Evaluating MBG453 Plus Decitabine or Azacitidine in High-Risk MDS and AML

The anti-TIM-3 checkpoint inhibitor MBG453, when added to decitabine or azacitidine, was associated with antileukemic activity and durable response rates in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), according to a study presented by Uma Borate, MD, at EHA25 Virtual, the 25th European Hematology Association Annual Congress.

MBG453 is a monoclonal antibody that targets TIM-3, a key factor in tumor tolerance and leukemic stem cell preservation, Dr. Borate explained. TIM-3 is expressed on leukemic stem cells and blasts, but not on normal hematopoietic stem cells, making it a promising target in MDS/AML.

“Using this approach to build on existing standard-of-care therapies has the potential to increase efficacy and duration of response,” she said. “By exploring further studies and novel combinations, we hope it can improve survival for our patients as well.”

In this phase I trial, investigators enrolled a total of 106 patients with Revised International Prognostic Scoring System (R-IPSS) high or very high-risk MDS (n=34) or newly diagnosed or relapsed/refractory AML (n=72). All patients were naïve to hypomethylating agents (HMAs) and were considered poor candidates for intensive chemotherapy. The median age of the study population was 71 years.

Patients received escalating doses of intravenous MBG453 240 mg or 400 mg once every 2 weeks (days 8 and 22) or 800 mg once every 4 weeks (day 8), plus intravenous decitabine 20 mg/m2 on days 1-5 or subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7, every 28 days.

The median exposure durations were 4.9 months (range = 0.7-26.7) for the MBG453/decitabine group and 3.0 months (range = 0.1-9.2) for the MBG453/azacitidine group. A total of 15 patients and 19 patients in the decitabine and azacitidine groups, respectively, had ongoing exposure at time of data cutoff.

The maximum tolerated dose was not reached for either combination therapy by the time of data cutoff. Only 1 dose-limiting toxicity (DLT) – a corticosteroid-responsive grade 3 elevation in alanine transaminase (ALT) – was observed with MBG453 240 mg plus decitabine once every 2 weeks. There were no DLTs with MBG453 and azacitidine, the researchers reported.

The most common grade 3 and 4 treatment-emergent adverse events (AEs) in the MBG453 plus decitabine and MBG453 plus azacitidine arms included thrombocytopenia (41% vs. 52%, respectively), febrile neutropenia (46% vs. 21%), neutropenia (42% vs. 38%), and anemia (25% vs. 28%).

There were no treatment-related deaths. Four patients in the MBG453/decitabine combination group had ≥1 potentially immune-related and treatment-related grade ≥3 AE, which included an increase in ALT, arthritis, hepatitis, hypothyroidism, and rash. In the MBG453/azacitidine group, there were no treatment-related grade ≥3 potentially immune-related AEs.

The response rates for evaluable patients in the decitabine and azacitidine arms are presented in the TABLE. Response rates appeared to be higher among patients treated with decitabine, which Dr. Borate attributes to a shorter follow-up and smaller patient population in the azacitidine arm and which will need to be reassessed with longer follow-up and more mature data.

In the pharmacokinetics and pharmacodynamics analyses, the investigators predicted that MBG453 400 mg once every 2 weeks and 800 mg once every 4 weeks have similar mean steady state pharmacokinetic concentrations and similar high receptor occupancy rates, including >95% occupancy in approximately 95% of patients.

“I am encouraged to see that immune-based therapy in the form of a monoclonal antibody targeting TIM-3 in combination with HMAs appears to not only be active, but also very well tolerated in this patient population,” Dr. Borate told ASH Clinical News when asked about the clinical implications of these findings. “If further studies continue to show efficacy, I can envision subsets of MDS and AML that respond well to targeting the immune microenvironment in addition to HMAs or targeted therapies.”

Study authors report relationships with Novartis, which sponsored this trial.


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 I study. Abstract S185. Presented as part of EHA25 Virtual, June 12, 2020.