SABATOLIMAB PLUS HYPOMETHYLATING AGENTS (HMAS) IN PATIENTS (PTS) WITH HIGH-/VERY HIGH-RISK MYELODYSPLASTIC SYNDROME (HR/VHR-MDS) AND ACUTE MYELOID LEUKEMIA (AML): SUBGROUP ANALYSIS OF A PHASE 1 STUDY
Author(s): ,
Andrew Wei
Affiliations:
The Alfred Hospital and Monash University,Melbourne,Australia
,
Jordi Esteve
Affiliations:
Hospital Clínic,Barcelona,Spain
,
Kimmo Porkka
Affiliations:
Department of Hematology,Helsinki University Hospital Comprehensive Cancer Center,Helsinki,Finland
,
Steve Knapper
Affiliations:
Cardiff University,Cardiff,United Kingdom
,
Elie Traer
Affiliations:
Oregon Health & Science University,Portland,United States
,
Sebastian Scholl
Affiliations:
University Hospital Jena,Jena,Germany
,
Guillermo Garcia-Manero
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Norbert Vey
Affiliations:
Institut Paoli-Calmettes,Marseille,France
,
Martin Wermke
Affiliations:
University Hospital Dresden,Dresden,Germany
,
Jeroen Janssen
Affiliations:
Amsterdam University Medical Centers,location VUmc,Amsterdam,Netherlands
,
Rupa Narayan
Affiliations:
Massachusetts General Hospital,Boston,United States
,
Sun Loo
Affiliations:
The Alfred Hospital,Melbourne,Australia
,
Natalia Tovar
Affiliations:
Hospital Clínic,Barcelona,Spain
,
Mika Kontro
Affiliations:
Department of Hematology,Helsinki University Hospital Comprehensive Cancer Center,Helsinki,Finland
,
Oliver Ottmann
Affiliations:
Cardiff University,Cardiff,United Kingdom
,
Purushotham Naidu
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
,
Sema Kurtulus
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,United States
,
Elena Orlando
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,United States
,
Nidhi Patel
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,United States
,
Jessica Makofske
Affiliations:
Novartis Institutes for BioMedical Research,Cambridge,United States
,
Fei Ma
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
,
Na Zhang
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
,
Uma Borate
Affiliations:
Oregon Health & Science University,Portland,United States
Andrew M. Brunner
Affiliations:
Massachusetts General Hospital,Boston,United States
EHA Library. Wei A. 06/09/21; 324576; S168
Andrew H. Wei
Andrew H. Wei
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S168

Type: Oral Presentation

Session title: Novel targets in MDS

Background

Novel therapies providing improved and durable outcomes with a favorable safety profile are needed in higher-risk MDS and AML. Sabatolimab (MBG453) is a novel immuno-myeloid therapy targeting TIM-3, an immune regulator expressed on immune and myeloid leukemic cells but not on normal hematopoietic stem cells. In a Ph 1b study (NCT03066648), sabatolimab+HMA showed promising overall response rates in pts with HR/vHR-MDS (64%) and newly diagnosed (ND)-AML (41%). Response durability was encouraging, with an estimated 84% and 79% still in response after 6 mo. Treatment-emergent AE profile was consistent with that reported for HMA alone (Brunner ASH 2020).

Aims

To further explore safety/tolerability, efficacy in pt subgroups, and biomarkers with sabatolimab+HMA.

Methods

Study design/eligibility criteria have been reported. Pts with HR/vHR-MDS (per IPSS-R) or ND-AML who were HMA-naïve and ineligible for intensive chemotherapy received sabatolimab (1-2 infusions/mo) + decitabine or azacitidine. Primary objectives were safety/tolerability; secondary objectives included PK and preliminary efficacy. Data cutoff 22 Sep 2020; updated data will be presented.

Results

To explore sabatolimab+HMA safety/tolerability, sabatolimab dose interruption (>7 d delay), reduction, and discontinuation due to AE/death were assessed in 89 pts with HR/vHR-MDS (n=41) and ND-AML (n=48). Of 89 pts, 36 (40%) had sabatolimab dose interruption, 1 (1%) had sabatolimab dose reduction, 2 (2%) had dose interruption and reduction, 5 (6%) discontinued, and 3 (3%) had dose interruption and discontinued. Dose interruption rate in first 2 cycles was low (21% [19/89]). Of 8 discontinuations, 4 were due to AE (1/4 related to study treatment) and 4 to death. Of 22 pts with gr 4 neutropenia/thrombocytopenia at baseline (BL), 4 (18%) had dose interruption, 2 (9%) discontinued, 1 (5%) had dose interruption and discontinued, and none had dose reduction.


In analyses of remission rates (CR+mCR/CRi+PR) by BL factors, response was independent of BM blast burden in pts with HR/vHR-MDS or ND-AML. Remission rates were similar in pts ≥75 and 65-74 y: 50% (6/12) and 65% (11/17) with HR/vHR-MDS and 42% (8/19) for both groups with ND-AML. Response durability in pts ≥75 and 65-74 y was encouraging: an estimated 83% and 86% with HR/vHR-MDS and 69% and 88% with ND-AML remained in remission after 6 mo. In pts with TP53 mutation or pts with ≥1 mutation conferring ELN high risk (TP53, RUNX1, ASXL1), respectively, remission rates were 55% (6/11; 4/6 in remission >200 d) and 59% (13/22; 8/13 in remission >200 d) for HR/vHR-MDS and 25% (1/4; in remission 129 d) and 50% (6/12; 2/6 in remission >200 d) for ND-AML. 6/7 responders with TP53 mutation had complex karyotype.


Biomarker analyses identified IL-1β, a proinflammatory cytokine reported to promote expansion of AML progenitor cells, as one of the most differentially expressed genes in BM of responders vs nonresponders to sabatolimab+HMA, with expression levels inversely correlated with remission. Single-cell RNA sequencing showed sabatolimab+HMA downregulated IL-1β in blast cells but, consistent with prior observations in TIM-3 deficient pts, it upregulated IL-1β in myeloid cells.

Conclusion

Sabatolimab+HMA showed favorable tolerability in MDS/AML, including in pts with gr 4 cytopenias at BL. Promising remission rates were seen irrespective of BL blast burden and in older pts and pts with adverse risk mutation. This supports development of sabatolimab+HMA in the STIMULUS trial program in MDS/AML.

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

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S168

Type: Oral Presentation

Session title: Novel targets in MDS

Background

Novel therapies providing improved and durable outcomes with a favorable safety profile are needed in higher-risk MDS and AML. Sabatolimab (MBG453) is a novel immuno-myeloid therapy targeting TIM-3, an immune regulator expressed on immune and myeloid leukemic cells but not on normal hematopoietic stem cells. In a Ph 1b study (NCT03066648), sabatolimab+HMA showed promising overall response rates in pts with HR/vHR-MDS (64%) and newly diagnosed (ND)-AML (41%). Response durability was encouraging, with an estimated 84% and 79% still in response after 6 mo. Treatment-emergent AE profile was consistent with that reported for HMA alone (Brunner ASH 2020).

Aims

To further explore safety/tolerability, efficacy in pt subgroups, and biomarkers with sabatolimab+HMA.

Methods

Study design/eligibility criteria have been reported. Pts with HR/vHR-MDS (per IPSS-R) or ND-AML who were HMA-naïve and ineligible for intensive chemotherapy received sabatolimab (1-2 infusions/mo) + decitabine or azacitidine. Primary objectives were safety/tolerability; secondary objectives included PK and preliminary efficacy. Data cutoff 22 Sep 2020; updated data will be presented.

Results

To explore sabatolimab+HMA safety/tolerability, sabatolimab dose interruption (>7 d delay), reduction, and discontinuation due to AE/death were assessed in 89 pts with HR/vHR-MDS (n=41) and ND-AML (n=48). Of 89 pts, 36 (40%) had sabatolimab dose interruption, 1 (1%) had sabatolimab dose reduction, 2 (2%) had dose interruption and reduction, 5 (6%) discontinued, and 3 (3%) had dose interruption and discontinued. Dose interruption rate in first 2 cycles was low (21% [19/89]). Of 8 discontinuations, 4 were due to AE (1/4 related to study treatment) and 4 to death. Of 22 pts with gr 4 neutropenia/thrombocytopenia at baseline (BL), 4 (18%) had dose interruption, 2 (9%) discontinued, 1 (5%) had dose interruption and discontinued, and none had dose reduction.


In analyses of remission rates (CR+mCR/CRi+PR) by BL factors, response was independent of BM blast burden in pts with HR/vHR-MDS or ND-AML. Remission rates were similar in pts ≥75 and 65-74 y: 50% (6/12) and 65% (11/17) with HR/vHR-MDS and 42% (8/19) for both groups with ND-AML. Response durability in pts ≥75 and 65-74 y was encouraging: an estimated 83% and 86% with HR/vHR-MDS and 69% and 88% with ND-AML remained in remission after 6 mo. In pts with TP53 mutation or pts with ≥1 mutation conferring ELN high risk (TP53, RUNX1, ASXL1), respectively, remission rates were 55% (6/11; 4/6 in remission >200 d) and 59% (13/22; 8/13 in remission >200 d) for HR/vHR-MDS and 25% (1/4; in remission 129 d) and 50% (6/12; 2/6 in remission >200 d) for ND-AML. 6/7 responders with TP53 mutation had complex karyotype.


Biomarker analyses identified IL-1β, a proinflammatory cytokine reported to promote expansion of AML progenitor cells, as one of the most differentially expressed genes in BM of responders vs nonresponders to sabatolimab+HMA, with expression levels inversely correlated with remission. Single-cell RNA sequencing showed sabatolimab+HMA downregulated IL-1β in blast cells but, consistent with prior observations in TIM-3 deficient pts, it upregulated IL-1β in myeloid cells.

Conclusion

Sabatolimab+HMA showed favorable tolerability in MDS/AML, including in pts with gr 4 cytopenias at BL. Promising remission rates were seen irrespective of BL blast burden and in older pts and pts with adverse risk mutation. This supports development of sabatolimab+HMA in the STIMULUS trial program in MDS/AML.

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

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