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TOLERABILITY AND EFFICACY OF THE FIRST-IN-CLASS ANTI-CD47 ANTIBODY MAGROLIMAB COMBINED WITH AZACITIDINE IN FRONTLINE PATIENTS WITH TP53-MUTATED ACUTE MYELOID LEUKEMIA: PHASE 1B RESULTS
Author(s): ,
Naval G Daver
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,États-unis;The University of Texas MD Anderson Cancer Center,Houston,Vereinigte Staaten;The University of Texas MD Anderson Cancer Center,Houston,Stati Uniti;The University of Texas MD Anderson Cancer Center,Houston,United States;The University of Texas MD Anderson Cancer Center,Houston,Estados Unidos;The University of Texas MD Anderson Can
,
Paresh Vyas
Affiliations:
University of Oxford,Oxford,Royaume-uni;University of Oxford,Oxford,Vereinigtes Königreich;University of Oxford,Oxford,Regno Unito;University of Oxford,Oxford,United Kingdom;University of Oxford,Oxford,Reino Unido;University of Oxford,Oxford,Verenigd Koninkrijk;University of Oxford,Oxford,Reino Unido;University of Oxford,Oxford,Соединённое Королевство;University of Oxford,Oxford,Storbritannien
,
Suman Kambhampati
Affiliations:
Healthcare Midwest,Kansas City,États-unis;Healthcare Midwest,Kansas City,Vereinigte Staaten;Healthcare Midwest,Kansas City,Stati Uniti;Healthcare Midwest,Kansas City,United States;Healthcare Midwest,Kansas City,Estados Unidos;Healthcare Midwest,Kansas City,Verenigde Staten;Healthcare Midwest,Kansas City,Estados Unidos;Healthcare Midwest,Kansas City,United States;Healthcare Midwest,Kansas City,USA
,
Monzr M Al Malki
Affiliations:
City of Hope National Medical Center,Duarte,États-unis;City of Hope National Medical Center,Duarte,Vereinigte Staaten;City of Hope National Medical Center,Duarte,Stati Uniti;City of Hope National Medical Center,Duarte,United States;City of Hope National Medical Center,Duarte,Estados Unidos;City of Hope National Medical Center,Duarte,Verenigde Staten;City of Hope National Medical Center,Duarte,Esta
,
Richard Larson
Affiliations:
University of Chicago,Chicago,États-unis;University of Chicago,Chicago,Vereinigte Staaten;University of Chicago,Chicago,Stati Uniti;University of Chicago,Chicago,United States;University of Chicago,Chicago,Estados Unidos;University of Chicago,Chicago,Verenigde Staten;University of Chicago,Chicago,Estados Unidos;University of Chicago,Chicago,United States;University of Chicago,Chicago,USA
,
Adam Asch
Affiliations:
University of Oklahoma,Oklahoma City,États-unis;University of Oklahoma,Oklahoma City,Vereinigte Staaten;University of Oklahoma,Oklahoma City,Stati Uniti;University of Oklahoma,Oklahoma City,United States;University of Oklahoma,Oklahoma City,Estados Unidos;University of Oklahoma,Oklahoma City,Verenigde Staten;University of Oklahoma,Oklahoma City,Estados Unidos;University of Oklahoma,Oklahoma City,U
,
Gabriel Mannis
Affiliations:
Stanford University,Stanford,États-unis;Stanford University,Stanford,Vereinigte Staaten;Stanford University,Stanford,Stati Uniti;Stanford University,Stanford,United States;Stanford University,Stanford,Estados Unidos;Stanford University,Stanford,Verenigde Staten;Stanford University,Stanford,Estados Unidos;Stanford University,Stanford,United States;Stanford University,Stanford,USA
,
Wanxing Chai-Ho
Affiliations:
University of California Los Angeles,Los Angeles,États-unis;University of California Los Angeles,Los Angeles,Vereinigte Staaten;University of California Los Angeles,Los Angeles,Stati Uniti;University of California Los Angeles,Los Angeles,United States;University of California Los Angeles,Los Angeles,Estados Unidos;University of California Los Angeles,Los Angeles,Verenigde Staten;University of Cali
,
Tiffany Tanaka
Affiliations:
University of California San Diego,San Diego,États-unis;University of California San Diego,San Diego,Vereinigte Staaten;University of California San Diego,San Diego,Stati Uniti;University of California San Diego,San Diego,United States;University of California San Diego,San Diego,Estados Unidos;University of California San Diego,San Diego,Verenigde Staten;University of California San Diego,San Die
,
Terrence Bradley
Affiliations:
University of Miami,Miami,États-unis;University of Miami,Miami,Vereinigte Staaten;University of Miami,Miami,Stati Uniti;University of Miami,Miami,United States;University of Miami,Miami,Estados Unidos;University of Miami,Miami,Verenigde Staten;University of Miami,Miami,Estados Unidos;University of Miami,Miami,United States;University of Miami,Miami,USA
,
Deepa Jeyakumar
Affiliations:
University of California Irvin,Irvine,États-unis;University of California Irvin,Irvine,Vereinigte Staaten;University of California Irvin,Irvine,Stati Uniti;University of California Irvin,Irvine,United States;University of California Irvin,Irvine,Estados Unidos;University of California Irvin,Irvine,Verenigde Staten;University of California Irvin,Irvine,Estados Unidos;University of California Irvin,
,
Eunice Wang
Affiliations:
Roswell Park Comprehensive Cancer Center,Buffalo,États-unis;Roswell Park Comprehensive Cancer Center,Buffalo,Vereinigte Staaten;Roswell Park Comprehensive Cancer Center,Buffalo,Stati Uniti;Roswell Park Comprehensive Cancer Center,Buffalo,United States;Roswell Park Comprehensive Cancer Center,Buffalo,Estados Unidos;Roswell Park Comprehensive Cancer Center,Buffalo,Verenigde Staten;Roswell Park Compr
,
Guan Xing
Affiliations:
Gilead Sciences, Inc.,Foster City,États-unis;Gilead Sciences, Inc.,Foster City,Vereinigte Staaten;Gilead Sciences, Inc.,Foster City,Stati Uniti;Gilead Sciences, Inc.,Foster City,United States;Gilead Sciences, Inc.,Foster City,Estados Unidos;Gilead Sciences, Inc.,Foster City,Verenigde Staten;Gilead Sciences, Inc.,Foster City,Estados Unidos;Gilead Sciences, Inc.,Foster City,United States;Gilead Scie
,
Mark Chao
Affiliations:
Gilead Sciences, Inc.,Foster City,États-unis;Gilead Sciences, Inc.,Foster City,Vereinigte Staaten;Gilead Sciences, Inc.,Foster City,Stati Uniti;Gilead Sciences, Inc.,Foster City,United States;Gilead Sciences, Inc.,Foster City,Estados Unidos;Gilead Sciences, Inc.,Foster City,Verenigde Staten;Gilead Sciences, Inc.,Foster City,Estados Unidos;Gilead Sciences, Inc.,Foster City,United States;Gilead Scie
,
Giri Ramsingh
Affiliations:
Gilead Sciences, Inc.,Foster City,États-unis;Gilead Sciences, Inc.,Foster City,Vereinigte Staaten;Gilead Sciences, Inc.,Foster City,Stati Uniti;Gilead Sciences, Inc.,Foster City,United States;Gilead Sciences, Inc.,Foster City,Estados Unidos;Gilead Sciences, Inc.,Foster City,Verenigde Staten;Gilead Sciences, Inc.,Foster City,Estados Unidos;Gilead Sciences, Inc.,Foster City,United States;Gilead Scie
,
Camille Renard
Affiliations:
Gilead Sciences, Inc.,Foster City,États-unis;Gilead Sciences, Inc.,Foster City,Vereinigte Staaten;Gilead Sciences, Inc.,Foster City,Stati Uniti;Gilead Sciences, Inc.,Foster City,United States;Gilead Sciences, Inc.,Foster City,Estados Unidos;Gilead Sciences, Inc.,Foster City,Verenigde Staten;Gilead Sciences, Inc.,Foster City,Estados Unidos;Gilead Sciences, Inc.,Foster City,United States;Gilead Scie
,
Indu Lal
Affiliations:
Gilead Sciences, Inc.,Foster City,États-unis;Gilead Sciences, Inc.,Foster City,Vereinigte Staaten;Gilead Sciences, Inc.,Foster City,Stati Uniti;Gilead Sciences, Inc.,Foster City,United States;Gilead Sciences, Inc.,Foster City,Estados Unidos;Gilead Sciences, Inc.,Foster City,Verenigde Staten;Gilead Sciences, Inc.,Foster City,Estados Unidos;Gilead Sciences, Inc.,Foster City,United States;Gilead Scie
,
Joshua Zeidner
Affiliations:
Lineberger Comprehensive Cancer Center,University of North Carolina,Chapel Hill,États-unis;Lineberger Comprehensive Cancer Center,University of North Carolina,Chapel Hill,Vereinigte Staaten;Lineberger Comprehensive Cancer Center,University of North Carolina,Chapel Hill,Stati Uniti;Lineberger Comprehensive Cancer Center,University of North Carolina,Chapel Hill,United States;Lineberger Comprehensive
David Sallman
Affiliations:
Moffitt Cancer Center,Tampa,États-unis;Moffitt Cancer Center,Tampa,Vereinigte Staaten;Moffitt Cancer Center,Tampa,Stati Uniti;Moffitt Cancer Center,Tampa,United States;Moffitt Cancer Center,Tampa,Estados Unidos;Moffitt Cancer Center,Tampa,Verenigde Staten;Moffitt Cancer Center,Tampa,Estados Unidos;Moffitt Cancer Center,Tampa,United States;Moffitt Cancer Center,Tampa,USA
(Abstract release date: 05/26/22) EHA Library. G Daver N. 06/10/22; 356996; S132
Dr. Naval G Daver
Dr. Naval G Daver
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S132

Type: Oral Presentation

Session title: Novel treatment options and prognostic markers in AML

Background
Patients (pts) with TP53-mutated acute myeloid leukemia (AML) have a poor prognosis, with limited responses to currently available therapies and low survival outcomes, representing a significant unmet medical need. Magrolimab is a monoclonal antibody blocking CD47, a “don’t eat me” signal overexpressed on cells in cancers such as AML. This blockade induces phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals.

Aims
To report tolerability and efficacy data from a phase 1b trial of magrolimab + AZA in frontline pts with TP53-mutated AML unsuitable for intensive chemotherapy (NCT03248479).

Methods
Frontline pts with AML not suitable for intensive chemotherapy received magrolimab IV starting with a priming dose (1 mg/kg) followed by ramp-up to 30 mg/kg QW or Q2W as the maintenance dose. AZA 75 mg/m2 was given IV or SC on days 1-7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate by European LeukemiaNet (ELN) 2017 criteria. 

Results
72 pts with TP53-mutated AML were treated (Table). Common all-grade treatment-emergent adverse events (TEAEs) were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Most common grade ≥3 TEAEs were febrile neutropenia (37.5%), anemia (29.2%; grade 3, 26.4%; grade 4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). Grade 3 hemolysis was reported in 1 pt (1.4%); no grade 4 hemolysis was reported. Objective response rate by intent to treat was 48.6% (CR, 33.3%; CR with incomplete hematologic recovery [CRi]/CR with partial hematologic recovery [CRh], 8.3%; morphologic leukemia-free state [MLFS], 1.4%; partial remission, 5.6%). Stable disease and progressive disease (PD) were reported in 16.7% and 5.6% of pts, respectively; 30- and 60-day mortality rates were 8.3% and 18.1%, respectively. Response assessments were unavailable in an additional 4.2% of pts who discontinued due to AEs and 6.9% due to other reasons, prior to the cycle 3 day 1 assessment. Median time to CR/CRi was 2.2 months (range, 1.7-7.2 months) and to CR was 3.0 months (range, 1.8-9.6 months); 14 of 31 (45.2%) evaluable pts with CR/CRi/CRh/MLFS achieved negative MRD by flow cytometry (investigator reported). Of 24 pts with CR, 8 had a longitudinal TP53 variant allele frequency (VAF) assessment and 5 of 8 (63%) had VAF decreased to ≤5%. Treatment was stopped due to stem cell transplant (9 [12.5%]), PD (26 [36.1%]), death (8 [11.1%]), AE (13 [18.1%]), and other (14 [19.4%]). Median durations of CR and CR/CRi were 7.7 months (95% CI, 4.7-10.9 months) and 8.7 months (95% CI, 5.3-10.9 months), respectively. Median overall survival (OS) in 72 pts was 10.8 months (95% CI, 6.8-12.8 months) (figure), with median follow-up of 8.3 months.

Table. Baseline characteristics

N=72

Age (range), years

73 (31-89)

ECOG, n (%)

 

0-1

61 (84.7)

2

11 (15.3)

ELN cytogenetic risk, n (%)

 

Favorable

1 (1.4)

Intermediate

2 (2.8)

Adverse

57 (79.2)

Unknown

12 (16.7)

AML with MDS-related changes, n (%)

34 (47.2)

Therapy-related AML, n (%)

15 (20.8)

ECOG, Eastern Cooperative Oncology Group; MDS, myelodysplastic syndrome.

Conclusion
In high-risk frontline pts with TP53-mutated AML unsuitable for intensive chemotherapy, magrolimab + AZA showed durable responses and encouraging OS in a single-arm study. A Phase 3 trial of this combination vs standard of care in TP53-mutated AML (ENHANCE-2; NCT04778397) is ongoing.

Keyword(s): Acute myeloid leukemia, Azacitidine, Immunotherapy, TP53



© 2022 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2022 ASCO Annual Meeting. All rights reserved.
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S132

Type: Oral Presentation

Session title: Novel treatment options and prognostic markers in AML

Background
Patients (pts) with TP53-mutated acute myeloid leukemia (AML) have a poor prognosis, with limited responses to currently available therapies and low survival outcomes, representing a significant unmet medical need. Magrolimab is a monoclonal antibody blocking CD47, a “don’t eat me” signal overexpressed on cells in cancers such as AML. This blockade induces phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals.

Aims
To report tolerability and efficacy data from a phase 1b trial of magrolimab + AZA in frontline pts with TP53-mutated AML unsuitable for intensive chemotherapy (NCT03248479).

Methods
Frontline pts with AML not suitable for intensive chemotherapy received magrolimab IV starting with a priming dose (1 mg/kg) followed by ramp-up to 30 mg/kg QW or Q2W as the maintenance dose. AZA 75 mg/m2 was given IV or SC on days 1-7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate by European LeukemiaNet (ELN) 2017 criteria. 

Results
72 pts with TP53-mutated AML were treated (Table). Common all-grade treatment-emergent adverse events (TEAEs) were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Most common grade ≥3 TEAEs were febrile neutropenia (37.5%), anemia (29.2%; grade 3, 26.4%; grade 4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). Grade 3 hemolysis was reported in 1 pt (1.4%); no grade 4 hemolysis was reported. Objective response rate by intent to treat was 48.6% (CR, 33.3%; CR with incomplete hematologic recovery [CRi]/CR with partial hematologic recovery [CRh], 8.3%; morphologic leukemia-free state [MLFS], 1.4%; partial remission, 5.6%). Stable disease and progressive disease (PD) were reported in 16.7% and 5.6% of pts, respectively; 30- and 60-day mortality rates were 8.3% and 18.1%, respectively. Response assessments were unavailable in an additional 4.2% of pts who discontinued due to AEs and 6.9% due to other reasons, prior to the cycle 3 day 1 assessment. Median time to CR/CRi was 2.2 months (range, 1.7-7.2 months) and to CR was 3.0 months (range, 1.8-9.6 months); 14 of 31 (45.2%) evaluable pts with CR/CRi/CRh/MLFS achieved negative MRD by flow cytometry (investigator reported). Of 24 pts with CR, 8 had a longitudinal TP53 variant allele frequency (VAF) assessment and 5 of 8 (63%) had VAF decreased to ≤5%. Treatment was stopped due to stem cell transplant (9 [12.5%]), PD (26 [36.1%]), death (8 [11.1%]), AE (13 [18.1%]), and other (14 [19.4%]). Median durations of CR and CR/CRi were 7.7 months (95% CI, 4.7-10.9 months) and 8.7 months (95% CI, 5.3-10.9 months), respectively. Median overall survival (OS) in 72 pts was 10.8 months (95% CI, 6.8-12.8 months) (figure), with median follow-up of 8.3 months.

Table. Baseline characteristics

N=72

Age (range), years

73 (31-89)

ECOG, n (%)

 

0-1

61 (84.7)

2

11 (15.3)

ELN cytogenetic risk, n (%)

 

Favorable

1 (1.4)

Intermediate

2 (2.8)

Adverse

57 (79.2)

Unknown

12 (16.7)

AML with MDS-related changes, n (%)

34 (47.2)

Therapy-related AML, n (%)

15 (20.8)

ECOG, Eastern Cooperative Oncology Group; MDS, myelodysplastic syndrome.

Conclusion
In high-risk frontline pts with TP53-mutated AML unsuitable for intensive chemotherapy, magrolimab + AZA showed durable responses and encouraging OS in a single-arm study. A Phase 3 trial of this combination vs standard of care in TP53-mutated AML (ENHANCE-2; NCT04778397) is ongoing.

Keyword(s): Acute myeloid leukemia, Azacitidine, Immunotherapy, TP53



© 2022 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2022 ASCO Annual Meeting. All rights reserved.

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