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Journal of Clinical Oncology, Vol 23, No 24 (August 20), 2005: pp. 5420-5423 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.905
Ecteinascidin-743 (ET-743): Early Test or Effective Treatment in Soft Tissue Sarcomas?Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands 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.1-3 Most likely, the compound is produced by the marine tunicate as a defense mechanism to survive in its natural environment.1,4 The cytotoxic effects of ET-743 seem to result from the selective alkylation in GC-rich regions of the minor groove of DNA.5-7 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.8 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.9 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.10,11 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-743.12 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/m2 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 patients13 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.14 Yovine et al15 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 al16 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 3- and 24-hour infusion of the same dose,17 progression-arrest rates ranged from 47% to 64%. It is important to note that in an analysis of all patients entered onto those phase II studies, it was shown that patients were selected with a clearly and sometimes even rapidly progressing tumor,18 suggesting that there was no selection bias toward a population that would respond more favorably. The fact that the data are obtained through different research groups also suggests that, despite the lack of randomized data, the remarkable consistency in outcome between the studies is not a result of patient selection and can be considered to be a true observation. In this issue of JCO, Garcia-Carbonero et al19 report on their experience using ET-743 at a dose of 1.5 mg/m2 given as a 24-hour continuous intravenous infusion every 21 days in 36 patients who did not receive prior chemotherapy for advanced disease. Previous neoadjuvant/adjuvant chemotherapy was allowed if it was concluded more than 12 months before study entry, but this only involved 11% of the study population. Objective responses were achieved in six of 35 assessable patients (one complete and five partial responses), for an overall response rate of 17% (95% CI, 7% to 34%). If one excludes the single case of chondrosarcoma, the response rate was 18%. The fact that the tumor bulk was more than 5 cm in two thirds of the patients and more than 10 cm in 19% of the patients suggests that the investigators did not select a "better" population. Although the study basically confirms activity of ET-743 in soft tissue sarcomas, it suggests that the single-agent activity may be in the same range as for the only two other agents with activity in this disease, doxorubicin and ifosfamide.20-23 Their single-agent first-line activity is reported to be between 10% and 30%, depending on the study. In most reported randomized studies, single-agent doxorubicin yields similar response rates as combination treatment,24 yet this is still debated in clinical practice. However, there is consensus in the studies that a combination of agents does not yield a better survival rate.21,24-26 Even dose-intensified chemotherapy was unable to improve survival in randomized studies,27,28 although it clearly increases toxicity. In this respect, the data in the Garcia-Carbonero et al19 study are intriguing. The observed median duration of response was 16.5 months (range, 5.1 to 32.5 months), and the overall survival rate at 1 year was 72% (95% CI, 59% to 88%). The median overall survival was 15.8 months. At the very least, these data suggest a survival rate in the same range as, if not better than, that achieved with not only single-agent doxorubicin or ifosfamide (8 to 12 months)21-25 but also with combination chemotherapy (9 to 12 months),21,25,26 including dose-intensified chemotherapy.27 This obviously will have to be confirmed in a randomized comparison. As was seen originally with doxorubicin and ifosfamide, ET-743 activity was detected in a patient who had received prior therapy,28,29 but it is remarkable that even patients failing two previous lines of chemotherapy can respond to ET-743.12,13,15,16 This further indicates that ET-743 is an active agent in soft tissue sarcomas. Tumor responses were observed in a number of different sarcoma subtypes, and given the limited numbers of patients per subtype, even if taken across the studies, it is far too early to suggest that a particular subtype is more sensitive than another. It will be important to find such differentiating factors, if any exist. It may well be that subtype is far less important than molecular features. The important survival figures obtained with ET-743 balanced against the relatively modest objective regression rates lend additional support to the idea that we have wrongly ignored the relevance of stable disease in soft tissue sarcomas in previous decades. This is exemplified by the fact that in almost all of the phase II studies performed in the United States, the number of patients with stable disease is not even published.30 In an analysis of the progression-arrest rate, ET-743 also ranks among the active agents in soft tissue sarcomas, again jointly with doxorubicin and ifosfamide. Because of this, most recent studies in soft tissue sarcomas have shifted to reporting progression-free disease rates at 3 and/or 6 months, as suggested by the EORTC,31 instead of response rates. It is clear that for soft tissue sarcomas, a duration component should be included in activity assessment. Distinguishing the effects of therapy from the natural history of the disease in patients with stable disease will be challenging for both investigators and regulators (eg, US Food and Drug Administration), especially if randomized trials are not feasible because of the rarity of the disease. The activity of ET-743 comes at a cost of manageable toxicity. Garcia-Carbonero et al19 report that grade 3 to 4 leukopenia and neutropenia occurred in 22% and 33% of the patients, respectively, with no episodes of neutropenic fever. The other major adverse event was hepatic toxicity, which in 34% (AST) and 36% (ALT) of the patients was of grade 3 or 4. These liver-enzyme elevations occurred within 3 to 4 days of drug administration and reverted to baseline values in all instances, never causing treatment discontinuation. This result is consistent with the reported data on second-line use.13-16 Also, all studies report that patients may tolerate up to 38 cycles at a dose intensity of 90%, indicating that toxicity is not cumulative, which is in contrast to the cumulative toxicity observed with both doxorubicin and ifosfamide.32 When appropriately dealing with the necessity to modify doses based on bilirubin and/or alkaline phosphatase changes, ET-743 seems to be a relatively safe drug. Garcia-Carbonero et al19 also report pharmacokinetic parameters that were similar to reports from other studies. It is important to note that total body clearance was not significantly correlated with body-surface area (r = –0.28; P = .21), confirming previous observations.33 Severity of treatment-related toxicity was not correlated with pharmacokinetic variables. Thus, delivering a fixed amount of drug without adjustment for the height or weight of the patient may be more appropriate than dosing per body-surface area. This adds ET-743 to the long list of drugs for which dosing per body-surface area does not really make sense.34-36 It is unfortunate that the use of body-surface area–based dosing has not yet been eliminated from the ongoing studies of this agent. The development of ET-743 has been difficult, partly because it is focused primarily on a rare disease. Yet, it stimulated the revision of the best assessment of drug activity in phase II screening studies in soft tissue sarcomas and exemplifies the fact that dosing strategies may need revision as well. Nevertheless, it is evident that the agent has major activity in soft tissue sarcomas. For a final appraisal of its place in the treatment of soft tissue sarcomas, randomized studies have been designed and are currently ongoing. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members has indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,999 (C)
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23. Verweij J, Lee SM, Ruka W, et al: Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: A study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 18:2081-2086, 2000 24. Bramwell VHC, Anderson D, Charette ML: Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: A meta-analysis and clinical practice guideline. Sarcoma 4:103-112, 2000 25. Santoro A, Tursz T, Mouridsen H, et al: Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: A randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 13:1537-1545, 1995
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35. Baker SD, Verweij J, Rowinsky EK, et al: Role of body-surface area in dosing of investigational anticancer agents in adults: 1991-2001. J Natl Cancer Inst 94:1883-1888, 2002 36. Felici A, Verweij J, Sparreboom A: Dosing strategies for anticancer drugs: The good, the bad and body-surface area. Eur J Cancer 38:1677-1684, 2002 Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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