trabectedin
Regulatory sources consulted
Approved indications
- Advanced soft-tissue sarcoma after failure of anthracyclines/ifosfamide or when unsuitable, and relapsed platinum-sensitive ovarian cancer with pegylated liposomal doxorubicin.
Contraindications
Absolute
- Hypersensitivity; severe or uncontrolled infection; breastfeeding; yellow-fever vaccine.
Clinical warnings
- Monitor blood counts before each cycle and through the nadir. Do not administer outside a specialist oncology protocol; myelosuppression may cause fatal infection or bleeding. — CIMA/AEMPS, ficha técnica 89148
- Administer through a central venous line: extravasation may cause necrosis and has no specific antidote. Check LVEF at baseline and every 2–3 months, liver, CPK/rhabdomyolysis, kidneys, and capillary leak; discontinue for capillary leak or severe toxicity. — CIMA/AEMPS, ficha técnica 89148
Drug interactions
- HighStrong CYP3A4 inhibitors or inducers and alcohol
Mechanism: CYP3A4 modulators change exposure; alcohol increases hepatic risk.
Recommendation: Avoid strong CYP3A inhibitors from the day before infusion until at least 1 week afterward; avoid strong inducers and monitor P-gp substrates/inhibitors. Do not drink alcohol.
CIMA/AEMPS, ficha técnica 89148
Pregnancy and lactation
It may cause fetal harm. Women use contraception during treatment and for 8 months afterward; men during treatment and for 5 months afterward. Do not breastfeed during treatment or for 3 months afterward. Consider gamete preservation.
Recent literature (PubMed)
The addition of trabectedin to doxorubicin, followed by trabectedin maintenance, may have superior efficacy to doxorubicin alone as first-line treatment in patients with advanced leiomyosarcoma. We conducted a phase 3 trial involving patients with metastatic or unresectable leiomyosarcoma who had not received chemotherapy previously. Patients were randomly assigned to receive either single-agent doxorubicin (six cycles) or doxorubicin plus trabectedin (six cycles), with continued trabectedin as maintenance therapy in patients in the doxorubicin-trabectedin group who did not have disease progression. Surgery to resect residual disease was allowed in each group after six cycles of therapy. Analyses of progression-free survival (primary end point) and overall survival (secondary end point) were adjusted for two stratification factors: tumor origin site (uterine vs. soft tissue) and disease stage (locally advanced vs. metastatic). The primary end-point results were reported previously. A total of 150 patients underwent randomization. At a median follow-up of 55 months (interquartile range, 49 to 63), a total of 107 patients had died (47 in the doxorubicin-trabectedin group and 60 in the doxorubicin group). The median overall survival was longer in the doxorubicin-trabectedin group (33 months; 95% confidence interval [CI], 26 to 48) than in the doxorubicin group (24 months; 95% CI, 19 to 31); the adjusted hazard ratio for death was 0.65 (95% CI, 0.44 to 0.95). In a finding consistent with earlier reports, progression-free survival was longer in the doxorubicin-trabectedin group (12 months; 95% CI, 10 to 16) than in the doxorubicin group (6 months; 95% CI, 4 to 7); the adjusted hazard ratio for progression or death was 0.37 (95% CI, 0.26 to 0.53). The incidence of adverse events and the percentage of patients with dose reductions were higher with doxorubicin plus trabectedin than with doxorubicin alone. Combination therapy with doxorubicin and trabectedin induction, follo
Metastatic leiomyosarcomas have a poor prognosis, and currently doxorubicin alone is used as the standard first-line treatment. Doxorubicin combined with trabectedin has shown promising results in phase 1 and 2 studies. We aimed to identify and compare the progression-free survival of patients with metastatic or unresectable uterine or soft tissue leiomyosarcoma treated with doxorubicin and trabectedin combined as first-line therapy versus doxorubicin alone in a phase 3 trial. LMS-04 was a randomised, multicentre, open-label, superiority phase 3 trial, which included patients from 20 centres of the French Sarcoma Group (anticancer centers or hospitals with an oncological unit) in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-1, and had metastatic or relapsed unresectable leiomyosarcomas that had not previously been treated with chemotherapy. Patients were randomly assigned (1:1), by means of an interactive web response system (permuted blocks of different sizes from two to six), to receive either intravenous doxorubicin alone (75 mg/m2) once every 3 weeks for up to six cycles or of intravenous doxorubicin (60 mg/m2) plus intravenous trabectedin (1·1 mg/m2) once every 3 weeks up to six cycles followed by maintenance with trabectedin alone. Surgery for residual disease was allowed in both groups after six cycles of treatment. Randomisation was stratified by tumour location (uterine vs soft tissue) and disease (locally advanced vs metastatic). The primary endpoint was progression-free survival assessed by blinded independent central review and according to Response Evaluation Criteria in Solid Tumours 1.1 criteria. Efficacy analyses were performed on all randomly assigned patients, based on the intention-to-treat principle. The safety population included all randomly assigned patients who received at least one cycle of treatment. This trial is registered with ClinicalTrials.gov, NCT02997358, and