Trabectedin
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Trabectedin: From Soft Tissue Sarcoma / Ovarian Cancer to Breast Carcinoma
One-Sentence Summary
Trabectedin is a marine-derived DNA-binding antineoplastic agent, established in the literature for the treatment of soft tissue sarcoma and platinum-sensitive relapsed ovarian cancer (in combination with pegylated liposomal doxorubicin). The TxGNN model predicts it may be effective for Female Breast Carcinoma, with 2 clinical trials and 20 publications currently supporting this direction, including a completed Phase II randomized trial in advanced breast cancer.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not on file in Danish registration data (0 authorisations); per published literature, approved for soft tissue sarcoma and relapsed ovarian cancer (combination with PLD) |
| Predicted New Indication | Female Breast Carcinoma |
| TxGNN Prediction Score | 99.73% |
| Evidence Level | L2 |
| Denmark Market Status | Not marketed |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, structured mechanism of action data is not available in the Evidence Pack (flagged as a High-severity data gap, DG002). Based on information contained in the supporting literature, trabectedin binds the DNA minor groove, interferes with DNA-repair machinery and transcription-regulation proteins, and also acts on the tumour microenvironment by depleting tumour-associated macrophages (TAM).
Trabectedin’s approved indications — soft tissue sarcoma and ovarian cancer — share a mechanistic thread with breast cancer through DNA damage repair biology. Several supporting publications specifically report activity in germline BRCA1/2-mutated and homologous-recombination-deficient (HRD) tumours (PMID 24692579, 27710871), a biology also central to trabectedin’s established ovarian cancer indication. This provides a plausible rationale for extending activity to BRCA-mutated or HRD breast cancer subgroups, consistent with the TxGNN prediction.
Preclinical data further support the mechanistic plausibility: trabectedin has demonstrated apoptosis induction and anti-angiogenic effects in breast cancer cell lines (PMID 23792433, 24941346), and enhances IL-12-driven NK-cell antitumour activity in triple-negative breast cancer models (PMID 39777457).
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00786838 | Phase 2 | Completed | 76 | Cardiac safety (QT/QTc interval) study of single-dose trabectedin in advanced solid tumour malignancies; not breast-cancer-specific but relevant to overall safety profile |
| NCT03470805 | Phase 2 | Completed | 9 | Olaparib maintenance after response to trabectedin + pegylated liposomal doxorubicin in recurrent ovarian carcinoma (BRCA1/2-related biology, not breast-cancer-specific) |
Note: neither registered trial directly enrolled breast cancer patients; breast-cancer-specific clinical evidence in this pack comes from the published literature below.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 25239225 | 2014 | RCT (Phase II) | Clinical Breast Cancer | Multicenter randomized Phase II study of single-agent trabectedin in advanced breast cancer after anthracycline/taxane treatment, comparing two administration regimens |
| 24692579 | 2014 | Phase II | Annals of Oncology | International first-in-class Phase II trial of trabectedin in germline BRCA1/2-mutated metastatic breast cancer |
| 27266804 | 2016 | Phase II | Clinical Breast Cancer | Trabectedin 1.3 mg/m² in HR+/HER2- advanced breast cancer, stratified by XPG gene expression as predictive biomarker |
| 26592307 | 2016 | Review | Expert Opinion on Investigational Drugs | Overview of trabectedin’s antitumour mechanism and potential in breast cancer |
| 27710871 | 2016 | Review | Cancer Treatment Reviews | Trabectedin as a chemotherapy option in patients with BRCA deficiency |
| 18410797 | 2008 | Review | Seminars in Oncology | Emerging agents (including trabectedin) for anthracycline/taxane-refractory metastatic breast cancer |
| 19114300 | 2009 | Phase I | European Journal of Cancer | Trabectedin + doxorubicin combination in advanced soft tissue sarcoma and breast cancer, pharmacokinetics and feasibility |
| 39777457 | 2025 | Preclinical | Cancer Immunology Research | Trabectedin enhances IL-12 antitumour effects via myeloid-cell depletion in triple-negative breast cancer models |
| 23792433 | 2013 | Preclinical | Toxicology Letters | Trabectedin induces diverse apoptosis mechanisms in MCF-7 and MDA-MB-453 breast cancer cell lines |
| 24941346 | 2014 | Preclinical | European Cytokine Network | Anti-angiogenic effects of trabectedin on human breast cancer cell lines and HUVECs |
Denmark Market Information
Currently no marketing authorisation for Trabectedin is registered in Denmark (0 licenses on file; market status: not marketed).
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (marine-derived DNA minor-groove binder, alkylating-like mechanism) |
| Myelosuppression Risk | High — literature reports Grade 3-4 neutropenia in ~50% and thrombocytopenia in ~20% of patients (PMID 19496709) |
| Emetogenicity Classification | Please refer to the Summary of Product Characteristics (SmPC) — not specified in available data |
| Monitoring Items | CBC with differential, liver function tests (hepatic toxicity reported alongside haematological toxicity), renal function |
| Handling Protection | Standard cytotoxic/hazardous drug handling precautions required |
Safety Considerations
Please refer to the approved Summary of Product Characteristics (SmPC) for safety information. Key warnings, contraindications, and drug interaction data are not currently available in this Evidence Pack (Blocking data gap DG001).
Conclusion and Next Steps
Decision: Hold
Rationale:
- A Blocking-severity data gap (DG001: missing SmPC warnings/contraindications) prevents entry into initial safety screening (S1), and the drug currently holds no marketing authorisation in Denmark. While the breast cancer signal reaches Evidence Level L2 (one completed Phase II RCT plus supportive Phase II and mechanistic data, particularly in BRCA1/2-mutated disease), safety review cannot proceed without label-level data.
To proceed, the following is needed:
- SmPC/label warnings and contraindications (DG001, source: TFDA/EMA product label)
- Confirmed mechanism of action data (DG002, source: DrugBank)
- Drug-drug interaction data (currently not_found)
- Clarification of EU/EMA marketing status (e.g., Yondelis authorisation) even though no Danish national license is on file
- If pursuing development, prioritize a BRCA1/2-mutated or HRD-enriched breast cancer population given the strongest mechanistic and clinical signal
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.