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Rigosertib fails to prolong OS in refractory MDS
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Rigosertib failed to significantly prolong OS compared with best supportive care in patients with myelodysplastic syndromes who had experienced hypomethylating drug treatment failure, according to the results of an open-label, randomized phase 3 trial.
Hypomethylating drugs — such as azacitidine (Vidaza, Celgene) or decitabine — serve as the standard treatment for patients with high-risk myelodysplastic syndromes (MDS). However, patients who experience hypomethylating drug treatment failure experience poor OS outcomes and have no approved second-line therapy.
Guillermo Garcia-Manero, MD, chair of the myelodysplastic syndromes section and deputy chair of translational research in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues sought to determine whether the Ras-binding small molecule rigosertib (ON 0190, Onconova Therapeutics) improved OS compared with best supportive care in 299 patients (median age, 74 years; range, 69-79) with MDS who had experienced treatment failure with azacitidine or decitabine within the prior 2 years. All patients had refractory anemia with excessive blasts, chronic myelomonocytic leukemia or refractory anemia with excessive blasts in transformation.
Guillermo Garcia-Manero
The researchers randomly assigned patients to biweekly rigosertib (n = 199) at 1,800 mg every 24 hours via a 72-hour continuous IV or to best supportive care (n = 100), with or without low-dose cytarabine.
OS in the intention-to-treat population served as the primary endpoint. Median follow-up was 19.5 months (interquartile range, 11.9-27.3).
The researchers observed a nonsignificant OS benefit in favor of rigosertib (median, 8.2 months vs. 5.9 months; HR = 0.87; 95% CI, 0.67-1.14).
No patients in either group achieved an overall complete or partial response. Fifty-three patients assigned rigosertib (27%) and 17 patients assigned best supportive care (17%) achieved a confirmed complete or partial bone marrow blast response.
Results of a post-hoc analysis showed rigosertib extended OS among patients with very high-risk baseline disease (7.6 months vs. 3.2 months; HR = 0.61; 99% CI, 0.36-1.03).
Rigosertib was associated with a higher rate of grade 3 or worse adverse events, including anemia (18% vs. 8%), thrombocytopenia (19% vs. 7%), neutropenia (17% vs. 8%), febrile neutropenia (12% vs. 11%) and pneumonia (12% vs. 10%).
Seventy-one patients (rigosertib, n = 41; best supportive care, n = 30) died due to adverse events, with three deaths directly attributed to rigosertib treatment.
The researchers acknowledged the trial’s concurrent enrollment of U.S. and European patients as a potential study limitation, because best supportive care options may differ between countries.
“A randomized phase 3 study is underway to assess the effect of rigosertib on OS for patients in selected subgroups that seemed to benefit from rigosertib,” Garcia-Manero and colleagues wrote.
Biomarkers should be included into the design of trials for MDS, Emilio P. Alessandrino, MD, and Matteo G. Della Porta, MD, both of University of Pavia Medical School in Italy, wrote in an accompanying editorial.
“In the next generation of clinical trials, whole populations of people with myelodysplastic syndromes will undergo comprehensive molecular analysis, and experimental treatment will be allocated according to the presence of specific predictive biomarkers,” Alessandrino and Della Porta wrote.
Molecular-based design of trails should improve OS in patients with MDS, they added.
“Structural changes in health care to support the use of genomic information in clinical trials and drug development are warranted, including the creation of genome diagnostic networks to address accrual of sufficient patients to enable adequate power and implementation of regulatory models for rapid testing of novel drugs in patients with specific genetic alterations,” Alessandrino and Della Porta concluded. – by Cameron Kelsall
Disclosure: Onconova Pharmaceuticals provided funding for this study. Garcia-Manero reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Alessandrino and Della Porta report no relevant financial disclosures.
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