Abstract: Myelodysplastic syndromes/neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. While the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS and in their ability to fully capture clinical benefits of novel investigational drugs or to serve as valid surrogates for longer-term clinical endpoints (e.g., overall survival). Further, issues related to ambiguity and practicality of some criteria lead to variability in interpretation and inter-observer inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in higher-risk MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery (CRL) and CR with partial hematologic recovery (CRh) as provisional response criteria, elimination of marrow CR, and specific recommendations for standardization of time-to-event endpoints and the derivation and reporting of responses. The updated criteria should lead to better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action.

Abstract: Background: Pts with higher-risk MDS and AML need treatment options that provide durable responses with sustained clinical benefit and favorable safety/tolerability. Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3, an immune regulator expressed on immune cells and myeloid leukemic progenitors but not on normal hematopoietic stem cells. Sabatolimab + HMA has been shown to deliver promising durable responses in a phase (Ph) Ib study in pts with vHR/HR-MDS or newly diagnosed (ND) AML (Wei et al. EHA 2021; NCT03066648). We report updated data from this study, including new analyses evaluating a potential relationship between immune-mediated effects of sabatolimab and response. Final results with additional follow-up will be reported at the time of presentation. Methods: Eligibility criteria and design of this multicenter, open-label study have been previously reported (Wei et al. EHA 2021). The primary objective was to evaluate safety and tolerability. Preliminary efficacy, a key secondary objective, was assessed with overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS) endpoints. Safety and preliminary efficacy are reported for sabatolimab + HMA in pts with vHR/HR-MDS (per IPSS-R) or ND-AML. The proportion of pts who had a possible immune-mediated adverse event (imAE) was evaluated among pts who achieved remission (CR + PR + CRi/mCR) compared with pts that have not achieved remission. The outcomes of pts who received hematopoietic stem cell transplantation (HSCT) after coming off the study were assessed independent of the study by investigators. Results: As of the 15 Jun 2021 data cutoff, 53 pts with vHR/HR-MDS and 48 with ND-AML were treated with sabatolimab + HMA. The combination was safe and well tolerated, with the most common (≥15% in either vHR/HR-MDS or ND-AML) gr ≥3 AEs similar to HMA alone, consisting of thrombocytopenia (43.4%, 45.8%), neutropenia (47.2%, 50.0%), anemia (28.3%, 33.3%), and febrile neutropenia (35.8%, 29.2%), respectively. No pt with vHR/HR-MDS and only 3 with ND-AML discontinued treatment due to an AE regardless of relationship to treatment. In vHR/HR-MDS, 24.5% of pts had improvement allowing them to undergo HSCT. While on study, 6 pts with vHR/HR-MDS and 10 with ND-AML had possible imAEs regardless of relationship to study treatment. Few pts had clinically significant possible imAEs, with no gr ≥3 possible imAEs in pts with vHR/HR-MDS. In ND-AML, 5 pts had gr 3 and none had gr 4/5 possible imAEs. Among 51 pts with vHR/HR-MDS evaluable for response, ORR was 56.9%, with a median DOR (mDOR) of 16.1 mo (Table). The mDOR in pts with CR was 21.5 mo (95% CI, 12.1-NE). Estimated 12-mo PFS rate was 51.9% (95% CI, 30.6%-69.6%). In 40 evaluable pts with ND-AML, ORR was 40.0% and mDOR was 12.6 mo. The mDOR in pts with CR was 23.0 mo (95% CI, 1.3-NE). Estimated 12-mo PFS rate was 27.9% (95% CI, 14.9%-42.5%). Durable responses were also observed in pts with adverse-risk mutations, including TP53 mutations in pts with vHR/HR-MDS (ORR: 71.4% [10/14]; mDOR 21.5 mo [95%CI, 6.7-NE] ) and at least 1 ELN adverse-risk mutation (TP53/RUNX1/ASXL1) in pts with ND-AML (ORR: 53.8% [7/13]; mDOR 12.6 mo [95%CI, 1.3-NE] ). Although the majority (75%) of pts who went into remission did not experience an imAE, pts in the vHR/HR-MDS cohort who achieved remission more often had a possible imAE (6/24 [25%]) than pts without remission (n=27), none of whom had an imAE. Notably, all 6 pts with vHR/HR-MDS who had an imAE achieved remission. Among pts with ND-AML, the frequency of possible imAEs was similar regardless of remission status. Of the subset of pts who proceeded to HSCT, post-HSCT outcomes in pts with vHR/HR-MDS treated with sabatolimab + HMA were generally favorable without excess toxicities related to graft-versus-host disease. Conclusions: Sabatolimab + HMA was safe and well tolerated and demonstrated durable clinical responses in pts with vHR/HR-MDS and ND-AML. Responses were also durable in pts with adverse-risk mutations. The observed relationship between response and possible imAEs in vHR/HR-MDS would need further confirmation in ongoing studies, but suggests that an immunomodulatory mechanism of sabatolimab may be contributing to clinical responses. The STIMULUS clinical trial program is evaluating sabatolimab-based combination therapy in multiple Ph II and III studies in MDS and AML. Co-senior authors Uma Borate and Andrew H. Wei contributed equally. Figure 1 Figure 1. Disclosures Brunner: Celgene, Forty Seven Inc, Jazz: Other: Advisory Board; Novartis, Celgene, Takeda, AstraZeneca: Research Funding. Esteve: Bristol Myers Squibb/Celgene: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Knapper: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Traer: Schrodinger: Research Funding; ImmunoGen: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier/Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding. Janssen: Uppsala County Council: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Speakers Bureau; Avillion: Research Funding; Ellipses Pharma: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Incyte Biosciences Benelux BV: Research Funding, Speakers Bureau; Glycomimetics: Research Funding. Narayan: Novartis: Research Funding; Sanofi Genzyme: Other: Spouse employment & equity interest; Takeda: Other: Spouse employment & equity interest; Genentech: Other: Spouse employment & equity interest. Kontro: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ottmann: Celgene/BMS: Honoraria, Research Funding; Fusion: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Naidu: Novartis: Current Employment. Pelletier: Novartis: Current Employment. Han: Novartis: Current Employment, Current equity holder in publicly-traded company. Lewandowski: Novartis Institutes: Current Employment. Zhang: Novartis Institutes for BioMedical Research: Current Employment. Mohammed: Novartis: Current Employment. Rinne: Novartis: Current Employment; Qiagen: Consultancy. Borate: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: 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; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Wei: Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Astellas: Honoraria. OffLabel Disclosure: Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3 and is under investigation for the treatment of patients with myeloid malignancies

Abstract: Background: Sabatolimab (MBG453) is a high-affinity, humanized, IgG4 (S228P) antibody targeting TIM-3, an inhibitory receptor expressed on multiple immune cells and on leukemic stem/progenitor cells and blasts, but not on normal hematopoietic stem cells. Sabatolimab is being evaluated for treatment of patients (pts) with intermediate to very high risk MDS or AML in the STIMULUS clinical trial program. Here we report PK and clinical data supporting sabatolimab doses being evaluated in the STIMULUS program. Methods: PK analyses were done in a ph 1-1b/2 study in pts with adv solid tumors (NCT02608268) and a ph 1b study in pts with high/very high risk MDS (HR-MDS) or AML who were ineligible for intensive chemotherapy (NCT03066648). Pts with solid tumors received IV sabatolimab 80-1200 mg Q2W/Q4W or sabatolimab 20-800 mg Q2W/80-1200 mg Q4W + spartalizumab (PD-1 inhibitor). Based on findings in solid tumors, pts with HR-MDS/AML received IV sabatolimab 160-1200 mg Q2W/800 mg Q4W in treatment arms including sabatolimab monotherapy, + hypomethylating agent (HMA; decitabine [Dec] or azacitidine), and + spartalizumab (± Dec). Total sabatolimab serum concentration was used in population PK (popPK) modeling to simulate average (Cavg), maximal (Cmax), and trough (Ctrough) concentrations at steady state. Total serum soluble TIM-3 was measured and simulation was used to predict membrane-bound TIM-3 occupancy in the bone marrow (BM). PK exposure-response analysis (data cutoff 27 Nov 2019) and assessment of clinical safety/efficacy by dose (data cutoff 25 Jun 2020) were conducted in pts with HR-MDS/AML who received sabatolimab (dosed at 240 or 400 mg Q2W or 800 mg Q4W) + HMA. Results: Sabatolimab PK was similar for pts with solid tumors (n=252), HR-MDS, and AML (n=155 HR-MDS + AML); no drug-drug interactions were seen for any combinations. The estimated half-life of sabatolimab was ~16.7 days at linear PK dose levels and moderate accumulation was seen after multiple dosing. At lower doses (≤80 mg Q2W or ≤240 mg Q4W), sabatolimab exhibited nonlinear elimination indicative of target-mediated drug disposition, potentially related to internalization of the membrane-bound antibody-TIM-3 complex. At doses ≥240 mg Q2W and ≥800 mg Q4W, a plateau in the accumulated total soluble TIM-3 level was reached and PK approached a proportional dose-exposure relationship. Based on popPK modeling, among sabatolimab + HMA regimens 400 mg Q2W had the highest Ctrough at steady state, and 800 mg was predicted to be an equivalent Q4W dosing regimen. Both doses had similar steady state Cavg and similarly high occupancy rates for membrane-bound TIM-3 in the BM ( & gt;95% in ≥95% of pts with HR-MDS/AML), suggesting similarly high levels of TIM-3 engagement. PK exposure-safety analysis included 102 pts with HR-MDS/AML who received sabatolimab + HMA and were categorized into 4 exposure quartiles based on steady state Cmax and Cavg. There was no relationship between steady state Cmax or Cavg quartiles and incidence of treatment-related AEs. Similarly, exposure-efficacy analysis (n=92) showed no clear relationship between steady state Ctrough or Cavg and percent BM blast reduction or clinical benefit (CR/mCR/CRi/PR). The effect of sabatolimab dose on safety/efficacy was also evaluated in an updated clinical analysis in pts with HR-MDS/AML treated with sabatolimab + HMA. Overall, sabatolimab + HMA was safe and well tolerated with a low rate of study discontinuation due to AE (3.4% [4/116]). Rates of most common gr ≥3 treatment-emergent AEs and rates of gr ≥3 possible immune-mediated AEs related to study treatment did not appear to be dose dependent (Table). Among 35 evaluable pts with HR-MDS, CR/mCR/PR rates were 50.0%, 33.3% and 54.5% at sabatolimab doses of 240 mg Q2W, 400 mg Q2W and 800 mg Q4W. Among 60 evaluable pts with AML, CR/CRi/PR rates were 35.3%, 37.5% and 31.6%, respectively. There were no notable differences in responses across the 3 doses (Table). Conclusion: Sabatolimab 400 mg Q2W was predicted to have the highest steady state Ctrough and TIM-3 occupancy rate when combined with HMA, and 800 mg was predicted to be an equivalent Q4W dosing regimen. No clear relationship was seen between sabatolimab dose or steady state exposure and safety/efficacy at the doses tested. These results support clinical development of the sabatolimab 400 mg Q2W and 800 mg Q4W dosing regimens. Co-senior authors Andrew Brunner and Uma Borate contributed equally to the work. Table Disclosures Wei: AbbVie: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria; Amgen: Honoraria, Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Novartis: Honoraria, Research Funding, Speakers Bureau; 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; AstraZeneca: Honoraria, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Research Funding. Porkka:BMS/Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Knapper:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding. Wermke:MacroGenics: Honoraria. Janssen:MSD: 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; Daiichi-Sankyo: 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; Janssen: 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; 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; 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; BMS: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Traer:Notable Labs: Consultancy, Current equity holder in private company; Genentech: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: 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:Abbvie: Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ottmann:Amgen: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Fusion Pharma: Honoraria; Incyte: Honoraria, Research Funding. Liao:Novartis: Current Employment. Stein:Novartis: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Khanshan:Novartis: Current Employment. Naidu:Novartis Pharmaceuticals: Current Employment. Zhang:Novartis: Current Employment. Rinne:Novartis: Current Employment; Qiagen: Consultancy. Sun:Novartis: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Brunner:Biogen: Consultancy; Acceleron Pharma Inc.: 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. Borate:Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Pfizer: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.