T-cell immunoglobulin and mucin domain-3 (TIM-3) is an immune checkpoint that is expressed on multiple cell types, including leukemic stem cells (LSCs) and blasts. However, it is not expressed on normal hematopoietic stem cells, which makes it a potential target for treating myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). MBG453 (sabatolimab), a high-affinity, humanized, anti–TIM-3 IgG4, boosts immune cell–mediated killing of AML cells in vitro. It may also target TIM-3 on immune cells and LSCs. This multicenter, open-label, phase 1b, dose-escalation study was designed to evaluate MBG453 combined with the hypomethylating agents (HMAs) decitabine or azacitidine in patients with high-risk MDS or AML.
Patients were eligible if they were HMA-naïve and not candidates for intensive chemotherapy. Decitabine (20 mg/m2 intravenously on days 1-5) or azacitidine (75 mg/m2 subcutaneously or intravenously on days 1-7) were administered every 28 days. Patients also received escalating doses of MBG453 intravenously at 240 mg or 400 mg every 2 weeks (day 8, day 22) or 800 mg every 4 weeks (day 8). Safety and tolerability were primary objectives. Key secondary objectives were pharmacokinetics and preliminary efficacy.
Of the 69 patients to receive MBG453 + decitabine, 19 had high-risk MDS (per Revised International Prognostic Scoring System) and 50 had AML. Of the 29 patients who received MBG453 + azacitidine, 13 had high-risk MDS and 16 had AML. Half (50%) of the patients in the combined AML cohort (N = 63) had adverse cytogenetic risk per the European LeukemiaNet 2017 classification. Median age was 71 and 74 years for the MBG453 + decitabine and MBG453 + azacitidine arms, respectively. Maximum tolerated dose was not reached for either combination. In the MBG453 + decitabine arm, there was 1 dose-limiting toxicity (a corticosteroid-responsive grade 3 abnormal alanine aminotransferase elevation). Median exposure duration was 4.9 months (range, 0.7-26.7 months) with 15 patients ongoing for MBG453 + decitabine and 3.0 months (range, 0.1-9.2 months) with 19 patients ongoing for MBG453 + azacitidine.
The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (41%, 52%), febrile neutropenia (46%, 21%), neutropenia (42%, 38%), and anemia (25%, 28%) for MBG453 + decitabine and MBG453 + azacitidine, respectively. Potentially treatment-related grade ≥3 immune-related adverse events occurred in 4 patients (3 AML, 1 MDS) in the MBG453 + decitabine arm. There were no potentially treatment-related grade ≥3 immune-related adverse events in the MBG453 + azacitidine arm. No treatment-related grade 4 immune-related adverse events or deaths occurred. Most patients on either combination were able to complete 8 cycles of therapy.
In the MBG453 + decitabine arm, overall response rate (ORR) among evaluable patients was 58% (11/19), 41% (7/17), and 24% (6/25) for high-risk MDS, newly diagnosed AML, and relapsed/refractory AML, respectively. Among responders, median exposure was 8.6 months (range, 2.0-26.7 months). In the MBG453 + azacitidine arm (median exposure duration 3.0 months), ORR among evaluable patients was 70% (7/10) for high-risk MDS and 27% (3/11) for newly diagnosed AML. In both arms, responses were seen with all 3 MBG453 doses. Doses of MBG453 400 mg every 2 weeks and 800 mg every 4 weeks were predicted to have similar average steady-state pharmacokinetic concentrations and similarly high receptor (TIM-3) occupancy rates (>95% occupancy in 95% of patients).
This study indicates that MBG453 combined with decitabine or azacitidine was safe and well-tolerated by these patient populations. Both combinations showed encouraging response rates and emerging durability.
Borate U, Esteve J, Porkka K, et al. Anti-TIM-3 Antibody MBG453 in Combination with Hypomethylating Agents (HMAs) in Patients (Pts) with High-Risk Myelodysplastic Syndrome (HR-MDS) and Acute Myeloid Leukemia (AML): A Phase 1 Study. Presented at: 25th European Hematology Association Congress Virtual; June 11-21, 2020. Abstract S185.