Trabectedin proved superior to standard dacarbazine therapy by numerous measures but not by overall survival in an industry-sponsored phase III clinical trial reported online Sept. 14 in Journal of Clinical Oncology.
Trabectedin, which has been used extensively in Europe for a decade but has not been approved in the U.S., has a complex mechanism of action that affects several critical cell biology processes within and surrounding tumor cells. It exhibited activity against metastatic soft tissue sarcomas in several phase II trials, said Dr. George D. Demetri of the Ludwig Center at Harvard Medical School and the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, both in Boston, and his associates.
Dr. George Demetri
In this study, trabectedin was assessed in 518 patients aged 15 years and older who had heavily pretreated and rapidly progressing advanced or metastatic liposarcoma or leiomyosarcoma and were treated at 85 sites in four countries. These participants were randomly assigned to receive either trabectedin (345 patients) or dacarbazine (173 patients) via central intravenous infusion in 3-week cycles.
Compared with dacarbazine, trabectedin reduced the risk of disease progression by 45% (hazard ratio, 0.55), and superior disease control was discernible at the first patient assessment at 6 weeks. Median progression-free survival was significantly longer with trabectedin (4.2 months) than with dacarbazine (1.5 months), a benefit that was consistent across all 19 subgroups of patients assessed in sensitivity analyses, regardless of disease histology, previous therapies, or any clinical characteristics. Trabectedin also bested dacarbazine with regard to objective response rate (9.9% vs. 6.9%), median duration of response (6.5 months vs. 4.2 months), achievement of stable disease (51% vs. 35%), and achievement of durable stable disease (34% vs. 19%).
Trabectedin showed only a nonsignificant 13% reduction in overall survival, which was the primary endpoint of this study. However, several previous studies have demonstrated that it can be extremely difficult to prolong overall survival despite robust improvements in progression-free survival in patients with advanced sarcomas. Given this “historical difficulty in demonstrating overall survival improvement,” the documentation of disease control such as that achieved in this study may be considered a measure of clinically relevant efficacy in this setting, Dr. Demetri and his associates wrote (J. Clin. Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4734]).
Adverse events in this study population “were consistent with the well-characterized safety and toxicity profiles of both study drugs.” Toxicity was more common with trabectedin, and deaths considered to be treatment-related occurred only in the trabectedin group: three cases of sepsis/septic shock and one each of rhabdomyolysis/sepsis, renal failure, cardiac arrest, and multiorgan failure, for a treatment-related mortality of 2.1%.