Trabectedin for Soft Tissue Sarcoma: Current Status and Future Perspectives

Abstract

Trabectedin (ET743, Yondelis®, manufactured by Baxter Oncology GmbH, Halle/Westfalen, Germany, for Janssen Products, LP, Horsham, PA), derived from the marine ascidian, Ecteinascidia turbinata, is a natural alkaloid with multiple complex mechanisms of action. On 23 October 2015, 15 years after the results of the first Phase 1 clinical trial using trabectedin for chemotherapy-resistant solid malignancies was reported, and 8 years after its approval in Europe, the United States Food and Drug Administration (USFDA) finally approved trabectedin for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma that has failed a prior anthracycline-containing regimen. Approval was based on the results of a pivotal Phase 3 trial involving a 2:1 randomization of 518 patients (who were further stratified by soft tissue sarcoma subtype), in which a significant improvement in progression-free survival was reported in the trabectedin-treated group vs. the dacarbazine-treated group (p < 0.001). In this trial, the most common adverse reactions were nausea, fatigue, vomiting, constipation, anorexia, diarrhea, peripheral edema, dyspnea, and headache, while the most serious were neutropenic sepsis, rhabdomyolysis, cardiomyopathy, hepatotoxicity, and extravasation leading to tissue necrosis. The most common grade 3–4 adverse events were laboratory abnormalities of myelosuppression in both arms and transient transaminitis in the trabectedin arm. In a recent Phase 2 trial, trabectedin had a similar outcome as doxorubicin when given as a single agent in the first-line setting. Studies are also being conducted to expand the use of trabectedin not only as a first-line cancer drug, but also for a number of other clinical indications, for example, in the case of mesenchymal chondrosarcoma, for which trabectedin has been reported to be exceptionally active. The possibility of combining trabectedin with targeted therapies, immune checkpoint inhibitors or virotherapy would also be an interesting concept. In short, trabectedin is an old new drug with proven potential to impact the lives of patients with soft tissue sarcoma and other solid malignancies.Funding: Sarcoma Oncology Center, Santa Monica, CA 90405.

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

“…Moreover, MLS was shown to be sensitive to trabectedin (ET-743, Ecteinascidin), a natural alkylating agent derived from a marine tunicate [11]. The drug has a complex mechanism of action that is not entirely elucidated but involves binding to the DNA-minor groove, interaction with DNA repair complexes, and additional effects on the tumor microenvironment [12].…”

Trial Watch: Immunotherapy plus radiation therapy for oncological indications

“…In addition, the safety and efficacy of EBRT combined with immunotherapy is being assessed in the context of (1) adoptive cell transfer, 87,212 in colorectal cancer patients receiving autologous DCs plus cytokine induced killer (CIK) cells along with FOLFOX (folinic acid plus 5-fluoruracil plus oxaliplatin) chemotherapy (NCT02202928), sarcoma patients treated with autologous CD8 C cytotoxic T lymphocytes (CTLs) genetically modified to recognize the TAA NY-ESO-1 (NCT02319824), and hepatocellular carcinoma patients receiving highly purified autologous CD8 C CTLs (NCT02678013); (2) TLR stimulation, 94 in soft tissue sarcoma patients receiving the experimental TLR4 agonist glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) 213,214 (NCT02180698), lymphoma patients concurrently administered with the experimental TLR9 agonist SD-101 215,216 (NCT02266147), and melanoma patients co-treated with the FDA-approved TLR7 agonist imiquimod [217][218][219][220][221] (NCT02394132); and (3) relatively unspecific immunostimulation with recombinant IL-2 or GM-CSF in patients with renal cell carcinoma (NCT02306954), glioblastoma (NCT02 663440), and NSCLC (NCT02735850), with thymalfasin (a recombinant version of the human T H 1-skewing peptide thymosin a1) 222 in colorectal cancer patients (NCT02535988), lung cancer patients (NCT02542137, NCT02542930), and esophageal cancer patients (NCT02545751), with TAM-targeting agents like trabectedin [223][224][225] or zoledronic acid 128,226 in subjects with soft tissue sarcoma (NCT02275286) or metastatic NSCLC (NCT02480634), with a chemical inhibitor of IDO1 (i.e., indoximod) 196,227 in children with brain tumors concurrently receiving temozolomidebased chemotherapy (NCT02502708), with chemical inhibitors of the TGFb1 receptor [228][229][230] in breast carcinoma patients (NCT025 38471) and rectal carcinoma patients concurrently treated with standard-of-care chemotherapy (NCT026887129), and with celecoxib, an inhibitor of the immunosuppressive enzyme prostaglandin-endoperoxide synthase 2 (PTGS2; best known as COX2), 231,232 in HNSCC patients (NCT02739204) ( Table 2).…”

Natural and Biomimetic Antitumor Pyrazoles, A Perspective

“…Natural products were, traditionally, the main source of medicinal actives, and today they continue to provide useful new drugs. Examples of natural antitumorals include paclitaxel (taxol) [1] and a few marine drugs such as cytarabine, eribulin, and trabectedin [2][3][4][5][6]. Notably, five-membered heterocycles are found in a variety of natural antitumor compounds.…”