Background
Phase 2, randomized, double-blind, placebo-controlled trial. 127 patients with previously untreated IPSS-R Intermediate, High, or Very High-risk MDS. Median age 73 years; 68% male; 61% White. Sabatolimab (MBG453) targets TIM-3, an immuno-myeloid regulator expressed on immune cells and leukemic stem cells. HMA backbone was investigator's choice of decitabine or azacitidine. 54 sites in 17 countries.
Interventions and follow up
Arm A: Sabatolimab 400 mg IV on days 8 and 22 + HMA (decitabine 20 mg/m² IV days 1–5, or azacitidine 75 mg/m² IV/SC days 1–7 or 5+2+2) every 28 days (n=65)
Arm B: Placebo + HMA (same schedule as Arm A) (n=62)
Primary endpoint: CR rate (IWG 2006) and progression-free survival (PFS)
mFollow up: 17.8 months (sabatolimab), 19.2 months (placebo) for PFS analysis
Arm B: Placebo + HMA (same schedule as Arm A) (n=62)
Primary endpoint: CR rate (IWG 2006) and progression-free survival (PFS)
mFollow up: 17.8 months (sabatolimab), 19.2 months (placebo) for PFS analysis
Results
CR rate: 22% (14/65) vs 18% (11/62), P=.77 (not significant)
Median PFS: 11.1 vs 8.5 months, HR 0.75 (95% CI 0.48–1.17), P=.1022 (not significant)
Median PFS: 11.1 vs 8.5 months, HR 0.75 (95% CI 0.48–1.17), P=.1022 (not significant)
Adverse events
Hematologic: neutropenia 56% vs 68%, thrombocytopenia 48% vs 51% (any grade); febrile neutropenia 35% vs 24%
GI: constipation 47% vs 38%, diarrhea 44% vs 22% (higher with sabatolimab)
Other: one treatment-related death in the sabatolimab arm (pneumonitis)
GI: constipation 47% vs 38%, diarrhea 44% vs 22% (higher with sabatolimab)
Other: one treatment-related death in the sabatolimab arm (pneumonitis)
Conclusions
Neither primary endpoint was met. Sabatolimab added to HMA did not significantly improve CR rates or PFS versus HMA alone in untreated HR-MDS. The HR of 0.75 for PFS represents a non-significant trend in this phase 2 study. A phase 3 trial (STIMULUS-MDS2) evaluating OS benefit is ongoing.
Key Limitations
Phase 2 sample size (n=127) was modest and likely underpowered to detect the observed PFS trend (HR 0.75). CR rate as a primary endpoint may underestimate immunotherapy benefit, which can manifest as delayed or durable responses not captured by CR. Higher diarrhea and febrile neutropenia rates with sabatolimab warrant monitoring. OS data were immature, and definitive efficacy awaits the larger phase 3 STIMULUS-MDS2 trial.
Clinical Context
STIMULUS-MDS1 is a phase 2 study that did not meet either primary endpoint. The non-significant PFS trend prompted continued evaluation in the phase 3 STIMULUS-MDS2 trial powered for OS. Sabatolimab (anti-TIM-3) is not approved for MDS. Azacitidine or decitabine monotherapy remains the standard HMA backbone in transplant-ineligible HR-MDS per ELN/ESMO guidance; TIM-3-targeting immunotherapy remains investigational pending phase 3 readout.