FDA Approves YONDELIS® for Soft Tissue Sarcomas

SUMMARY: The U.S. FDA approved YONDELIS® (Trabectedin) for the treatment of patients with unresectable or metastatic Liposarcoma or Leiomyosarcoma, who have received a prior Anthracycline-containing regimen. Soft Tissue Sarcomas are a heterogeneous group of tumors of mesenchymal origin with over 50 different histological variants. The American Cancer Society estimates that in 2015, about 11,930 new soft tissue sarcomas will be diagnosed in the United States and 4,870 patients will die of the disease. The most common types of Soft Tissue Sarcomas in adults are undifferentiated pleomorphic sarcoma (previously called Malignant Fibrous Histiocytoma), Liposarcoma, and Leiomyosarcoma. Chemotherapy is the standard of care for advanced Soft Tissue Sarcomas. Following first line therapy with Anthracycline or Ifosfamide based chemotherapy regimens, Response Rates are low and second line treatment options are limited. YONDELIS® (Trabectedin) originally isolated from the Caribbean sea sponge (Ecteinascidia turbinate) is a synthetic alkaloid that binds to the minor groove of DNA and induces apoptosis by damaging the DNA.

Based on promising phase II trials, a randomized, open-label, multicenter, phase III trial was conducted, in which 518 patients with unresectable, locally advanced or metastatic Liposarcoma or Leiomyosarcomas were randomly assigned in a 2:1 to receive either YONDELIS® or Dacarbazine. YONDELIS® was dosed at 1.5 mg/m2, administered as an intravenous infusion over 24 hours (N=345) and Dacarbazine was dosed at 1000 mg/m2 administered as an intravenous infusion over 20 to 120 minutes (N=173) and the treatment was given once every 3 weeks. The median age was 56 years and enrolled patients were heavily pretreated and had received prior Anthracycline containing chemotherapy regimens. Close to 90% of the patients had received at least two prior lines of chemotherapy. Patients were stratified by Soft Tissue Sarcoma subtype (Leiomyosarcoma vs Liposarcoma), ECOG performance status, and number of prior chemotherapy regimens. The primary end point was Overall Survival (OS) and secondary end points included Progression Free Survival (PFS), Time To Progression, Objective Response Rate, Duration of Response, as well as safety.

This study demonstrated a statistically significant improvement in PFS in the YONDELIS® group with a 45% reduction in the risk of disease progression or death compared with Dacarbazine (HR= 0.55; P<0.001). The median PFS was 4.2 and 1.5 months in the YONDELIS® and Dacarbazine groups, respectively. This benefit was noted in patients with both Leiomyosarcoma and Liposarcoma. The greatest benefit in median PFS (5.6 months vs 1.5 months with YONDELIS® vs Dacarbazine, respectively) was noted in the myxoid or round cell Liposarcomas, which are considered as translocation-related sarcomas. This additional benefit can be explained based on the direct inhibition by YONDELIS®, of the chimeric FUS-CHOP translocation-generated oncoprotein, which regulates transcriptional activity in myxoid or round cell Liposarcomas. There was however no significant difference in the median Overall Survival between YONDELIS® and Dacarbazine (12.9 months vs 12.4 months, P=0.37). This may be due to crossover of close to 30% of patients who progressed on Dacarbazine to Receptor Tyrosine Kinase Inhibitor, VOTRIENT® (Pazopanib), which was approved in the U.S. during the course of this study. Most of patients who benefited from YONDELIS®, experienced stable disease as their best response for longer durations, compared to those with Dacarbazine (51% vs 35%).

The most common adverse reactions (20% or more) with YONDELIS® were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. The most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases. The authors concluded that YONDELIS® significantly improves Progression Free Survival with superior disease control compared to Dacarbazine, in patients with heavily pretreated, advanced Liposarcoma and Leiomyosarcoma. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. Demetri GD, von Mehren M, Jones RL, et al. J Clin Oncol, doi: 10.1200/JCO.2015.62.4734.