDS) experienced ≥1 potentially immune-related (IR) Gr ≥3 AE reported as being related to study treatment (ALT increase, arthritis, hepatitis, hypothyroidism, rash). For MBG453+Aza, no pt experienced treatment-related Gr ≥3 potential IRAEs. No treatment-related Gr 4 IRAEs or deaths were seen with either combination.

For MBG453+Dec, ORR among evaluable pts was 58% (11/19) for HR-MDS (5 CR, 4 mCR of whom 3 had hematologic improvement [HI], 2 HI), 41% (7/17) for ND-AML (4 CR, 1 CRi, 2 PR), and 24% (6/25) for R/R-AML (6 CRi). Median (range) exposure duration among responders was 8.6 (2.0–26.7) mo. For MBG453+Aza, with relatively short follow-up (median exposure duration, 3.0 mo), ORR among evaluable pts was 70% (7/10) for HR-MDS (6 mCR of whom 3 had HI, 1 PR) and 27% (3/11) for ND-AML (1 CR, 2 PR). Responses were observed across all 3 MBG453 doses with both combinations. Based on PK/PD modeling, MBG453 400mg Q2W and 800mg Q4W were predicted to have similar average steady state PK concentrations and similarly high receptor occupancy rates (>95% occupancy in 95% of pts). Updated response/safety data for both combinations will be presented.

Conclusion
MBG453 combined with Dec or Aza was safe and well tolerated in pts with HR-MDS and AML, with the most common TEAEs consistent with that for single-agent HMA. Both combinations showed antileukemic activity with encouraging response rates and emerging durability, supporting further development of MBG453 combined with HMAs in MDS/AML. (A Brunner & AH Wei contributed equally)

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Acute myeloid leukemia, Clinical trial, Immunotherapy, Myelodysplasia

Abstract: S185

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Novel treatments for MDS II

Background

MBG453 is a high-affinity, humanized, anti-TIM-3 IgG4 antibody being developed for treatment of MDS and AML. TIM-3, an immune checkpoint expressed on multiple immune cell types, has a complex role in regulating adaptive and innate immunity. TIM-3 is also expressed on leukemic stem cells (LSCs) and blasts, but not on normal hematopoietic stem cells, making it a promising target in MDS/AML. MBG453 enhances immune cell-mediated killing of AML cells in vitro and may target TIM-3 on both immune cells and LSCs.

Aims

A multicenter, open-label, phase 1b dose-escalation study to evaluate MBG453 combined with decitabine (Dec) or azacitidine (Aza) in pts with HR-MDS or AML (NCT03066648).

Methods
Pts with high or very high-risk MDS (per IPSS-R) and newly diagnosed (ND) or relapsed/refractory (R/R; after ≥1 prior therapy; MBG453+Dec arm only) AML were eligible if they were HMA naive and not candidates for intensive chemotherapy. Escalating doses of MBG453 were administered IV at 240 or 400mg Q2W (D8, D22) or 800mg Q4W (D8), combined with Dec (20mg/m2 IV D1–5) or Aza (75mg/m2 SC or IV D1–7) every 28 days. Primary objectives were safety/tolerability; secondary objectives included PK and preliminary efficacy (IWG response). 

Results
69 pts (median age 71y) with HR-MDS (n=19) or AML (n=50) received MBG453+Dec (data cutoff 27Nov2019) and 29 pts (median age 74y) with HR-MDS (n=13) or AML (n=16) received MBG453+Aza (data cutoff 14Jan2020). MTD was not reached for either combination. One DLT occurred with MBG453+Dec (at 240mg Q2W): a corticosteroid-responsive Gr 3 ALT elevation. No DLTs occurred with MBG453+Aza. Median (range) exposure duration was 4.9 (0.7–26.7) mo for MBG453+Dec with 15 pts ongoing, and 3.0 (0.1–9.2) mo for MBG453+Aza with 19 pts ongoing.

Both combinations were well tolerated. With MBG453+Dec and MBG453+Aza, respectively, most common Gr 3/4 treatment-emergent (TE) AEs were thrombocytopenia (41%; 52%), febrile neutropenia (46%; 21%), neutropenia (42%; 38%), and anemia (25%; 28%). For MBG453+Dec, only 4 pts (6%; 3 AML, 1 MDS) experienced ≥1 potentially immune-related (IR) Gr ≥3 AE reported as being related to study treatment (ALT increase, arthritis, hepatitis, hypothyroidism, rash). For MBG453+Aza, no pt experienced treatment-related Gr ≥3 potential IRAEs. No treatment-related Gr 4 IRAEs or deaths were seen with either combination.

For MBG453+Dec, ORR among evaluable pts was 58% (11/19) for HR-MDS (5 CR, 4 mCR of whom 3 had hematologic improvement [HI], 2 HI), 41% (7/17) for ND-AML (4 CR, 1 CRi, 2 PR), and 24% (6/25) for R/R-AML (6 CRi). Median (range) exposure duration among responders was 8.6 (2.0–26.7) mo. For MBG453+Aza, with relatively short follow-up (median exposure duration, 3.0 mo), ORR among evaluable pts was 70% (7/10) for HR-MDS (6 mCR of whom 3 had HI, 1 PR) and 27% (3/11) for ND-AML (1 CR, 2 PR). Responses were observed across all 3 MBG453 doses with both combinations. Based on PK/PD modeling, MBG453 400mg Q2W and 800mg Q4W were predicted to have similar average steady state PK concentrations and similarly high receptor occupancy rates (>95% occupancy in 95% of pts). Updated response/safety data for both combinations will be presented.

Conclusion
MBG453 combined with Dec or Aza was safe and well tolerated in pts with HR-MDS and AML, with the most common TEAEs consistent with that for single-agent HMA. Both combinations showed antileukemic activity with encouraging response rates and emerging durability, supporting further development of MBG453 combined with HMAs in MDS/AML. (A Brunner & AH Wei contributed equally)

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Acute myeloid leukemia, Clinical trial, Immunotherapy, Myelodysplasia

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