Sabatolimab, an immunotherapeutic therapy targeting TIM-3 on immune and myeloid cells, was well-tolerated and led to durable clinical responses when combined with hypomethylating agents (HMAs) in patients with very high/high-risk myelodysplastic syndrome (vHR/HR-MDS) and newly diagnosed acute myeloid leukemia (AML). These findings were presented during the 2021 ASH Annual Meeting by Andrew M. Brunner, MD, of the Massachusetts General Hospital in Boston.
The results represented updated data from a phase Ib study, which included 53 patients with vHR/HR-MDS and 48 patients with newly diagnosed AML at time of the data cutoff. All patients in the open-label, multicenter study had received sabatolimab plus HMAs.
Dr. Brunner and colleagues evaluated safety and tolerability of the combination. An additional secondary objective was to evaluate the combination’s preliminary efficacy, assessed using overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). In addition, the investigators evaluated the proportion of patients who experienced a possible immune-mediated adverse event (imAE) in patients who achieved disease remission.
The most common grade ≥3 adverse events (AE), reported in 15% or more patients, included thrombocytopenia (43.4% in vHR/HR-MDS and 45.8% in newly diagnosed AML), neutropenia (47.2% and 50.0%), anemia (28.3% and 33.3%), and febrile neutropenia (35.8% and 29.2%). Treatment discontinuation due to an AE was reported in only three patients with newly diagnosed AML.
Nearly 25% of patients with vHR/HR-MDS experienced a degree of improvement that allowed them to undergo hematopoietic cell transplantation (HCT). During the study, six patients with vHR/HR-MDS and 10 with ND-AML experienced possible imAEs. The researchers reported that few patients experienced clinically significant possible imAEs, and no grade ≥3 possible imAEs were reported in the vHR/HR-MDS group. Five patients with newly diagnosed AML experienced grade 3 imAEs, but none of the patients had grade 4/5 possible imAEs.
“The observed relationship between response and possible imAEs in vHR/HR-MDS would need further confirmation in ongoing studies, but suggests that an immunomodulatory mechanism of sabatolimab may be contributing to clinical responses,” the researchers wrote.
In the 51 patients with vHR/HR-MDS who were considered evaluable for response, the ORR was 56.9%. Additionally, the median DOR in the vHR/HR-MDS group was 16 months, while the median DOR in patients with CR was 21.5 months.
The estimated 12-month PFS was 51.9%. In the 40 patients with newly diagnosed AML, the ORR was 40.0% and the median DOR was 12.6 months. In addition, the median DOR in patients with CR was 23.0 months. The estimated 12-month PFS rate in the newly diagnosed AML population was 27.9%.
According to the investigators, there were durable responses in patients with adverse-risk mutations, including patients with vHR/HR-MDS and TP53 mutations (ORR = 71.4%; median DOR = 21.5 months) and patients with newly diagnosed AML and ≥1 European LeukemiaNet adverse-risk mutation (ORR = 53.8%; median DOR = 12.6 months).
Approximately 75% of patients in remission did not experience an imAE; however, a greater proportion of patients with vHR/HR-MDS who achieved remission had a possible imAE compared with patients without remission (25%). In the group of patients with newly diagnosed AML, the frequency of possible imAEs was similar regardless of remission achievement.
The authors added that, in patients with vHR/HR-MDS who underwent HCT, outcomes were generally favorable following the transplant procedure and no excess toxicities related to graft-versus-host disease were reported.
Study authors report relationships with Novartis, the manufacturer of sabatolimab.
Brunner AM, Esteve J, Porkka K, et al. Efficacy and Safety of Sabatolimab (MBG453) in Combination with Hypomethylating Agents (HMAs) in Patients (Pts) with Very High/High-Risk Myelodysplastic Syndrome (vHR/HR-MDS) and Acute Myeloid Leukemia (AML): Final Analysis from a Phase Ib Study. Abstract #244. Presented at the 2021 American Society of Hematology Annual Meeting, December 11, 2021.