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Other cytotoxics, enzymes and natural productsIn useNatural product

Trabectedin

Also known as Yondelis, ET-743, ecteinascidin 743

A drug obtained from a Caribbean sea squirt (tunicate). The FDA label calls it an alkylating drug; it is used for some soft-tissue sarcomas and, in the EU, with liposomal doxorubicin in ovarian cancer.

From discovery to approval

  1. 1990 · Earliest report found

    A 1990 paper by Rinehart and colleagues, titled as describing ecteinascidins 729, 743, 745, 759A, 759B and 770 as potent antitumour agents from the Caribbean tunicate Ecteinascidia turbinata, is the earliest report found. A 2000 review says antitumour extracts of the tunicate were first described in 1969.[2][3][4][5][6][7][8][9]

  2. 2007-09-17 · EMA exceptional

    Advanced soft-tissue sarcoma after failure of anthracyclines and ifosfamide, or in patients unsuited to receive these agents (also authorised for ovarian cancer). Authorised under exceptional circumstances; the EPAR page states they ended on 27 May 2015.[10]

  3. 2015-10-23 · FDA regular

    Unresectable or metastatic liposarcoma or leiomyosarcoma in patients who received a prior anthracycline-containing regimen (NDA 207953). The letter contains no accelerated-approval wording; the type 'regular' is an inference. The letter read is a replacement letter whose effective approval date remains 23 October 2015.[9]

How it works

The FDA label calls it an alkylating drug that binds guanine in the minor groove of DNA, forming adducts and bending the helix. This affects DNA-binding proteins and DNA repair pathways, disturbing the cell cycle and leading to cell death.[1]

Where it came from and why

The 2000 review says the small amount of ecteinascidins in the tunicate prevented their isolation for over a decade. A 1992 report found ecteinascidins protected mice against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma and human lung and mammary tumour xenografts.

Extracts of the tunicate Ecteinascidia turbinata were first described as antitumour in 1969, but the small amount of ecteinascidins in the tunicate prevented their isolation for over a decade [3]. In 1990 Kenneth Rinehart and colleagues published ecteinascidins, including number 743, as potent antitumour agents from the Caribbean tunicate [2]. A 1992 report described ecteinascidins protecting mice against several transplanted tumours and human tumour xenografts [4].

An earlier European application ran into difficulty. The committee that reviews medicines recommended against authorisation in July 2003 and confirmed this after an appeal in November 2003, citing concerns about the methods used and uncertainty about response and survival rates [6]. A later application led to a positive opinion in July 2007 and a Commission decision in September 2007, with authorisation under exceptional circumstances [7].

A phase III trial in liposarcoma or leiomyosarcoma compared trabectedin with dacarbazine; median progression-free survival was 4.2 versus 1.5 months, while overall survival, the primary endpoint, was 12.4 versus 12.9 months at an interim analysis [8]. The FDA approved trabectedin for these cancers in October 2015 [9].

Cancers

  • Liposarcoma and leiomyosarcoma

    The 2015 FDA label lists unresectable or metastatic liposarcoma or leiomyosarcoma after a prior anthracycline-containing regimen.[1]

  • Advanced soft-tissue sarcoma

    The EU authorisation of 2007 covers advanced soft-tissue sarcoma after failure of anthracyclines and ifosfamide, or in patients unsuited to receive these agents.[10]

  • Soft-tissue sarcoma (phase II)

    A phase II study of 36 previously treated patients gave 1 complete and 2 partial responses (overall response rate 8%, 95% CI 2% to 23%).[11]

  • Ovarian cancer

    The EPAR page lists use with pegylated liposomal doxorubicin in relapsed platinum-sensitive ovarian cancer.[10]

Family and partners

Drugs derived from it: Lurbinectedin

Worth knowing

  • In July 2003 the EU committee for medicines adopted a negative opinion on trabectedin for advanced soft-tissue sarcoma; after an appeal it confirmed the refusal on 20 November 2003, citing methodological concerns and uncertainty about response rate, progression-free survival and overall survival.[6]
  • The phase III trial against dacarbazine in liposarcoma or leiomyosarcoma enrolled 518 patients, with overall survival as the primary endpoint; the abstract reports median progression-free survival of 4.2 versus 1.5 months (hazard ratio 0.55) and, at an interim analysis, median overall survival of 12.4 versus 12.9 months (hazard ratio 0.87, P = .37).[8]
  • A 2009 review describes trabectedin as the first marine anticancer drug approved in the EU and gives October 2007; the EMA procedural document dates the European Commission decision 17 September 2007.[5]

On this site

References

  1. U.S. Food and Drug Administration. Yondelis (trabectedin) prescribing information, NDA 207953, original approval October 2015 (the label states it may not be the latest approved). Source
  2. Rinehart KL, Holt TG, Fregeau NL, Stroh JG, Keifer PA, Sun F, et al. Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata. J Org Chem. 1990;55(15):4512-5. DOI
  3. Rinehart KL. Antitumor compounds from tunicates. Med Res Rev. 2000;20(1):1-27. PubMedDOI
  4. Sakai R, Rinehart KL, Guan Y, Wang AH. Additional antitumor ecteinascidins from a Caribbean tunicate: crystal structures and activities in vivo. Proc Natl Acad Sci U S A. 1992;89(23):11456-60. PubMedDOI
  5. Molinski TF, Dalisay DS, Lievens SL, Saludes JP. Drug development from marine natural products. Nat Rev Drug Discov. 2009;8(1):69-85. PubMedDOI
  6. European Medicines Agency. Summary of opinion (negative) for Yondelis (trabectedin), CPMP/5706/03, London, 20 November 2003. Source
  7. European Medicines Agency. Yondelis (trabectedin): EPAR procedural steps taken before authorisation, CHMP positive opinion of 19 July 2007 and European Commission decision of 17 September 2007. Source
  8. Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, et al. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol. 2016;34(8):786-93. PubMedDOI
  9. US Food and Drug Administration. Replacement NDA approval letter, NDA 207953 (Yondelis, trabectedin), Janssen Products. The letter states the effective approval date remains 23 October 2015, the date of the original letter. Source
  10. European Medicines Agency. Yondelis (trabectedin): European public assessment report (EPAR) page. Marketing authorisation issued 17/09/2007 under exceptional circumstances; the page states the exceptional circumstances ended on 27 May 2015. Page read 2026-10-21. Source
  11. Garcia-Carbonero R, Supko JG, Manola J, Seiden MV, Harmon D, Ryan DP, et al. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol. 2004;22(8):1480-90. PubMedDOI