Abstract: Background: Sabatolimab (MBG453) is a high-affinity, humanized, IgG4 (S228P) antibody targeting TIM-3, an inhibitory receptor that regulates adaptive and innate immune responses. TIM-3 is expressed on immune cells as well as leukemic stem cells (LSCs) and blasts, but not normal hematopoietic stem cells, making it a promising target in AML/MDS. Sabatolimab is a potential first-in-class immunotherapeutic agent that can target TIM-3 on immune and myeloid cells. Blockade of TIM-3 by sabatolimab may restore immune function while also directly targeting LSCs and blasts. Study Design and Methods : This is a phase Ib, open-label, multicenter, dose-escalation study of sabatolimab + HMA (decitabine [Dec] or azacitidine [Aza] ) in patients (pts) with AML or HR-MDS (NCT03066648). Pts were adults with newly diagnosed (ND) or relapsed/refractory (R/R; ≥1 prior therapy) AML or IPSS-R high- or very high-risk MDS; pts with chronic myelomonocytic leukemia (CMML) were also eligible. Pts were HMA naive and ineligible for intensive chemotherapy. Escalating dose cohorts of IV sabatolimab examined were: 240 or 400 mg Q2W (D8, D22) or 800 mg Q4W (D8) combined with Dec (20 mg/m2; IV D1-5) or Aza (75 mg/m2; IV/SC D1-7) per 28-day cycle. Primary objectives included safety/tolerability; secondary objectives included preliminary efficacy and pharmacokinetics. Results: As of the data cutoff (25 Jun 2020), 48 pts with ND AML, 39 pts with HR-MDS, and 12 pts with CMML received sabatolimab + HMA. Data from 29 pts with R/R AML were previously reported. For a broader understanding of the effect of sabatolimab + HMA, results are reported here for the Dec and Aza arms both combined and separately (Table). Median (range) duration of sabatolimab exposure was 4.5 (0.3-28.3) mo for ND AML and 4.1 (0.7-33.6) mo for HR-MDS, with 17 and 11 pts ongoing, respectively. With sabatolimab + HMA, the most common ( & gt;10% in either disease cohort) gr ≥3 treatment-emergent adverse events (TEAEs) in pts with ND AML and HR-MDS, respectively, were thrombocytopenia (45.8%, 51.2%), neutropenia (50%, 46.1%), febrile neutropenia (29.2%, 41%), anemia (27.1%, 28.2%), and pneumonia (10.4%, 5.1%). Discontinuation due to AE was infrequent among pts with ND AML (6.3% [3/48]; 1 each of fatigue, febrile neutropenia, and possible HLH); none occurred among pts with HR-MDS. One dose-limiting toxicity occurred with sabatolimab 240 mg Q2W + Dec (gr 3 ALT elevation); the maximum tolerated dose was not reached with either combination. To comprehensively assess possible immune-mediated AEs (imAEs), events were evaluated across all disease cohorts. Seven gr 3 treatment-related possible imAEs were reported in 5 pts: arthritis, rash, possible HLH, and increased ALT in 1 pt each, and hypothyroidism, infusion-related reaction, and increased ALT in 1 pt. No gr 4 treatment-related possible imAEs occurred; however, there was a case of enterocolitis in a pt with HR-MDS who died of septic shock with neutropenic colitis. No other treatment-related deaths were reported. Among 34 evaluable pts with ND AML, overall response rate (ORR) was 41.2%: 8 CR, 3 CRi, 3 PR. Median (range) time to response (TTR) was 2.1 (1.8-13.1) mo and estimated 6-mo duration of response (DOR) rate was 85.1% (95% CI: 68-100%). Estimated 12-mo progression-free survival (PFS) rate was 44% (95% CI: 28-69.3%). Among 35 evaluable pts with HR-MDS, ORR was 62.9%: 8 CR, 8 mCR (5 with hematologic improvement [HI]), 6 SD with HI. Median (range) TTR was 2.0 (1.7-9.6) mo and estimated 6-mo DOR rate for CR/mCR/PR was 90% (95% CI: 73.2-100%). Encouraging response rates were achieved in both pts with high-risk MDS (ORR 50% [11/22] ) and very high-risk MDS (ORR 84.6% [11/13]). Of pts with HR-MDS, 8 (5 high-risk, 3 very high-risk) proceeded to transplant. Estimated 12-mo PFS rate was 58.1% (95% CI: 39.9-84.6%). Among 12 pts with CMML, the safety profile of sabatolimab + HMA was generally consistent with that for AML/HR-MDS (most common gr ≥3 TEAEs: thrombocytopenia, n=7; neutropenia, n=7; anemia, n=6). ORR among 11 evaluable pts was 63.6%: 2 CR, 3 mCR, 1 PR, 1 SD with HI. Conclusions: Sabatolimab + HMA is well tolerated in pts with AML and HR-MDS and continues to show promising antileukemic activity and emerging durability. These results support TIM-3 as a potential therapeutic target and provide a basis for further development of sabatolimab + HMA in pts with AML or higher-risk MDS. Co-senior authors Uma Borate and Andrew H. Wei contributed equally to the work. Table Disclosures Brunner: Acceleron Pharma Inc.: Consultancy; Biogen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Forty Seven, Inc: Consultancy; Jazz Pharma: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; GSK: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding. Porkka:Novartis: Consultancy, Honoraria, Research Funding; BMS/Celgene: Honoraria, Research Funding. Knapper:Novartis: Consultancy, Honoraria, Research Funding. Garcia-Manero:Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding. Wermke:MacroGenics: Honoraria. Janssen:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Takeda: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Daiichi-Sankyo: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Roche: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; MSD: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda. Traer:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Notable Labs: Consultancy, Current equity holder in private company; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Narayan:Sanofi-Genzyme: Other: Current Spouse employment ; Takeda: Other: Prior Spouse employment within 24 months; Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months. Kontro:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Ottmann:Novartis: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Fusion Pharma: Honoraria; Incyte: Honoraria, Research Funding. Naidu:Novartis Pharmaceuticals: Current Employment. Kurtulus:Novartis: Current Employment. Makofske:Novartis: Current Employment. Liao:Novartis: Current Employment. Sabatos-Peyton:Novartis: Current Employment, Patents & Royalties: Yes, patent related to MBG453 and also prior TIM-3 patents from grad student/ postdoc work at Harvard/BWH; CoStim Pharmaceuticals: Patents & Royalties: Held shares as employee, now paid via Novartis. Rinne:Qiagen: Consultancy; Novartis: Current Employment. Borate:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Jazz Pharmaceuticals: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Wei:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genetech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding.