Lay Summary: Yondelis is approved in Europe but is still investigational in the USA. However it is considered to be an Orphan Drug and is available under the Expanded Access Program.
Yondelis or Trabectedin is the first of a new class of antitumor agents. Trabectedin is a tetrahydroisoquinoline alkaloid isolated from the marine tunicate Ecteinascidia turbinate with potential antineoplastic activity. Binding to the minor groove of DNA, trabectedin inteferes with the transcription-coupled nucleotide excision repair machinery to induce lethal DNA strand breaks.and blocks the cell cycle in the G2 phase. In the USA it is made available through a single-arm, open-label, multicenter, study that is designed to provide access to trabectedin in patients with soft tissue sarcoma who are not expected to benefit from currently available therapeutic options for treatment of soft tissue sarcoma.
Trabectedin received European approval on September 20, following a positive opinion in July 2007, and is indicated for use in patients with advanced or metastatic soft-tissue sarcoma who have failed or are not suitable for first-line therapy with anthracyclines (doxorubicin or epirubicin) and ifosfamide, either sequentially or in combination. Trabectedin’s approval was based on an international randomized trial involving 270 patients, in which all patients received the active drug, but at 2 doses. Of the patients, 59% had high-grade tumors and 67% had bulky disease (> 5 cm). One of the inclusion criteria was that patients had to have good liver function as trabectedin may cause elevations in liver-enzyme levels.
Trabectedin was administered by intravenous infusion, either at 1.5 mg/m2 over 24 hours every 3 weeks or at 0.58 mg/m2 over 3 hours weekly for 3 weeks on a 28-day cycle. All patients were premedicated with dexamethasone 20 mg intravenously 30 minutes prior to trabectedin.
The 3-week infusion produced significantly better results. The prespecified primary end point of time to progression was 3.7 months, compared with 2.3 months with the weekly infusion (hazard ratio [HR], 0.734; P = .0302). Secondary end points were also better with the 3-week dosing schedule: median progression-free survival was 3.3 months vs 2.3 months (HR, 0.755; P = .0418), and median survival was 13.8 months vs 11.8 months (HR, 0.823; P = .1984). Although this dosing schedule was associated with slightly more adverse effects (neutropenia, reversible liver elevations, vomiting, and fatigue), it was “reasonably well tolerated overall,” and no cumulative toxicities were seen. Febrile neutropenia was rare with both doses (0.8% – 1.6%).
On October 8, 2010, Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) not to cover this drug for use in NHS Scotland. It said that the manufacturer’s justification of the treatment’s cost in relation to its health benefits was not sufficient to gain acceptance by SMC and in addition, the manufacturer did not present a sufficiently robust economic case to gain acceptance by SMC.
Please see the post: “Yondelis for Sarcoma”.