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Published on 17 March 2008

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Trabectedin (Yondelis®; ET-743): a drug of marine origin for soft-tissue sarcomas

teaser

Trabectedin’s efficacy in treating advanced soft-tissue sarcoma (STS) has been shown in phase II trials. It is the first real drug innovation for STS since the introduction of doxorubicine and ifosfamide

 

Patrick Schöffski
MD MPH

Professor

Guiseppe Floris
MD

Hans Wildiers
MD PhD

Cristiana Stefan
PhD

Aljosja Rogiers
Cand med

Herlinde Dumez
MD PhD

Department of General Medical Oncology
Leuven Cancer Institute
University Hospital Gasthuisberg
Leuven
Belgium

Soft-tissue sarcomas (STS) account for only 1% of all adult cancers.(1) Approximately 50% of patients develop distant metastases and cannot be cured by surgery. Most patients with metastatic disease die from the disease and median survival following diagnosis of metastases is in the range of only one year.(2,3) Systemic chemotherapy is the main treatment modality for metastatic sarcomas when complete resection of all metastases is not possible. STS is relatively insensitive to currently available chemotherapy agents. The standard first-line palliative treatment is single-agent doxorubicin, which produces response rates of only 10–25%.(4–8) Combination chemotherapy based on doxorubicin and ifosfamide increases response rates but does not improve overall survival as compared with single-agent anthracycline treatment.(4–7) Until very recently there were no approved options for patients failing both doxorubicin and ifosfamide.

A wide range of different agents have been investigated but best response rates have been only approximately 10% and no improvement in overall survival has been observed.(9) For this reason there is an urgent need for additional agents with significant activity in these tumours. Trabectedin recently received marketing approval from the European regulatory authorities for the treatment of STS.

Main discussion
Mode of action and preclinical antitumour activity
Trabectedin is a synthetically produced DNA-binding agent, originally derived from the marine tunicate Ecteinascidia turbinata. It binds reversibly to the minor groove of DNA (see Figure 1), but unlike other agents it bends the DNA towards the major groove, and interferes with the binding of other proteins to the DNA.(10) The antitumour effects result from this interference in the binding of other proteins to DNA, in particular transcription factors and DNA-repair proteins.

[[HPE37_fig1a_19]]

Trabectedin inhibits transcriptional activation of inducible genes.(11) Since transcription activation of specific genes is often important for the abnormal growth of cancer cells, inhibition of this activation can be expected to have an antitumour effect. The drug functions independently of human P-glyco­protein, and may therefore be effective in the treatment of multidrug-resistant tumours. Trabectedin slows progression of cells through the S phase of the cell cycle and arrests cells in G2/M, resulting in p53-independent apoptosis.(12,13) Cells in G1 are the most sensitive to inhibition by trabectedin.

Trabectedin interacts with the transcription ­coupled nucleotide-excision repair complex (TC-NER) pathway to induce lethal DNA strand breaks. The inhibitory effects of trabectedin are highly dependent on the presence of the TC-NER machinery, since cells lacking functional TC-NER are resistant to the cytotoxic effects of trabectedin. This is a unique characteristic, since the activity of other DNA-binding cytotoxic agents is either unaffected or decreased by the presence of functional DNA repair within the cell.(14)

The antitumour activity of trabectedin has been investigated both in vitro and in vivo. Trabectedin exhibits cytotoxic activity against various cancer models, and STS cell lines and xenografts are particularly sensitive.(15)

Dose finding and pharmacology
A number of phase I studies have established the recommended regimen for phase II studies in adult STS to be 1.5 mg/m2 administered as a 24-hour infusion three-weekly. The pharmacokinetics of this regimen was then studied in patients with sarcoma16 as well as other solid tumours.(17) The data are summarised in Table 1.

[[HPE37_tbl1a_19]]

Trabectedin undergoes extensive hepatic meta­bolism. Cytochrome P450 3A4 is the major enzyme involved in its metabolism but other P450 isozymes including CYP2C9, CYP2C19, CYP2D6 and CYP2E1, as well as the enzymes uridine diphospho­glucuronosyl and glutathione S-transferase are also involved.(18,19) Less than 1% of an administered dose is excreted unchanged in urine or faeces.(20) Following hepatic metabolism, trabectedin is largely excreted in the faeces.

Renal impairment does not influence the pharmaco­kinetics of trabectedin. Trabectedin has, however, not been investigated in patients with creatinine clearance of < 30 ml/min. However, hepatic impairment affects the pharmacokinetics of ­trabectedin. A correlation between liver dysfunction and severe toxicity became apparent during early phase II studies, leading to the introduction of strict criteria regarding liver function to be met for administering the drug.

Clinical efficacy
In patients with metastatic STS, prolongation of survival is the most important endpoint, which may not in all cases necessarily correlate directly with the tumour response rate. This has been demonstrated in an analysis of data from more than 2,000 patients.(21)

The general consensus is that progression-free survival (PFS) and overall survival (OS) are the most appropriate measures of efficacy in this setting.

The global outcome for sarcoma patients with prolonged stable disease is similar to that of patients achieving a partial response (PR).(6) Thus, tumour control rate (TCR, or progression-free rate, PFR), which includes patients who achieve a complete response (CR), PR, minor response or prolonged stable disease, seems more meaningful than the objective response rate (ORR) (ie, CR + PR) in assessing the benefit of such treatment. Thus, both PFS/OS and TCR are considered to be relevant parameters for assessing the efficacy of new agents in advanced STS.

The efficacy of trabectedin in previously treated patients with advanced STS has been demonstrated in three single-arm phase II studies involving 189 patients, with different STS subtypes.(22–25) ­Trabectedin was administered according to the recommended dose schedule as described above. Tumour responses were assessed after every two cycles of therapy.

In the three studies, one patient achieved a CR and 12 achieved PRs, giving ORRs of 3.7–8.3% (see Table 2). Median time to progression/progression-free survival was 1.7–3.5 months and median OS was 9.3–12.8 months (see Table 3).

[[HPE37_tbl2]]

[[HPE37_tbl3_19]]

A pooled analysis of data from the three studies was also performed.(26) Objective responses were achieved in 7.7% of patients and 43.8% had minor responses or disease stabilisation, giving a TCR of 51.4% (see Table 2). PFS at > 6 months was 19.8%, median OS was 10.3 months, one-year OS was 47.5% (see Table 3) and two-year OS was 29.3%. This compares favourably with the progression-free rate of 14% at six months found for other active regi­mens in pre-treated patients in previous series.

Trabectedin has limited or no cross-resistance with conventional chemotherapeutic agents and can be of benefit to patients for whom there is currently no effective therapy, ie those failing standard drugs.

The efficacy of trabectedin in previously treated patients with liposarcoma or leiomyosarcoma has been further investigated in a randomised phase II study comparing the three-weekly regimen with a weekly regimen (0.58 mg/m2 given as a three-hour infusion weekly for three weeks out of four).(27)

Our group has reported the efficacy of ­trabectedin in 89 pretreated patients with advanced or metastatic soft tissue or bone sarcoma.(28) Patients received trabectedin at a dose of 0.9–1.5mg/m2 as a 24-hour infusion three-weekly. Six patients achieved responses, giving an ORR of 6.7%. The clinical benefit rate was 38% at three months and 23% at six months. Median duration of response was 10 months and median overall survival 8.25 months.

Thus, data from these studies indicate that trabectedin can induce tumour control in approximately 50% of pretreated patients with advanced STS and that this is associated with a median OS of approximately 12 months in this poor-prognosis, pretreated-patient population. These data indicate that trabectedin is active in this setting and offers significant benefit to pretreated patients, which seems comparable with results achieved with classical agents in non-pretreated patients.

In previously-untreated patients with unresectable advanced STS, objective responses were seen in 17.1% of patients.(29) With a median follow-up of 25 months for surviving patients, median PFS was 1.6 months, PFS at six months was 24.4% and estimated one-year PFS was 21%. Median overall survival was 15.8 months and overall survival at one year was 72%. These results are generally ­comparable with the ORR and survival benefit achieved with standard chemotherapy.(3,30,5)

Safety and tolerability
The safety profile of trabectedin has been established in the three single-arm phase II studies.(22–24) Trabectedin is generally well tolerated, with adverse events being noncumulative, reversible and manageable. The main observed treatment-related severe toxicities (grade 3/4) were myelosuppression and elevations of hepatic transaminases (see Table 4). Severe neutropenia (grade 3/4) was found in 34–61% of patients. However, the incidence of febrile neutropenia was low (6–7%). Elevations in hepatic transaminases were transient and non-cumulative; peak levels occurred approximately four days after drug administration and returned to baseline by day 10–15. Grade 3/4 nausea and vomiting were observed in some patients. Unlike other commonly used cytotoxic agents, cardiotoxicity, neurotoxicity, alopecia, mucositis and diarrhoea were uncommon or not observed.

[[HPE37_tbl4_19]]

During the clinical trial programme, two key modifications were made concerning trabectedin administration, leading to improved safety profile of the drug.(16) Inclusion criteria for subsequent studies required normal alkaline phosphatase (ALP) levels. After taking into account these criteria patients were found to have a lower incidence of grade 3/4 toxicities (all types).(22) Furthermore, dex­amethasone was introduced as routine co-medication, reducing the incidence and severity of liver function abnormalities and other grade 3/4 events. Dexamethasone is now routinely given 20 mg of dexamethasone intravenously 30 minutes prior to Yondelis.

Thus, the results of these studies indicate that trabectedin is generally well tolerated and has a manageable safety profile when administered to appropriately selected patients (see Table 5) with dexamethasone as premedication.

[[HPE37_tbl5_19]]

Regulatory status and future perspective
Since STSs are rare cancers, an orphan status for trabectedin has been recognised in the EU. Marketing authorisation for trabectedin in pretreated STS patients was recently given by the European regulatory authorities. The drug is not yet approved on other continents.

Ongoing research suggests that it may be possible to identify patients who are likely to respond to trabectedin by analysing the expression of particular genes in the STS tumours.

In a recent retrospective study 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, especially compared with patients with low levels of ERCC1 and XPD and high levels of BRCA1.(31)

Myxoid/round-cell liposarcomas might be particularly sensitive to trabectedin.(32) Early changes in such tumours are followed by late-onset shrinkage of metastases leading to CR or PR in a considerable proportion of patients. While further studies are required to confirm this observation, these data suggest that trabectedin may be particularly effective against myxoid/round-cell liposarcomas. Various translational research projects are currently ongoing to elucidate this finding.

The unique mechanism of action of trabectedin and its distinct toxicity profile and limited cross-resistance with other cytotoxic agents suggest that further improvements in response and survival may be achieved by using trabectedin in combination with other agents.

The feasibility of combining trabectedin with ­doxorubicin, liposomal doxorubicin, docetaxel, ­paclitaxel or capecitabine has already been investigated in a number of phase I studies involving patients with solid tumours.(33–37) The drug should also be explored further in earlier settings of STS, and in other tumour types.

Conclusions
Trabectedin is a novel anticancer agent that has demonstrated significant activity in pre-treated patients with advanced STS, a class of patients for whom there are currently very few or no treatment options. Trabectedin exerts its effects through binding to the minor groove of DNA and therefore disrupts the function of DNA binding proteins.

STS cell lines and xenografts are particularly sensitive to trabectedin and the antitumour activity of ­trabectedin has been investigated in a number of phase II studies. The optimum dose and schedule of trabectedin is 1.5 mg/m2, administered as a 24-hour IV infusion every three weeks in adult patients. Routine co-medication involves dexamethasone and routine antiemetics.

The results of three phase II studies in previously treated patients with STS have shown that ­trabectedin can induce tumour control in approximately 50% of patients and is associated with a median OS of approximately 12 months. Thus, trabectedin is active in this setting and offers significant benefit to patients who have failed to respond to doxorubicin, ifosfamide or both. Trabectedin has also demonstrated interesting activity in previously untreated patients.

Trabectedin is generally well tolerated with adverse events being noncumulative, reversible and manageable. The most frequently reported severe adverse events are myelosuppression and transient elevations of hepatic transaminases.

Trabectedin is an important new anticancer agent that offers much promise for the treatment of advanced soft-tissue sarcomas. ■

References
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27. Samuels BL, et al. Randomized phase II study of trabectedin (ET-743) given by two different dosing schedules in patients with leiomyosarcomas or liposarcomas refractory to conventional doxorubicin and ifosfamide chemotherapy. ASCO 2004: abstract 9000.
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31. Schöffski P. DNA repair functionality as a molecular signature for sensitivity/resistance in sarcoma patients treated with trabectedin. AACR, 14–18 April 2007.
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33. Gianni L, et al. Definition of the least toxic sequence and optimal therapeutic dose of Yondelis in combination with doxorubicin in patients with untreated metastatic soft tissue sarcomas and advanced pre-treated anthracycline-naive breast cancer patients. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2003: abstract A49.
34. Cohen RB, et al. Final results of a combination study between trabectedin and pegylated liposomal doxorubicin in patients with advanced malignancies. ASCO 2005: Abstract 3074.
35. Papadopoulos KP, et al. Phase I and pharmacokinetic study of sequential paclitaxel and trabectedin every 2 weeks in patients with advanced solid tumors. ASCO 2006: abstract 2029.
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37. Gore L, et al. Phase I combination study of trabectedin and capecitabine in patients with advanced malignancies. ASCO 2006: abstract 2079.



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