No Significant Survival Advantage for Rigosertib in High-Risk Myelodysplastic Syndromes, but Subgroups May Benefit
As reported in The Lancet Oncology by Garcia-Manero et al, the phase III ONTIME trial showed that treatment with the Ras mimetic rigosertib did not significantly improve overall survival vs best supportive care in patients with high-risk myelodysplastic syndromes after failure of hypomethylating drug treatment. Rigosertib binds to the Ras-binding domain of multiple kinases, including RAF, PI3K, and RalGDS.
Study Details
In the open-label trial, 299 patients from 74 sites in the United States and Europe were randomly assigned two to one between December 2010 and August 2013 to receive rigosertib at 1,800 mg/24 hours via 72-hour continuous intravenous (IV) infusion every other week (n = 199) or best supportive care with or without low-dose cytarabine (n = 100). The primary outcome was overall survival in the intention-to-treat population.
Overall Survival
Median follow-up was 19.5 months. Median overall survival was 8.2 months (95% confidence interval [CI] = 6.1–10.1 months) in the rigosertib group vs 5.9 months (95% CI = 4.1–9.3 months) in the best supportive care group (hazard ratio = 0.87, P = .33). In a preplanned exploratory analysis among patients who had primary hypomethylating drug failure (127 in the rigosertib group, 57 in the best supportive care group), median overall survival was 8.6 vs 5.3 months (HR = 0.72, P = .060). In a post hoc analysis among patients with very high-risk disease on the Revised International Prognostic Scoring System (93 in the rigosertib group, 41 in the best supportive care group), median overall survival was 7.6 vs 3.2 months (HR = 0.61, P = .015).
Adverse Events
The most common grade ≥ 3 adverse events in the rigosertib group were thrombocytopenia (19% vs 7%), anemia (18% vs 8%), neutropenia (17% vs 8%), febrile neutropenia (12% vs 11%), and pneumonia (12% vs 11%). Three deaths were considered related to rigosertib treatment.
The investigators concluded: “Rigosertib did not significantly improve overall survival compared with best supportive care. A randomized phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria.”
The study was funded by Onconova Therapeutics and the Leukemia & Lymphoma Society.
Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author of The Lancet Oncology article.
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