Adding Evofosfamide to Doxorubicin in Advanced Soft-Tissue Sarcoma
A phase III trial (TH CR-406/SARC021) has shown no survival benefit of adding evofosfamide to doxorubicin in the first-line treatment of locally advanced unresectable or metastatic soft-tissue sarcoma. Trial results were reported in The Lancet Oncology by Tap et al. Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard.
Study Details
In the open-label trial, 640 patients from 81 sites in 13 countries were randomized between September 2011 and January 2014 to receive evofosfamide plus doxorubicin (n = 317) or doxorubicin alone (n = 323). Doxorubicin was given at 75 mg/m² via bolus injection over 5 to 20 minutes or continuous infusion for 6 to 96 hours on day 1 of every 21-day cycle for up to 6 cycles. Evofosfamide was given at 300 mg/m² intravenously for 30 to 60 minutes on days 1 and 8 of every 21-day cycle for up to 6 cycles. After 6 cycles, patients in the doxorubicin group were followed, and patients with stable or responsive disease in the combination group were permitted to continue evofosfamide monotherapy until disease progression. The primary endpoint was overall survival in the intention-to-treat population.
Overall Survival
Median follow-up was 28.9 months. Median overall survival was 18.4 months in the combination group vs 19.0 months in the doxorubicin group (hazard ratio [HR]= 1.06, P = .527). Objective response was observed in 28% vs 18% (P = .0026). Median progression-free survival was 6.3 months vs 6.0 months (HR = 0.85, P = .099). Subsequent therapy was received by 74% of the combination group and 80% of the doxorubicin group.
Toxicity
The most common grade ≥ 3 adverse events in both groups were hematologic toxicities, including anemia (48% of the combination group vs21% of the doxorubicin group), neutropenia (15% vs 30%), febrile neutropenia (18% vs 11%), and leukopenia (7% vs 6%). Grade 3 or 4 stomatitis occurred in 8% vs 2% of patients. Serious adverse events occurred in 46% vs 32%. Treatment-related adverse events occurred in five patients in the combination group and one patient in the doxorubicin group.
The investigators concluded: “The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas, and so this combination cannot be recommended in this setting.”
The study was funded by Threshold Pharmaceuticals.
William D. Tap, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of The Lancet Oncology article.
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