ASH 2022 | Primary results from the STIMULUS-MDS1 trial: HMAs in combination with sabatolimab for HR-MDS

So in the ASH meeting I presented our randomized Phase II trial called the STIMULUS-MDS1 in patients with high-risk MDS. So this trial randomized patients with high-risk MDS into two groups, one to receive standard of care hypomethylating agents with placebo. And the other group, which is a randomized, or the interventional arm, used hypomethylating agents with sabatolimab.

So sabatolimab is an immune checkpoint inhibitor. It’s an antibody against an immune receptor called TIM-3. TIM-3 is present not only on the T-cells, so it modulates the adaptive immune system, but also it works on the innate immune system such as NK cells and the macrophages, as well as on the leukemia stem cells. And early data suggested that inhibition of TIM-3 can lead to clinical activity in a Phase Ib study that was presented earlier.

So based on this data, the randomized Phase II study called the STIMULUS-MDS1 was conducted. So this is a large global study, it enrolled 127 patients. It enrolled in, I think, close to 15 countries and 47 centers. The patient had to be very high, or high, or intermediate risk according to the revised IPSS, but if they were intermediate risk, they had to have 5% or more blasts. And they were randomized into the two arms I mentioned in a one-to-one fashion, based or certified by the type of HMA as well as the IPSS revised risk group. The primary endpoint of the study was complete response rate and progression-free survival, and there were a number of secondary endpoints including overall survival.

So a total 427 patients were treated on the study. They were typical MDS patients, the median age was 73. Most of those patients had higher risk disease according to the revised IPSS. And around one third of patients, 35% surprisingly had TP53 in mutation, which is more than what we typically expect. And I think that’s partly because investigators chose to enroll these patients because their disease generally is very poorly responsive to standard treatment.

So in terms of toxicity and safety evaluation, it was very similar to the earlier studies. We did not pick up any new signals. Generally the drug was well tolerated, and the immune related adverse events were generally rare. It doesn’t seem to add to the myelosuppression of HMA-based treatment. In terms of the efficacy, the primary endpoint of the study was not met, so there was no statistically significant difference in CR rate or in progression-free survival. However, when you look at the progression-free survival curves, there appears to be a late separation, which could be related to the late impact of the sabatolimab as an immunotherapy.

And we did a number of exploratory analyses that suggested that some of the benefit, if there’s a benefit, is going to be seen in patients with lower burden disease with less than 10% plus, or among patients who have intermediate or high IPSS molecular risk group.

Patients with TP53 surprisingly, even those on the control arm had a median survival of 15 months, which is much longer than typically seen on clinical studies. And I think this highlights the importance of a randomized study. There was no difference in the overall survival between the two groups either.

So based on this, there’s already a randomized Phase III trial that is fully accrued. It’s called STIMULUS-MDS2. We expect results from this study in 2024, and I think it’s going to provide the definitive answer on the role of sabatolimab in patients with MDS.