An investigational first-in-class anticancer quinolone derivative, vosaroxin, extended median overall survival (OS) when used with cytarabine (Cytosar-U) in a phase 3 clinical trial of patients with relapsed or refractory acute myeloid leukemia (AML), although the difference was not significant.
The benefit was more pronounced in older patients aged >60 years, a group in which the favorable effect of vosaroxin did achieve significance, according to Farhad Ravandi, MD, Professor of Medicine, Department of Leukemia, M.D. Anderson Cancer Center, Houston.
Vosaroxin intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-specific DNA damage, G2 arrest, and apoptosis. The FDA has granted orphan drug status to vosaroxin for AML, and a fast track designation for the potential treatment of relapsed or refractory AML in combination with cytarabine.
Dr Ravandi discussed data from a 124-site international randomized trial of 711 patients with relapsed or unresponsive AML. All patients received intravenous cytarabine 1 g/m2 on days 1 to 5, and were randomized to the addition of placebo or intravenous vosaroxin 90 mg/m2 on days 1 and 4 for induction and 70 mg/m2 for subsequent cycles.
The median OS times were 7.5 months in the vosaroxin arm and 6.1 months in the placebo arm, with a hazard ratio (HR) of 0.865 (P = .06). A predefined analysis of OS censoring for stem-cell transplantation showed that patients randomized to the vosaroxin arm had a median OS of 6.7 months compared with 5.3 months in the placebo arm (HR, 0.809; P = .02). The secondary end point of complete remission rate of vosaroxin versus placebo was 30.1% versus 16.3%, respectively (P <.001).
The trial also stratified patients by age ≥60 years and <60 years. Within a predefined analysis of patients aged <60 years, the combination of vosaroxin and cytarabine had a median OS of 9.1 months compared with 7.9 months for placebo plus cytarabine, a nonsignificant difference.
In patients aged ≥60 years, the median OS was 7.1 months in the vosaroxin arm compared with 5.0 months in the placebo arm (HR, 0.755; P = .006).
“Although it is clear that we still have a long way to go to improve outcomes for such patients, these data provide support that the vosaroxin/cytarabine combination is the most effective approach to date for treatment of older patients with this challenging condition,” said Dr Ravandi.
David P. Steensma, MD, a hematologist/oncologist at Dana-Farber Cancer Institute, Boston, called these results “underwhelming” and “not a great leap forward.” Dr Steensma noted, “AML is a really difficult population, no question about it, but there’s also no question that 7.5 months is pretty crummy, and we need to do better than that.”
Dr Ravandi countered that 1-month and 2-month improvements in survival are exciting in the treatment of solid tumors, “and I don’t see why we shouldn’t be excited in AML as well,” he said. “In my opinion, these data support the use of this therapy in older patients with AML.”
As expected, the vosaroxin arm had greater toxicity, “because if you use 2 cytotoxic agents, you are going to see more myelosuppression,” Dr Ravandi said. The toxicity with vosaroxin was mainly related to myelosuppression, with no increase in organ toxicity.