Low Impact Studies: 01/01/2024
Evaluating Sabatolimab in High-Risk Myelodysplastic Syndromes: Insights from the STIMULUS-MDS1 Phase 2 Trial.
The phase 2 trial, "Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1)", aimed to assess the efficacy and safety of sabatolimab in combination with hypomethylating agents in patients with untreated higher-risk myelodysplastic syndromes (MDS) (1). This double-blind, placebo-controlled study enrolled 127 patients across 54 sites in 17 countries, randomizing them to receive either sabatolimab or placebo alongside standard hypomethylating therapy. The primary outcomes, complete response rate, and progression-free survival showed no significant difference between the two groups. The safety profile of sabatolimab was manageable, with common adverse events including neutropenia and thrombocytopenia. Overall, the addition of sabatolimab did not significantly improve outcomes compared to standard treatment, although a phase 3 trial is in progress to further investigate its potential benefits.
Evaluation of Clinical Impact: Based on the study's findings, the clinical impact of adding sabatolimab to standard treatment for higher-risk MDS is evaluated as low. The lack of significant improvement in primary endpoints (complete response rate and progression-free survival) indicates that sabatolimab, in this context, does not substantially enhance the efficacy of existing treatments. However, its manageable safety profile and the ongoing phase 3 trial warrant continued investigation.
1. Zeidan AM, Ando K, Rauzy O, Turgut M, Wang MC, Cairoli R, Hou HA, Kwong YL, Arnan M, Meers S, Pullarkat V, Santini V, Malek K, Kiertsman F, Niolat J, Ramos PM, Menssen HD, Fenaux P, Miyazaki Y, Platzbecker U. Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Haematol. 2024 Jan;11(1):e38-e50. doi: 10.1016/S2352-3026(23)00333-2. Epub 2023 Dec 5. PMID: 38065203.
Histone Deacetylase Inhibitor (Entinostat)/Anti-PD1 Antibody (Pembrolizumab)
The study was a phase Ib multicenter trial exploring the combination of entinostat, a histone deacetylase inhibitor, and pembrolizumab, an anti-PD1 antibody, in treating myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) that are refractory to hypomethylating agents (2). Targeting 28 patients (25 with MDS and 3 with AML), the trial used a 3 + 3 dose escalation design, with entinostat administered orally and pembrolizumab intravenously. The study reported limited efficacy, with only two patients achieving marrow complete remission and notable toxicity, including severe adverse events like pneumonia and pharyngeal mucositis. The findings suggest limited clinical benefit and considerable toxicity, emphasizing the necessity for further research in treating advanced MDS and AML.
Clinical Impact Evaluation
The potential clinical impact of this study is Low. Despite the innovative approach of combining entinostat with pembrolizumab, the trial demonstrated limited efficacy and significant toxicity. The lack of protocol-defined responses in the majority of patients, coupled with severe adverse events, highlights the challenges in treating MDS and AML refractory to hypomethylating agents and underscores the need for alternative therapeutic strategies.
2. Bewersdorf JP, Shallis RM, Sharon E, Park S, Ramaswamy R, Roe CE, Irish JM, Caldwell A, Wei W, Yacoub A, Madanat YF, Zeidner JF, Altman JK, Odenike O, Yerrabothala S, Kovacsovics T, Podoltsev NA, Halene S, Little RF, Piekarz R, Gore SD, Kim TK, Zeidan AM. A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents. Ann Hematol. 2024 Jan;103(1):105-116. doi: 10.1007/s00277-023-05552-4. Epub 2023 Dec 1. PMID: 38036712.