P582: first results of a phase ii study (stimulus-aml1) investigating sabatolimab + azacitidine + venetoclax in patients with newly diagnosed acute myeloid leukemia

Background: The BCL-2 inhibitor venetoclax (VEN) in combination with a hypomethylating agent (HMA) has improved outcomes for patients with newly diagnosed (ND) acute myeloid leukemia (AML) who are unfit for intensive chemotherapy (IC; DiNardo CD, N Engl J Med, 2020); however, responses are often transient. 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 shown promising durable responses in a Phase Ib study in patients with ND-AML and myelodysplastic syndrome (Wei AH, ASH 2021; NCT03066648). Treatment with sabatolimab + VEN + azacitidine (AZA) may also induce different pathways of cancer cell elimination. Aims: In this first presentation of the study, we report findings from the dose-escalation part of STIMULUS-AML1 (NCT04150029), a Phase II, single-arm study of sabatolimab + AZA + VEN in adult patients with AML. Methods: Adult patients with ND-AML ineligible for IC were enrolled. In dose-escalation part 1 (safety run-in), patients received either 400 mg (Cohort 1) or 800 mg (Cohort 2) sabatolimab every 4 weeks (Q4W) plus 400 mg VEN once a day every day, plus 75 mg/m2 AZA on Days (D) 1-7, or D1-5+D8-9, or D1-6+D8 of a 28-day cycle (Zeidan A, ESH-AML 2022). For the safety run-in part, the primary endpoint was assessment of the incidence of dose-limiting toxicities (DLTs) between Cycle 1 D8 and the end of Cycle 2. Results: As of the Sep 6, 2021 data cutoff, 18 patients have been treated in part 1 of the study with sabatolimab + AZA + VEN (Cohort 1, n=5; Cohort 2, n=13). Baseline demographics are shown in Table 1. Treatment was ongoing for 9 (50%) patients (Cohort 1, n=1; Cohort 2, n=8). Reasons for study treatment discontinuation included adverse events (AEs; n=3), progressive disease (n=3, including a case of chloroma), planned stem cell transplant (n=2), and physician decision (n=1). Only 1 DLT (elevated troponin T/asymptomatic myocarditis) was reported in Cohort 2 and no DLTs were reported in Cohort 1. Table 2 summarizes AEs observed in >20% of patients in the study. Consistent with AEs often observed during AZA + VEN therapy (DiNardo CD, N Engl J Med, 2020), the 5 most common AEs regardless of relationship to study treatment were constipation (all grades [gr]: 39%; gr ≥3: 0%) and hematologic events, including anemia (33%; 28%), decreased platelets (33%; 33%), neutropenia (39%; 39%), and febrile neutropenia (gr: 50%). Treatment-related AEs gr ≥3 in >25% of all patients included neutropenia (39%), decreased platelet count (33%), and decreased neutrophil count (28%). Treatment-related AEs led to study treatment discontinuation in 3 patients (platelet count decreased [n=2], troponin level increased/asymptomatic myocarditis [n=1]). AEs led to sabatolimab dose interruption in 6 patients, all in Cohort 2. No sabatolimab dose reduction was observed. Fourteen patients had dose interruption of VEN due to AEs. Five patients had dose reduction of VEN (none due to AEs). Serious AEs were reported in 14 (78%) patients; the most common was febrile neutropenia (44%). No other serious AEs were reported in >1 patient. Efficacy data will be presented at the EHA meeting. Image:Summary/Conclusion: Safety and tolerability of sabatolimab + AZA + VEN were comparable at 2 dose levels (400 and 800 mg) of sabatolimab and were overall comparable to the reported safety profile of VEN + AZA doublet therapy. These findings supported initiation of the expansion cohort of STIMULUS-AML1 at a sabatolimab 800 mg dose.