Background
Phase III international, multicentre, open-label RCT (TH CR-406/SARC021). N=640 with locally advanced unresectable or metastatic soft-tissue sarcoma (STS), no prior palliative chemotherapy, ECOG PS 0-1; 81 sites, 13 countries. Evofosfamide (TH-302) is a hypoxia-activated prodrug releasing bromo-isophosphoramide mustard (Br-IPM) in hypoxic tumor; hypothesis: hypoxia-activated alkylation complements doxorubicin in well-oxygenated compartments. NCT01440088.
Interventions and follow up
Arm A: Doxorubicin 75 mg/m² IV q3wk + evofosfamide (TH-302) 300 mg/m² IV days 1 and 8 of each 21-day cycle, up to 6 cycles; evofosfamide monotherapy thereafter at investigator discretion
Arm B: Doxorubicin 75 mg/m² IV q3wk alone, up to 6 cycles
Primary endpoint: Overall survival (all patients and prespecified leiomyosarcoma/angiosarcoma subgroup)
mFollow up: ~24 mo
Arm B: Doxorubicin 75 mg/m² IV q3wk alone, up to 6 cycles
Primary endpoint: Overall survival (all patients and prespecified leiomyosarcoma/angiosarcoma subgroup)
mFollow up: ~24 mo
Results
mOS (all STS): no significant difference; HR ~1.0 (95% CI crossing unity), P>.05 (NS)
mOS (doxorubicin alone): 19.0 mo (95% CI 16.2-22.4)
mPFS: no significant difference between arms
ORR: numerically higher with combination but no OS benefit
mOS (doxorubicin alone): 19.0 mo (95% CI 16.2-22.4)
mPFS: no significant difference between arms
ORR: numerically higher with combination but no OS benefit
Adverse events
Grade ≥3 (more frequent with evo+dox): nausea, mucositis, anaemia, neutropenia
Hematologic toxicity: greater with combination, with more dose reductions
Skin/mucosal: toxicities characteristic of the bromo-alkylating metabolite
Discontinuation: higher in combination arm
Hematologic toxicity: greater with combination, with more dose reductions
Skin/mucosal: toxicities characteristic of the bromo-alkylating metabolite
Discontinuation: higher in combination arm
Conclusions
Adding evofosfamide to doxorubicin did not improve OS or PFS versus doxorubicin alone in advanced STS, despite higher response rates and toxicity. Hypoxia-activation did not translate to survival benefit in unselected STS; the combination cannot be recommended.
Key Limitations
Unselected, histologically heterogeneous STS population without a hypoxia biomarker to enrich for evofosfamide responders, likely diluting any benefit. Open-label design; higher combination toxicity may have limited dose intensity. Negative primary endpoint.
Clinical Context
A pivotal negative trial: single-agent doxorubicin remains the first-line standard for most advanced STS per ESMO, with evofosfamide not adopted. Reinforces that anthracycline-doublet additions have repeatedly failed to improve OS in unselected STS, supporting biomarker-driven and histology-specific strategies.