Trabectedin and the L-Sarcomas: A Decade-Long Odyssey

Soft tissue sarcomas (STS) are a complex, heterogeneous group of more than 50 neoplasms ofmesenchymal origin. According to the American Cancer Society, in 2015, approximately 11,930 patients in theUnited States will be diagnosedwith STS and nearly 4,870 will die as a result of the disease. In the metastatic setting, cytotoxic chemotherapy is the standard of care and is often considered palliative. In first-line treatment, chemotherapy consists of doxorubicin (with or without ifosfamide) or gemcitabine plus docetaxel. Second-line therapies can include either dacarbazine or pazopanib. On the basis of data from the European Organisation for the Research and Treatment of Cancer, an active regimen in the second-line setting is one in which 40%of patients are progression free at 12 weeks. So, the bar to identify a successful second-line regimen in patients with metastatic STS has been set very low. In the article that accompanies this editorial, Demetri et al report on the first randomized, phase III trial of trabectedin in patients with chemotherapy-refractory leiomyosarcoma or liposarcoma. Although the compound is now chemically synthesized, trabectedin (Ecteinascidin-743, ET-743; PharmaMar, Madrid, Spain) was originally isolated from the Caribbean sea sponge Ecteinascidia turbinate. It covalently binds to the minor groove of DNA to cause drug-induced DNA damage, which results in perturbations in the cell cycle and induction of apoptosis. On the basis of several nonrandomized, phase II studies reported a decade ago and of a randomized trial in which two different dosing schedules of trabectedin were evaluated, the drug was approved by European regulators in 2007 for patients with advanced STS who experienced failure of treatment with doxorubicin and ifosfamide. This decisionwas also based in part on a promising 12-week progression-free survival of 52% that exceeded the lower standard set for all active second-line agents for sarcoma by the European Organisation for the Research and Treatment of Cancer. Trabectedin administered by intravenous infusion at 1.5 mg/m over 24 hours every 3 weeks seemed to produce themost efficacy, especially in patients with leiomyosarcoma and liposarcoma (the L-sarcomas); therefore, this dose and schedule for these specific sarcoma subtypes were selected for the randomized, phase III US trial. Five hundred eighteen patients with leiomyosarcoma and liposarcoma were randomly assigned 2:1 to receive either trabectedin or dacarbazine. The patient population was heavily pretreated: 88% had received at least two prior lines of chemotherapy. The primary end point was overall survival (OS), and the secondary end point was progression-free survival (PFS). In terms of PFS, the study achieved favorable PFS rates at 3 and 6months of 56% and 37%, respectively, in the trabectedin arm versus 34% and 14%, respectively, in the dacarbazine arm. The median PFS was better with trabectedin at 4.2 months than with dacarbazine at 1.5 months. This PFS benefit was observed for patients with both leiomyosarcoma and liposarcoma. In terms of median OS, there was no significant difference between trabectedin (12.9 months) versus dacarbazine (12.4 months). What have we learned from this large, randomized, phase III trial? It confirmed what the European investigators claimed a decade ago—that trabectedin, in fact, is an active agent in the treatment of specific STS subtypes. The degree of toxicity, especially neutropenia and transaminitis, is consistent with we have known about the drug, and the grade 4 toxicities are quite similar to those of dacarbazine. On the basis of prior experience with this drug in clinical trials, the benefit in leiomyosarcoma (both uterine and nonuterine) was expected. However, because dacarbazine is considered an active agent in leiomyosarcoma, it was not clear until this randomized study was completed how much better trabectedin activity would be. Yet, of all the results of this study, the most surprising is its reported benefit in patients with a diagnosis of liposarcoma. Liposarcoma is a complex disease, because it consists of several subtypes: well differentiated (WDLS), dedifferentiated (DDLS; often an admixture of the two, or WD/DDLS), myxoid/round cell (MRCL), and pleomorphic. The benefit of trabectedin in the MRCL subtype is consistent with clinical activity reported with this agent in patients with the so-called translocation-related sarcomas, of which theMRCL variant is included. The genetic hallmark of MRCL is a translocation, t(12; 16)q13;p11), that creates a chimeric fusion protein, FUS-CHOP, that binds to specific DNA promoters. Because trabectedin binds to and alters DNA-protein interactions, it is not surprising to see clinical benefit in this patient population. This is consistent with small clinical trials from Europe that have already reported clinical activity with trabectedin in this liposarcoma subtype. In fact, the median PFS of 5.6 months with trabectedin in MRCL in this current randomized, phase III trial exceeds the median PFS observed for leiomyosarcoma (4.3 months) with this same agent. However, the benefit of trabectedin versus dacarbazine reportedly occurs in all liposarcoma subtypes. This is most surprising for the WDLS and the DDLS subtypes, which together rank among the most common of all sarcomas. Clinically, when the WDLS subtype predominates, the disease can be indolent, such that patients can live for years without any intervention other than surgery. When the DDLS subtype predominates, the tumor can be aggressive, and systemic therapies are often considered.We have learned a lot about the biology of these two subtypes during the past several years. Both of these