teaser
Trabectedin has shown impressive activity in soft-tissue sarcomas, with a manageable noncumulative toxicity profile, and is preferentially active against myxoid liposarcomas and leiomyosarcoma. Combinations with other agents are being investigated
Jan H Beumera,b
PharmD PhD
Assistant Professor
Hussein Tawbia,c,d
MD
Assistant Professor
aMolecular Therapeutics/
Drug Discovery Program,
University of Pittsburgh
Cancer Institute
bDepartment of
Pharmaceutical Sciences
School of Pharmacy
cDepartment of Medicine
School of Medicine
dSarcoma Program
University of Pittsburgh
Pittsburgh, PA
Sarcomas consist of a wide range of different histologies. Soft-tissue sarcomas (STS) are malignancies of the connective tissue, totalling more than 50 histological subtypes with heterogeneous clinical and pathological features. Sarcomas account for 1% of adult malignancies.[1] The multidisciplinary management of STS is best done in highvolume centres by experienced teams.[1,2] Surgery is the only curative option for localised sarcomas. Adjuvant radiotherapy improves outcome, while adjuvant chemotherapy remains controversial.
Despite optimal treatment, 30-50% of patients with localised STS develop metastases, leading to 50-60% five-year overall survival (OS).[3-5] Patients with nonresectable metastatic disease have a one-year median survival.
Chemotherapy
A few agents have shown single-agent activity in metastatic disease: doxorubicin, ifosfamide, dacarbazine, gemcitabine and, most recently, trabectedin.[6,7] Doxorubicin is the first-line treatment of choice and results in a 20-25% response rate (RR).[8] Ifosfamide results in a RR of 45%.[8] Adding it to doxorubicin increases RR to 50-60%, but at the expense of added toxicity and without improvement in OS.[9-13] Responses to single-agent gemcitabine have varied from 4-18%. A randomised phase II trial of the combination of gemcitabine and docetaxel showed improved overall and progression-free survival and has emerged as an alternative regimen.[14]
In summary, combinations of drugs have been studied but do not result in significant improved RR and are associated with increased toxicity and no improvement in OS.[8] There is a clear need for new agents, preferably with novel mechanisms of action. Trabectedin (Yondelis, ET-743) is such a drug and has received ever-increasing interest from the sarcoma community.
Trabectedin
Trabectedin belongs to the ecteinascidins – tetrahydroisoquinoline compounds isolated from the marine tunicate Ecteinascidia turbinata. Trabectedin displays sequence-specific binding to the minor groove of duplex DNA and bends the double helix, thereby affecting gene transcription.[15] Numerous other mechanisms of action have been postulated, including transcription-coupled nucleotide excision repair pathway (TC-NER).[3,16] However, these observations have been made at concentrations above those achieved clinically (Cmax of 1.8 ng/ml for the 24 h infusion).[16-18] Trabectedin blocks the G2/M phase of the cell cycle, and is a selective inhibitor of activated gene transcription, such as that of MDR1.[3,17,19,20] Trabectedin has shown activity against a variety of solid-tumour cell lines, including ovarian, breast, prostate and renal cancer, melanoma and nonsmall-cell lung cancer.[3;21-23] Resistance to trabectedin appears to be associated with loss of nucleotide excision repair but not with expression of MDR1.[17,20]
Pharmacology
Trabectedin displays linear pharmacokinetics and has a volume of distribution of 3,900 l, with large interpatient variability (CV of Cmax and AUC >39%.[3] CYP450 metabolism is the main clearance mechanism, with less than 1% of dose excreted as parent drug in either faeces or urine, while faeces was the predominant route of excretion.[15,24]
Efficacy
A randomised phase II study compared the schedule of 1.5 mg/m2 over 24 h every three weeks with the schedule of 0.58 mg/m2 over 3 h weekly for three out of four weeks in previously treated patients with leiomyosarcoma and liposarcoma.[25] The three-weekly schedule resulted in a time to progression of 3.7 compared with 2.3 months (p = 0.032). The clinical benefit rate was 39% vs 24% (p = 0.022),[26] and 60% of patients on the three-weekly schedule were still alive at one year.[3] Trabectedin seems most promising in myxoid liposarcoma with an RR of 51% and a median progressionfree survival of one month.[27,28] Interestingly, changes in tumour density by CT or MRI often preceded tumour shrinkage.
Toxicity
Adverse events are generally reversible, dose- and time-dependent, and noncumulative, allowing prolonged treatment.[3,29] The most common grade 3 and 4 toxicities are neutropenia[30] and reversible elevations of serum transaminases, alkaline phosphatase and bilirubin in up to 50% of patients. However, monitoring of these liver function tests ensures safe use of trabectedin in the clinic.[31] Renal toxicity can be manifested by minor reversible elevations of creatinine, but rhabdomyolysis leading to irreversible renal failure and death has also been reported.[32] Careful monitoring of renal function and creatine phosphokinase levels (CPK) is required. Other side-effects include anaemia, thrombocytopenia, fatigue, nausea and vomiting.[3] Interestingly, the use of dexamethasone as premedication results in dramatic reduction of hepatotoxicity and myelosuppression.[33] Trabectedin toxicities are largely nonoverlapping with the toxicities associated with anthracyclines and ifosfamide, such as cardiotoxicity, neurotoxicity, mucositis and alopecia.[3]
Approval
Intravenous trabectedin is approved as monotherapy in Europe for use in patients with advanced soft-tissue sarcoma after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents.[34] Trabectedin has received orphan drug status in STS in the USA and in ovarian cancer in patients with recurrent ovarian cancer in both the USA and Europe.[3] The recommended dose for STS is 1.5 mg/m2 administered over 24 h every three weeks, with intravenous 20 mg dexamethasone pretreatment 30 min before trabectedin.[34]
Laboratory guidelines for initiation of trabectedin treatment include adequate haematological status, hepatic (bilirubin ≤ULN) and renal function, and creatine phosphokinase ≤2.5ULN.[34] Additional monitoring of the haematological parameters bilirubin, alkaline phosphatase, aminotransferases and CPK should occur weekly during the first two cycles of therapy, and at least once between treatments in subsequent cycles.[34]
Coadministration of trabectedin with CYP450 inhibitors and concomitant use of alcohol should be avoided.[3,34,35] Trabectedin (Yondelis) is formulated as 0.25 mg and 1 mg powder for concentrate for solution for infusion. The market authorisation holder in Europe is PharmaMar SA of Spain.[34]
Conclusion
Trabectedin has shown impressive single-agent activity in pretreated metastatic STS with a manageable toxicity profile. The lack of cumulative toxicity of trabectedin allows for longer treatment, as opposed to anthracyclines. Combining trabectedin with traditional cytotoxics is appealing by virtue of the nonoverlapping toxicity profiles and disparate mechanisms of action. An ongoing phase III trial is investigating trabectedin with liposomal doxorubicin in relapsed ovarian cancer, and phase II trials are being conducted in breast, prostate and endometrial cancer.[3]
Trabectedin appears to be preferentially active against certain STS subtypes, such as myxoid liposarcomas and leiomyosarcoma, reminiscent of noncytotoxic targeted agent selectivity – a concept that should be heeded in future trials. Clinical trials in STS should recognise the heterogeneity of the disease, and trial design should allow for stratification based on differing clinical-pathological behaviour, to more rationally direct the development of new agents.
References
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18. Soares DG, et al. Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743. Proc Natl Acad Sci USA 2007;104(32):13062-7.
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20. Beumer JH, et al. Trabectedin (ET-743, Yondelis) is a substrate for P-glycoprotein, but only high expression of P-glycoprotein confers the multidrug resistance phenotype. Invest New Drugs 2007;25(1):1-7.
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25. Morgan JA, et al. Randomized phase II study of trabectedin in patients with liposarcoma and leiomyosarcoma (L-sarcomas) after failure of prior anthracylines (A) and ifosfamide (I). J Clin Oncol 2007 ASCO Annual Meeting Proceedings Part I 25[18S]. 2007.
26. Le Cesne A, et al. Assessing the clinical impact of trabectedin in patients with leiomyosarcomas or liposarcomas progressing despite prior conventional chemotherapy: clinical benefit rate, growth modulation index and tumor variation as parameters of treatment effect in a randomised international trial of two trabectedin dosing regimens. Eur J Cancer 2007;Suppl 5(4):405.
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Resources
US National Comprehensive Cancer Network W: www.NCCN.org
EMEA’s EPAR on trabectedin W: www.emea.europa.eu/humandocs/Humans/EPAR/
yondelis/yondelis.htm
