The addition of palifosfamide to doxorubicin failed to improve survival in a phase III trial of patients with metastatic soft-tissue sarcoma.
The addition of palifosfamide to doxorubicin failed to improve progression-free survival (PFS) or overall survival (OS) vs doxorubicin alone in a phase III trial of patients with metastatic soft-tissue sarcoma (STS). The observed survival times can serve as benchmarks for future trials in this malignancy, according to the researchers.
“More than 40 years after the first reports of activity in sarcoma, doxorubicin is still the standard first-line treatment for most patients,” wrote study authors led by Christopher W. Ryan, MD, of Oregon Health & Science University in Portland. Ifosfamide is also considered a good treatment option, but it requires careful management and carries significant toxicity risks. Palifosfamide is that agent’s active metabolite, and could bypass some of the toxicities.
On the basis of a PFS advantage shown in a phase II trial with doxorubicin and palifosfamide, the researchers conducted a randomized phase III trial including 447 patients with metastatic STS who had received no prior systemic therapy. A total of 226 patients received doxorubicin plus palifosfamide, and 221 received doxorubicin plus placebo. The results were published in the Journal of Clinical Oncology.
The primary endpoint of PFS was no different between the groups, with a median of 6.0 months with the combination and 5.2 months with placebo, for a hazard ratio (HR) of 0.86 (95% CI, 0.68–1.08; P = .19). No subgroups showed any improvement with palifosfamide over placebo.
The median OS was also similar, at 15.9 months with palifosfamide and 16.9 months without it, for an HR of 1.05 (95% CI, 0.79–1.39; P = .74).
There were more responses with palifosfamide than with placebo (P = .047); most of these were partial responses, with only 3 and 2 patients in each group achieving a complete response. The clinical benefit rate, defined as complete or partial response or stable disease for 12 weeks, was 51.8% with palifosfamide and 41.2% without it (P = .02). The duration of responses was similar between the groups.
All of the 434 patients available for safety evaluation experienced at least one treatment-emergent adverse event, but the combination group had more toxicity. Grade 3/4 adverse events occurred in 63.6% of palifosfamide patients and in 50.9% of doxorubicin plus placebo patients (P = .0075). Among the more common grade 3/4 adverse events were anemia, neutropenia, febrile neutropenia, and thrombocytopenia, all of which occurred more frequently with palifosfamide.
“Although higher response rates suggest some level of increased antitumor activity with combination regimens, the lack of significant differences in OS across several studies provides an argument against the routine use of combination doxorubicin-based cytotoxic therapy in the metastatic setting,” the authors wrote. They noted that the median PFS and OS of 5.2 and 17 months should be used as a reference in the design of future metastatic STS trials.