First-Line Evofosfamide Plus Doxorubicin Fails To Improve Advanced Soft-Tissue Sarcoma OS

Patients with inoperable locally advanced or metastatic soft-tissue sarcoma do not derive an overall survival benefit from the addition of evofosfamide to doxorubicin chemotherapy

medwireNews: Phase III trial findings do not support the combination of doxorubicin and evofosfamide for treatment-naive patients with locally advanced, unresectable or metastatic soft-tissue sarcoma.

The primary endpoint of overall survival (OS) was slightly shorter for the patients given doxorubicin with the hypoxia-activated prodrug of bromo-isophosphoramide mustard than for those given doxorubicin alone, at a median of 18.4 versus 19.0 months and a nonsignificant hazard ratio (HR) of 1.06.

Progression-free survival (PFS) was also comparable, at 6.3 months for the combination arm and 6.0 months for doxorubicin monotherapy, despite patients given evofosfamide plus doxorubicin having significantly higher rates of overall response (28 vs 18%) and disease control (73 vs 66%).

Further analysis demonstrated a significant OS gain with combined therapy among patients with synovial sarcoma compared with doxorubicin alone, with a HR of 0.32. But “the benefit noted needs to be taken with some consideration” as the subgroup included just 33 patients, the researchers remark in The Lancet Oncology.

“We would like to see an additional study in synovial sarcoma and think the majority of the sarcoma community would be in favour and supportive of such a trial”, write William Tap, from the Memorial Sloan Kettering Cancer Center in New York, USA, and co-authors.

And although the combined therapy was “generally well tolerated, it was more toxic than doxorubicin monotherapy”, the researchers say, with higher rates of grade 3 or more severe anaemia (48 vs 21%), febrile neutropenia (18 vs 11%) and thrombocytopenia (14 vs 1%).

The open-label multicentre study included 317 patients randomly assigned to receive up to six 21-day cycles of intravenous evofosfamide 300 mg/m2 for 30–60 minutes on days 1 and 8, alongside doxorubicin 75 mg/m2 given as a bolus over 5–20 minutes or as a 6–96 hour infusion on day 1 of each cycle. A further 323 patients received the doxorubicin regimen alone.

The authors explain that the study design followed a nonrandomised phase II trial of evofosfamide indicating “substantial activity” in soft-tissue sarcoma, including additional responses in patients who received maintenance evofosfamide.

However, as in the phase II study, the phase III trial allowed rather than mandated continuous evofosfamide monotherapy and may therefore have missed the opportunity to show a stronger survival benefit, they say.

There was also a lack of placebo and study blinding, the researchers highlight, and doxorubicin-only patients were censored for PFS after a median of 192 days, mainly when they went onto receive further treatment, versus 638 days for the combined group.

“The imbalance in design could also have affected overall survival because patients in the doxorubicin group received subsequent therapy sooner and more frequently than those in the combination group”, they say.

William Tap et al note that any enhanced activity of a later line treatment in the doxorubicin-only group relative to evofosfamide also had the potential to impact OS, especially as time on treatment was much shorter, at a median of 4.5 months, than the OS in the doxorubicin monotherapy arm.

“This time after treatment is not inconsequential because of recent advancements in the sarcoma treatment landscape (eg, trabectedin , eribulin , and votrient)”, they add.

The authors therefore conclude: “Although the combination did not improve overall survival compared with doxorubicin alone, the study further defines outcomes for doxorubicin as a single drug when used in the first-line setting for patients with metastatic soft-tissue sarcoma and raises important issues regarding the design of large randomised clinical trials in this rare, heterogeneous, and difficult-to-treat group of malignancies.”


Tap WD, Papai Z, Van Tine BA, et al. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol; Advance online publication 23 June 2017. DOI:

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