Ecteinascidin-743 (ET-743): early test or effective treatment in soft tissue sarcomas?

Historically, phase II oncology studies have been used only for early screening, given that a control group is usually not used. Positive results in such single-arm studies are then followed by phase III studies to evaluate whether a new drug is a new standard of care. Sometimes, however, particularly in rare diseases for which randomized studies are difficult, two or more single-arm phase II studies may strongly suggest that a change in the standard of care is forthcoming. This issue of the Journal of Clinical Oncology includes such an example. In the late 1960s, extracts of the Caribbean marine tunicate Ecteinascidia turbinata were found to inhibit cell proliferation. However, it was not until the 1990s that the active compound, ecteinascidin-743 (ET-743; also known as trabectedin and Yondelis), was isolated, purified, and synthesized. Most likely, the compound is produced by the marine tunicate as a defense mechanism to survive in its natural environment. The cytotoxic effects of ET-743 seem to result from the selective alkylation in GC-rich regions of the minor groove of DNA. Although loss of mismatch repair does not affect the cytotoxicity of ET-743, lack of functional DNA-dependent protein kinase (involved in the DNA double-strand break repair pathway) leads to an increase in cytotoxicity. In preclinical studies, ET-743 was found to be particularly potent against a variety of soft tissue sarcoma cell lines, even those resistant to many other cytotoxic agents. The cytotoxicity of ET-743 was dose and time related (4 to 72 hours exposure). Cytotoxic concentrations of ET-743 produced an S/G2 block in all of the cell lines tested. All but one line had mutations in p53 and/or overexpressed the MDM2 protein and expressed the retinoblastoma protein. Because of its unique features, ET-743 was taken into clinical development, and activity in soft tissue sarcomas was suggested even in the phase I studies. Before formally testing the agent in this group of diseases, a pooled analysis from a phase I study and compassionate-use program reported that 14 of 25 patients with soft tissue sarcomas did not progress while on ET-743. Subsequently, a series of phase II studies were performed in patients failing prior chemotherapy. All studies have been using ET-743 at a dose of 1.5 mg/m as a 24-hour continuous infusion every 3 weeks. The European Organisation for Research and Treatment of Cancer (EORTC) studied ET-743 in 99 assessable patients who received a total of 410 cycles. There were eight partial responses (8%) and 45 patients with stable disease (44%), which lasted 6 months in 26% of the patients. Taken together, these results indicate a progression-arrest rate (partial response no change) of 53% (95% CI, 42% to 62%). The median duration of the time to progression was 105 days, and the 6-month progression-free survival rate was 29%. The median duration of survival was 9.2 months. In gastrointestinal stromal tumors, no activity was noted. Yovine et al treated 52 patients who were pretreated more heavily than those treated by the EORTC and received a median of three cycles (range, 1 to 20); 28% received six or more cycles. They observed two partial responses and 13 patients (25%) with stable disease, for a progression-arrest rate of 29% (95% CI, 17% to 43%). The 6-month progression-free survival rate was 24%. Median survival was 12.8 months, with 30% of patients alive at 2 years. Garcia-Carbonero et al treated 36 patients and observed one complete and two partial responses, for an overall response rate of 8% (95% CI, 2% to 23%). Responses were durable for up to 20 months. Unfortunately, the authors did not provide data on the number of patients with stable disease, but the estimated 1-year time to progression and overall survival rates were 9% (95% CI, 3% to 27%) and 53% (95% CI, 39% to 73%), respectively. In an ongoing randomized phase II study comparing a 3and 24-hour infusion of the same dose, progression-arrest rates ranged from 47% to 64%. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 24 AUGUST 2