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ET-743
Risto S Cvetkovic1, David P Figgitt, Greg L Plosker
1Adis International Limited, Auckland, New Zealand. demail@adis.co.nz
Abstract:
ET-743 is a novel antineoplastic DNA-binding agent derived from the marine tunicate Ecteinascidia turbinata. It has significant cytotoxic activity against soft tissue sarcomas (STS). It also has in vitro activity against melanoma, breast, ovarian, colon, renal, non-small cell lung and prostate carcinomas. The drug has unique mechanism of action which includes in vitro inhibition of transcription-dependent nucleotide excision repair pathways and inhibition of cell cycle progression leading to p53-independent apoptosis. It also selectively inhibits transcriptional activation of multidrug-resistance (MDR1) gene in human sarcoma cells in vivo. The efficacy of ET-743 has been investigated in patients with advanced STS in three multicentre phase II clinical trials. Patients receiving ET-743 as second- or third-line treatment had partial tumour response rates of 6 to 8%. Patients receiving ET-743 as first-line chemotherapy had a partial response rate of 18%. Forty-two to 50% of all patients in these trials achieved stable disease. All responses were durable up to 14 months. A pooled analysis of the three multicentre phase II trials showed the following: median overall survival time of 10.2 months, 1-year survival rate of 40% and 6-month progression-free rate of 27.2%. ET-743 is generally well tolerated. The most common adverse events in clinical trials were non-cumulative haematological and hepatic toxicities. Transient and reversible elevation of hepatic transaminases, nausea, vomiting and asthenia were common but seldom severe and never treatment-limiting. Mucositis, alopecia and cardiac or neurotoxicities were not observed.
Insights
Ecteinascidin 743 (ET-743), a marine-derived DNA-binding agent, shows promise in treating advanced soft tissue sarcomas (STS). Clinical trials indicate durable tumor responses and manageable toxicities, suggesting its potential as an effective antineoplastic therapy.
Area of Science:
- Pharmacology
- Oncology
- Marine Biotechnology
Background:
- Ecteinascidin 743 (ET-743) is a novel DNA-binding antineoplastic agent derived from the marine tunicate Ecteinascidia turbinata.
- ET-743 exhibits significant in vitro cytotoxic activity against various cancer types, including soft tissue sarcomas (STS), melanoma, and carcinomas of the breast, ovary, colon, kidney, lung, and prostate.
Purpose of the Study:
- To evaluate the efficacy and safety of ET-743 in patients with advanced soft tissue sarcomas (STS).
- To investigate the unique mechanism of action of ET-743, including its effects on DNA repair, cell cycle progression, apoptosis, and multidrug resistance (MDR1) gene expression.
Main Methods:
- Three multicenter Phase II clinical trials were conducted to assess ET-743 efficacy in advanced STS patients.
- Pooled analysis of trial data included response rates, duration of response, overall survival, and progression-free survival.
- Adverse events were systematically recorded to evaluate the safety profile of ET-743.
Main Results:
- Partial tumor response rates ranged from 6-8% for second/third-line treatment and 18% for first-line chemotherapy.
- 42-50% of patients achieved stable disease, with durable responses up to 14 months.
- Median overall survival was 10.2 months, with a 1-year survival rate of 40% and a 6-month progression-free rate of 27.2%.
Conclusions:
- ET-743 demonstrates notable efficacy in advanced STS, with durable responses and encouraging survival outcomes.
- The drug is generally well-tolerated, with manageable hematological and hepatic toxicities being the most common adverse events.
- ET-743's unique mechanism of action, including inhibition of transcription-dependent repair and MDR1 gene expression, contributes to its antineoplastic activity.