MDS-476 Sabatolimab (MBG453) Combination Treatment Regimens for Patients With Higher-Risk Myelodysplastic Syndromes (HR-MDS): The Myelodysplastic Syndromes Studies in the STIMULUS Immuno-Myeloid Clinical Trial Program

Context: Patients with HR-MDS unfit for hematopoietic stem cell transplant (HSCT) have poor outcomes with hypomethylating agents (HMAs). Novel treatments with durable responses and survival benefit are needed. 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 leukemic stem cells (LSCs). Early phase trials of sabatolimab+HMAs show promising efficacy and response durability, with few significant immunologic AEs. Objective: To summarize the designs of 4 ongoing STIMULUS trials evaluating the safety and efficacy of sabatolimab-based combination therapies in untreated adults with HR-MDS ineligible for intensive chemotherapy or HSCT. Study Summaries: STIMULUS-MDS1 (NCT03946670): an international, randomized, double-blind, placebo-controlled, Phase II trial evaluating sabatolimab+HMA in very-high, high-, or intermediate-risk (vH/H/IR)-MDS patients; enrollment complete (N=127). Primary endpoints: CR and PFS. STIMULUS-MDS2 (NCT04266301): an international, randomized, double-blind, placebo-controlled, Phase III trial of sabatolimab+azacitidine in vH/H/IR-MDS or chronic myelomonocytic leukemia-2 patients. Recruitment completed (N=530). Primary endpoint: OS. Key secondary endpoints: time to definitive deterioration of fatigue; RBC transfusion-free interval; improvement of fatigue, physical, and emotional functioning. STIMULUS MDS-US (NCT04878432): a US-based, open-label, single-arm, Phase II trial of sabatolimab+HMA of investigator's choice (azacitidine IV or subcutaneous, decitabine IV, or oral decitabine/cedazuridine) in vH/H/IR-MDS patients. Target enrollment (N=90). Primary endpoint: safety. Key secondary endpoints: CR, PFS, leukemia-free survival (LFS), and OS. STIMULUS-MDS3 (NCT04812548): an international, open-label, single-arm, Phase II trial of sabatolimab+azacitidine+venetoclax in vH/HR-MDS patients. Part 1: two safety run-in cohorts (~6 patients receiving sabatolimab 400mg +azacitidine+venetoclax; and ~12 receiving sabatolimab 800mg +azacitidine+venetoclax). Primary endpoint (Part 1): safety. If both regimens are safe, ~58 patients in expansion cohort will receive sabatolimab 800mg Q4W +azacitidine+venetoclax. Primary endpoint: CR. Key secondary endpoints: CR+mCR rate, overall response rate (CR+mCR+PR+hematologic improvement), OS, PFS, LFS, and event-free survival. Summary: The STIMULUS immuno-myeloid clinical trial program is investigating the efficacy and safety of sabatolimab-based combination therapies in patients with myeloid malignancies. The STIMULUS-MDS trials aim to elucidate the durable benefit of sabatolimab combination therapies in HR-MDS patients. Study sponsored by Novartis Pharmaceuticals Corporation.