P787: SABATOLIMAB (MBG453) COMBINATION TREATMENT REGIMENS FOR PATIENTS WITH HIGHER-RISK MYELODYSPLASTIC SYNDROMES: THE MYELODYSPLASTIC SYNDROMES STUDIES IN THE STIMULUS IMMUNO-MYELOID CLINICAL TRIAL PROGRAM

Abstract

Background: Patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) unfit for hematopoietic stem cell transplant (HSCT) have poor outcomes with single-agent hypomethylating agent (HMA) therapy. Novel treatments with durable responses and survival benefit are needed. TIM-3 regulates innate and adaptive immunity and is expressed on leukemic stem cells (LSCs) and blasts but not normal hematopoietic stem cells. Sabatolimab is a novel immuno-myeloid therapy that binds to TIM-3 on immune cells, facilitating immune activation and phagocytosis of leukemic cells. Sabatolimab also binds to TIM-3 on leukemic cells, potentially impeding self-renewal of LSCs. Sabatolimab + HMAs had promising efficacy and response durability in HR-MDS in early-phase (ph) trials, with few significant immunologic adverse events (AEs; Brunner AM. ASH 2021. Oral 244). Aims: The STIMULUS immuno-myeloid clinical trial program investigates the safety, efficacy, and durability of sabatolimab-based combination therapies in patients with myeloid malignancies. Exploration of sabatolimab’s mechanism of action and identification of potential biomarkers predictive of response are planned. This abstract summarizes the design of 4 ongoing STIMULUS trials in previously untreated adult pts with HR-MDS ineligible for intensive chemotherapy or HSCT. Methods: STIMULUS-MDS1 (NCT03946670) is an international, randomized, double-blind, placebo-controlled, ph II trial evaluating sabatolimab + HMA in pts with very-high, high-, or intermediate-risk (vH/H/IR)-MDS who have completed enrollment (N=127). Primary endpoints are complete remission (CR) and progression-free survival (PFS). STIMULUS-MDS2 (NCT04266301) is an international, randomized, double-blind, placebo-controlled, ph III trial of sabatolimab + azacitidine (AZA) in pts with vH/H/IR-MDS or chronic myelomonocytic leukemia-2; the study has completed recruiting (N=530). Primary endpoint is overall survival (OS). Key secondary endpoints are time to definitive deterioration of fatigue; red blood cell transfusion-free interval; and improvement of fatigue, physical, and emotional functioning. STIMULUS MDS-US (NCT04878432) is a US-based, open-label, single-arm, ph II trial of sabatolimab + HMA of investigator’s choice (AZA intravenous [IV] or subcutaneous, decitabine IV, or oral decitabine/cedazuridine) in pts with vH/H/IR-MDS. Target enrollment is 90 pts. Primary endpoint is safety. Secondary endpoints include CR, PFS, leukemia-free survival (LFS), and OS. STIMULUS-MDS3 (NCT04812548) is an international, open-label, single-arm, ph II trial that explores triplet therapy of sabatolimab + AZA + BCL-2 inhibitor venetoclax (VEN) in pts with vH/HR-MDS. Part 1 is a safety run-in comprising 2 safety cohorts with ~6 pts receiving sabatolimab 400 mg + AZA + VEN and ~12 pts receiving sabatolimab 800 mg + AZA + VEN. Primary endpoint of part 1 is safety. If (both 400- and 800-mg doses) sabatolimab + AZA + VEN are safe, the trial will move to an expansion cohort (~58 pts) of sabatolimab 800 mg Q4W + AZA + VEN. Primary endpoint is CR. Secondary endpoints include CR + mCR rate, overall response rate (CR + mCR + PR + hematologic improvement), OS, PFS, LFS, and event-free survival. The STIMULUS immuno-myeloid clinical trial program is investigating the efficacy and safety profiles and the quality-of-life improvements for sabatolimab-based combination therapies in pts with myeloid malignancies. The STIMULUS-MDS trials aim to gain insight into the durable benefit of sabatolimab combination therapies in pts with HR-MDS. Results: None. Image:Summary/Conclusion: None.