Sabatolimab Plus Hypomethylating Agents as Frontline Therapy for Patients With Higher-Risk MDS

Results from the phase 2 STIMULUS-MDS1 trial

According to a recent study, the addition of sabatolimab to hypomethylating agents showed manageable safety, but did not result in a significant improvement in complete response rates (CRR) or progression-free survival (PFS) for patients with higher-risk myelodysplastic syndromes (MDS). 

This multicenter, randomized, double-blind, placebo-controlled, phase 2 trial—STIMULUS-MDS—was completed at 54 investigational sites in 17 countries and included adult patients (aged ≥18 years) with intermediate-risk, high-risk, and very high-risk myelodysplastic syndromes who had not received previous treatment. 

Patients were randomly assigned on a 1-to-1 basis to intravenous sabatolimab (400 mg on day 8 and day 22) or placebo plus a hypomethylating agent (intravenous decitabine 20 mg/m² on days 1 to 5 or intravenous or subcutaneous azacitidine 75 mg/m² on days 1 to 7 or days 1 to 5 and days 8 and 9) every 28 days until treatment discontinuation. The noted 2 primary endpoints were CRR and PFS, which were assessed in the full analysis set, and included all randomly assigned patients.

Between July 29, 2019, and Aug 10, 2020, 127 patients were randomly assigned to sabatolimab plus a hypomethylating agent group or placebo plus a hypomethylating agent; study findings demonstrated that the primary endpoints were not met. At the cutoff date of March 2021, complete response (CR) was achieved in 14 (22%; 95% confidence interval [CI], 12.3 to 33.5) of 65 patients in the sabatolimab group vs 11 (18%; 9.2 to 29.5) of 62 patients in the placebo group. At the cutoff date of the final analysis (March 1, 2022), the median follow-up for PFS was 17.8 months (interquartile range [IQR] 16.6 to 19.4) in the sabatolimab group and 19.2 months (17.7 to 22.3) in the placebo group. Additionally, the median PFS was 11.1 months (95% CI, 7.6 to 17.6) in the sabatolimab group vs 8.5 months (6.9 to 11.3) in the placebo group (hazard ratio [HR] 0.75 [95% CI, 0.48 to 1.17]; P = 0.1022).

Investigators noted that the most common adverse events of any grade included neutropenia, thrombocytopenia, constipation, diarrhea, anemia, febrile neutropenia, and leukopenia. It was recorded that 1 patient developed a serious potential treatment-related immune-mediated adverse event in the sabatolimab group. Additionally, there was one treatment-related death in the sabatolimab group due to pneumonitis.

Study authors concluded that while the addition of sabatolimab to hypomethylating agents did not result in a significant improvement in CRR and PFS, “sabatolimab had a manageable safety in most patients with higher-risk myelodysplastic syndromes.”

“A randomized phase 3 trial is ongoing to assess the potential benefit of sabatolimab plus azacitidine on overall survival in this setting,” they added.

Source:

Zeidan A, Ando K, Rauzy O, et al. Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): A randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Hematology. Published online December 5, 2023. doi: doi.org/10.1016/S2352-3026(23)00333-2