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Published on 3 October 2008

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Trabectedin in sarcoma

teaser

DNA-binding agent trabectedin is being explored for treating advanced soft tissue sarcoma and other cancers. Its antitumour activity and relatively low toxicity make it a promising therapy.

Ahmad Awada
MD PhD

Head

Thierry Gil
MD

Assistant Professor

Medical Oncology Clinic
Jules Bordet Institute
Brussels
Belgium

Trabectedin (Yondelis; ET-743) is a synthetically produced DNA-binding agent, originally derived from the marine tunicate Ecteinascidia turbinata. The antitumour effects of trabectedin
result from interference in binding of proteins to DNA such as transcription factors and DNA-repair proteins (see Figure 1). The antitumour activity of trabectedin has been investigated both in vitro and in vivo. Soft tissue sarcoma (STS) cell lines and xenografts are particularly sensitive.

The recommended regimen for phase II studies in adult STS has been established at 1.5mg/m2 administered as a 24-hour infusion three-weekly. Trabectedin metabolism is mainly hepatic by several cytochromes, in particular CYP P450 3A4. Following hepatic metabolism, trabectedin is largely excreted in the faeces.

Renal impairment does not influence the pharmacokinetics of trabectedin, but this drug has not been investigated in patients with creatinine clearance of <30ml/min.

Soft tissue sarcomas (STS)
STS account for only 1% of all adult cancers. Surgery is the main treatment used by experienced surgeons. Radiation therapy is indicated for large tumours and/or those with narrow margins. Chemotherapy (using doxorubicin or ifosfamide) may be discussed in the adjuvant setting in some patients with sarcomas of the extremities.

Approximately 50% of patients develop distant metastases and cannot be cured by surgery. Systemic chemotherapy is the main treatment modality when resection is not possible. Combination chemotherapy produces better response rate and progressionfree survival but does not improve overall survival as
compared with single-agent treatment.

Tumour control rate (CR, PR, minor response, prolonged stable disease), progression-free survival and overall survival are considered to be relevant parameters for assessing the efficacy of new agents in advanced STS.

Efficacy of trabectedin in STS
A pooled analysis of data from three studies in previously
treated patients has been reported.[2] Objective responses were achieved in 7.7% of patients, and 43.8% had minor responses or disease stabilisation, giving a tumour control rate of 51.4%. PFS at six months was 19.8%, median OS was 10.3 months, one-year OS was 47.5%. In previously untreated patients, objective responses were seen in 17.1% of patients, PFS at
six months was 24.4%, estimated one-year PFS was 21% and overall survival at one year was 72%.[3] These results are generally comparable with those achieved with standard chemotherapy.

In a recent restrospective analysis involving 181 STS patients treated with trabectedin, patients with high levels of expression of ERCC1 and XPD (markers of DNA nucleotide excision repair) and low levels of expression of BRCA1 (marker of double-strand DNA break repair capacity) were highly sensitive to trabectedin.[4] In addition, myxoid/round-cell liposarcomas might be particularly sensitive to trabectedin.[5]

Side-effects
The main observed treatment-related severe toxicities were noncumulative, reversible and manageable myelosuppression
and elevation of hepatic transaminases. Severe neutropenia (grade 3/4) was found in 34-61% of patients. However, the incidence of febrile neutropenia was low (7%). Elevations of hepatic transaminases were transient. Peak levels occurred approximately four days after drug administration and returned to baseline by day 10-15.

In order to reduce toxicities, inclusion criteria to be met for patients to receive trabectedin have been made more precise (see Table 1). Furthermore, 20mg of dexamethasone was introduced as routine comedication administered intravenously 30 min prior to trabectedin.[1]

In contrast to the situation with other commonly used cytotoxic agents, cardiotoxicity, neurotoxicity, alopecia, mucositis and diarrhoea were uncommon.

[[HPE40.18]]

Conclusions and perspectives
Trabectedin is an important new anticancer agent that offers much promise for the treatment of advanced STS. The feasibility of combining trabectedin with other cytotoxic agents has already been investigated, but the role of these combinations is not yet clear.

Molecular markers predictive of this drug’s efficacy are under investigation. Trabectedin has also been studied in other solid tumours, such as breast and ovarian cancers, where it has shown hints of antitumour activity.

Trabectedin was investigated in two phase II trials in an unselected group of patients with metastatic breast cancer (response rates were 13% and 14%, respectively).

Given the potential sensitivity of triple-negative (no oestrogen, progesterone, HER2 expression) to DNA-damaging agents and similarity to tumours with BRCA1 mutations, this agent is undergoing phase II testing in three subgroups of patients with metastatic breast cancer: triple-negative, HER2-positive and
BRCA1- or BRCA2-mutation carriers. With this trial design, the goal is to determine which subpopulation of breast cancer will best respond to treatment with trabectedin.[6]

[[HPE40.18b]]

References
1. Schoffski P, Floris G, Stefan C, et al. Trabectedin (Yondelis; ET-743): a drug of marine origin for soft-tissue sarcomas. Hosp Pharm Europe 2008;REF:19-23.
2. Le Cesne A, et al. Impact of Yondelis in the natural history of patients with pretreated advanced soft tissue sarcomas: long-term follow-up results. Paper presented at ACR-NCI-EORTC International Conference on Molecular Targets and Cancer
Therapeutics; 2003: abst 31.
3. Garcia-Carbonero R, et al. J Clin Oncol 2005;23(24):5484-92.
4. Schoffski P. DNA repair functionality as a molecular
signature for sensitivity/resistance in sarcoma patients treated with trabectedin. Paper presented at AACR, 14-18 April 2007.
5. Grosso F, et al. Lancet Oncol 2007;8(7):595-602.
6. Wasserman EJ, Tan AR. Evolving strategies for the treatment of “triple-negative” breast cancer. In: ASCO Educational Book 2008;120-6.



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