Trabectedin prolongs progression-free survival in soft tissue sarcomas
By Will Boggs MD
NEW YORK (Reuters Health) - Trabectedin prolongs progression-free but not overall survival in patients with metastatic liposarcoma or leiomyosarcoma who have failed conventional chemotherapy, according to a new trial.
"The aim of this trial was not to replace or displace dacarbazine as an active chemotherapy option for patients with sarcomas - the aim was to see if this new drug could control metastatic sarcomas better than dacarbazine," said Dr. George D. Demetri from Harvard Medical School, Dana-Farber Cancer Institute, Boston.
"In the real world of clinical practice, it will not be a choice between trabectedin versus dacarbazine - it will be a new option for physicians to use both in sequence to provide some more options to patients who are seeking new options to forestall the risk of death from these dreadful diseases after other standard chemotherapies have already failed to control the disease," Dr. Demetri told Reuters Health by email.
Trabectedin, a marine-derived drug, has shown activity against metastatic soft tissue sarcomas in several trials, and the drug is approved worldwide except in the USA, Brazil, and Australia where it is under regulatory review.
In the current study, Dr. Demetri and colleagues compared the efficacy and safety of trabectedin versus dacarbazine in 518 patients with advanced liposarcoma or leiomyosarcoma.
Compared with dacarbazine, treatment with trabectedin was associated with a 45% reduction in the risk of disease progression or death (p<0.001), according to the report, online September 14 in the Journal of Clinical Oncology.
Median progression-free survival (PFS) was 4.2 months with trabectedin and 1.5 months with dacarbazine. At three months, 56% of trabectedin patients and 34% of dacarbazine patients had not progressed, while at six months the rates were 37% and 14%, respectively.
There were no complete responses with either treatment, and partial responses were not significantly more common with trabectedin than with dacarbazine (9.9% vs. 6.9%; p=0.33).
The clinical benefit rate (which combines objective disease response and durable stable disease) was significantly higher with trabectedin than with dacarbazine (34% vs. 19%, p<0.001).
Median overall survival at the interim analysis did not differ significantly between trabectedin (12.4 months) and dacarbazine (12.9 months). Seven treatment-related deaths were reported, all in the trabectedin group.
"Overall survival is a composite endpoint in any clinical trial that includes what the study drugs do, but also what happens to patients after they stop participating in the clinical trial," Dr. Demetri said. "Often the post-study interventions may impact survival of individuals, and this can confound the composite endpoint of overall survival." "I might argue that because the endpoint of disease control . . . is the most direct measure of study drug activity, the fact that there was a highly statistically significant difference in favor of trabectedin over the older standard (and active) chemotherapy, dacarbazine, further confirms the activity of trabectedin against these forms of soft-tissue sarcomas," Dr. Demetri said.
"On the basis of this PFS data alone, should trabectedin receive regulatory approval in the United States?" asks Dr. Gary K. Schwartz from Columbia University School of Medicine in New York in a related editorial. "In sarcoma, there clearly is precedent for this. The recent approval of pazopanib for patients with sarcoma who experienced failure of first-line chemotherapy was based on an improvement in PFS, not overall survival (OS), versus placebo in a randomized, phase III trial."
"Therefore, one could argue that, with so few drugs available for patients with sarcoma and with the manageable toxicity of trabectedin, this drug does merit approval by US regulators," he said. "However, this approval process may be confounded by another drug, eribulin, which was also compared with dacarbazine in a recently completed, randomized, phase III study for the L-sarcomas, leiomyosarcoma and liposarcoma."
Dr. Schwartz added, "We still do not know the overall clinical benefits in other sarcoma subtypes, including synovial cell sarcoma or other translocation sarcomas. Although trabectedin activity tends to favor well differentiated/dedifferentiated liposarcoma (WD/DDLS) subtypes, the benefits here still seem small, and it remains unclear whether the data are now sufficient to make trabectedin the standard of care for all patients with L-sarcoma, especially those with the WD/DDLS subtype."
Janssen Pharmaceuticals sponsored the trial, employed four of the authors, and had various relationships with eight of the other authors, including Dr. Demetri.
SOURCE: http://bit.ly/1F2tBkp and http://bit.ly/1QhvfyN
J Clin Oncol 2015.
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