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853 Primary Results of Stimulus-MDS1: A Randomized, Double-Blind, Placebo-Controlled Phase II Study of TIM-3 Inhibition with Sabatolimab Added to Hypomethylating Agents (HMAs) in Adult Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological I
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Combination therapy, Clinical Research, Diseases, Therapies, Myeloid Malignancies, Human, Study Population
Monday, December 12, 2022: 2:45 PM

Amer M. Zeidan, MD1, Kiyoshi Ando, MD, PhD2, Odile Rauzy3*, Mehmet Turgut, MD4*, Ming-Chung Wang, MD5*, Roberto Cairoli6*, Hsin-An Hou, MD, PhD7*, Yok-Lam Kwong, MD8*, Montserrat Arnan Sangerman, PhD9*, Stef Meers10, Vinod A. Pullarkat, MD11*, Valeria Santini, MD, PhD12*, Kamel Malek13*, Flavia Kiertsman14*, Jiaying Lyu15*, Pedro Marques Ramos, PhD13*, Pierre Fenaux16, Yasushi Miyazaki, MD17 and Uwe Platzbecker, MD18

1Yale University and Yale Cancer Center, New Haven, CT
2Tokai University School of Medicine, Isehara, Japan
3Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
4Ondokuz Mayıs University, Samsun, Turkey
5Chang Gung Memorial Hospital, Kaohsiung City, Taiwan
6Niguarda Cancer Center, Milan, Italy
7National Taiwan University Hospital, Taipei City, Taiwan
8Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
9Institut Català d'Oncologia-Hospital Duran i Reynals, Barcelona, Spain
10AZ Klina, Brasschaat, Belgium
11City of Hope, Duarte, CA
12University of Florence, Florence, Italy
13Novartis Pharma AG, Basel, Switzerland
14Novartis Pharmaceuticals Corporation, East Hanover, NJ
15Novartis, China, Shanghai, China
16Service d'Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France
17Nagasaki University, Nagasaki, Japan
18University Hospital Leipzig, Leipzig, Germany

Background Patients (pts) with higher-risk MDS need tolerable treatment options with durable clinical benefits. Sabatolimab (MBG453) is a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), an immuno-myeloid regulator expressed on both immune cells and leukemic stem cells. Sabatolimab+HMAs delivered durable responses in a Phase (Ph) Ib study in pts with high-risk/very high risk (HR/vHR)-MDS (Brunner AM, ASH 2021). Here, we report the primary results from the ongoing STIMULUS-MDS1 (NCT03946670), a randomized, double-blind, placebo-controlled, Ph II study of sabatolimab+HMA in pts with intermediate risk (IR; and ≥5% bone marrow [BM] blasts), HR, or vHR-MDS who were ineligible for intensive chemotherapy or hematopoietic stem cell transplant at screening.

Methods Treatment-naive pts aged ≥18 years with IR/HR/vHR-MDS as defined by the Revised International Prognostic Scoring System (IPSS-R) were eligible. Pts were randomized 1:1 to sabatolimab+HMA or placebo+HMA and stratified by risk category (per investigator assessment) and type of HMA (azacitidine [AZA] or decitabine [DEC]; per investigator discretion). Intravenous (IV) sabatolimab (400 mg) or placebo were administered on Day (D)8 and D22 every 2 weeks, AZA (75 mg/m2 IV or subcutaneous) on D1-7 or D1-5 + D8-9, or DEC (20 mg/m2 IV) on D1-5. The 2 primary endpoints were complete remission (CR, per modified International Working Group-MDS criteria) rate and progression-free survival (PFS: time from randomization to relapse from CR, progression [including acute myeloid leukemia], or death). Secondary endpoints included response rates, overall survival (OS), duration of response, and safety.

Results A total of 127 pts were randomized (sabatolimab+HMA, N=65; placebo+HMA, N=62) between 29 JUL 2019 and 10 AUG 2020; 89% received AZA and 11% DEC. Reported results are from the primary analysis, when the study was unblinded (data cutoff 1 MAR 2022), unless noted otherwise. Median follow-up was 24 months (mo; randomization to cutoff). Baseline characteristics were similar between arms; median age was 73 years; 16.5%, 37.8%, and 45.7% of pts had IR, HR, and vHR-MDS, respectively. Median PFS was (sabatolimab+HMA vs placebo+HMA) 11.1 vs 8.5 mo (P=0.102, 1-sided; not significant [ns]; Figure A). Primary CR rate based on data up to 7 mo after the last pt’s first visit was evaluated earlier by an independent data monitoring committee; CR rate was (sabatolimab+HMA vs placebo+HMA) 21.5% (14/65) vs 17.7% (11/62) (P=0.769, 1-sided; ns). Updated CR rate at primary analysis was (sabatolimab+HMA vs placebo+HMA) 23.1% vs 21.0%, CR+partial remission (PR)+hematologic improvement (HI; includes marrow CR with HI and stable disease with HI) was 49.2% vs 37.1%, median duration of CR was 18.0 vs 9.2 mo, median duration of CR+PR+HI was 13.4 vs 9.2 mo, and OS was 19.0 vs 18.0 mo (hazard ratio 0.905 [95% CI: 0.565, 1.450]). In an exploratory subgroup analysis of pts with <10% BM blasts at baseline (sabatolimab+HMA, n=32; placebo+HMA; n=29), CR was 28.1% vs 17.2%; CR+PR+HI was 53.1% vs 34.5%; and median PFS was 11.3 vs 8.3 mo (Figure B). Similar beneficial results were seen in IR/HR IPSS-R pts. The grade ≥3 adverse events (AEs) with >20% in either arm were (sabatolimab+HMA vs placebo+HMA) neutropenia (53.2% vs 63.5%), thrombocytopenia (37.1% vs 42.9%), febrile neutropenia (35.5% vs 23.8%), anemia (22.6% vs 42.9%), and leukopenia (22.6% vs 28.6%). The most common non-hematological all grade AEs were constipation (46.8% vs 38.1%) and diarrhea (43.5% vs 22.2%). One pt developed a serious potential immune-mediated AE (pneumonitis) on study treatment (sabatolimab+DEC; 6 doses of 400 mg of sabatolimab) and was treated with immunosuppressants including steroids. This AE was suspected as study treatment related and resulted in fatality.

Conclusion Sabatolimab+HMA is associated with a favorable safety profile in pts with higher-risk MDS. Although improvements in CR and PFS were not statistically significant, when assessed with the better duration of response, the data may suggest a delayed-onset benefit in the sabatolimab arm, as well as a preferential effect in pts with lower disease burden. Additional exploratory and biomarker analyses will be reported in the meeting. The ongoing Ph III STIMULUS-MDS2 with a primary endpoint of OS (NCT04266301) has completed accrual and will definitively inform on the impact of sabatolimab in higher-risk MDS.

Disclosures: Zeidan: BMS, AbbVie, Takeda, Novartis, Aprea, Amgen, Otsuka, Gilead, Kura, Loxo Oncology, Geron, Mendus, Tyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ando: Astella: Honoraria; Celgene: Honoraria; Novartis international: Honoraria; Kyowa Kirin: Research Funding; Takeda Pharmaceutical: Research Funding; CHUGAI PHARMACEUTICAL: Research Funding. Rauzy: Celgene/BMS, Novartis: Research Funding. Cairoli: Novartis, Celgene: Speakers Bureau; Celgene, AbbVie, Daiichi Sankyo, Novartis: Consultancy; Gilead Sciences: Other: Travel, Accommodations. Hou: AbbVie, Celgene, Kirin: Research Funding; AbbVie, Astellas, AstraZeneca, BMS, Chugai, CSL Behring, Daiichi Sankyo, IQVIA, Johnson & Johnson, Kirin, Lotus, Merck Sharp & Dohme, Novartis, Ono, Panco Healthcare Co, Pfizer, PharmaEssential, Roche, Synmosa, Takeda, TSH Biopharm, TTY Biopharm Company, : Consultancy, Honoraria, Other: Travel. Kwong: Novartis, Merck, Bristol Meyer Squibb: Research Funding; Amgen, Astellas, Bayer, Beigene, Bristol Meyer Squibb, Celgene, Janssen, Merck, Otsuka, Novartis, Roche, Takeda: Consultancy, Speakers Bureau. Meers: Alexion, AbbVie, BMS/Celgene, Janssen, Novartis, Takeda: Consultancy, Honoraria, Other: Advisory Board Member. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Other: Advisory Board Member; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Santini: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Novartis: Honoraria; Syros: Membership on an entity's Board of Directors or advisory committees; Srvier: Membership on an entity's Board of Directors or advisory committees. Malek: Novartis Pharma AG: Current Employment. Kiertsman: Novartis Pharmaceuticals Corporation: Current Employment. Lyu: Novartis, China: Current Employment. Marques Ramos: Novartis Pharma AG: Current Employment. Fenaux: AbbVie, BMS, Janssen, Jazz, Novartis: Consultancy, Honoraria, Research Funding. Miyazaki: Otsuka Pharmaceutical: Honoraria; Pfizer: Honoraria; Kyowa-Kirin: Honoraria; Bristol-Myers: Honoraria; Chugai: Honoraria; SyinBio: Honoraria; Dainippon-Sumitomo Pharma: Honoraria, Research Funding; Astellas: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Nippon Shinyaku: Honoraria; Takeda: Honoraria; Daiichi-Sankyo: Honoraria; Janssen Pharmaceutical: Honoraria; Celgene: Honoraria. Platzbecker: Jazz: Honoraria; Novartis: Honoraria; Geron: Honoraria; Abbvie: Honoraria; BMS/Celgene: Honoraria; Silence Therapeutics: Honoraria; Janssen: Honoraria; Takeda: Honoraria.

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