Trabectedin
| 證據等級: L5 | 預測適應症: 1 個 |
目錄
Trabectedin: From Soft Tissue Sarcoma / Ovarian Cancer to Female Breast Carcinoma
One-Sentence Summary
Trabectedin (DrugBank DB05109) is a marine-derived DNA-binding cytotoxic agent internationally approved for soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for platinum-sensitive recurrent ovarian cancer. The TxGNN model predicts it may also be effective for Female Breast Carcinoma, with 2 clinical trials and 20 publications currently supporting this direction — though the drug is not yet marketed in this jurisdiction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not locally licensed; internationally approved for soft tissue sarcoma and platinum-sensitive recurrent ovarian cancer (per literature) |
| Predicted New Indication | Female Breast Carcinoma |
| TxGNN Prediction Score | 99.73% |
| Evidence Level | L2 |
| Germany Market Status | ✗ Not Marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Structured mechanism-of-action data is not available for this drug directly (DrugBank MOA field: data gap). Based on the mechanistic evidence compiled from the literature pack, trabectedin is a marine-derived, alkylating-type DNA minor-groove binding agent that interferes with transcription-coupled nucleotide excision repair (TC-NER) and modulates the tumor microenvironment by depleting tumor-associated monocytes/macrophages. This mechanism offers a theoretical synthetic-lethality rationale in BRCA1/2-deficient (homologous recombination-deficient) breast cancers, and in vitro studies show it can induce apoptosis in both HER2+/ER- and HER2-/ER+ breast cancer cell lines, with additional evidence of synergy with IL-12-mediated immune activation in triple-negative breast cancer (TNBC).
Breast cancer is not currently a primary approved indication for trabectedin — its established uses are soft tissue sarcoma and platinum-sensitive ovarian cancer, both of which share a DNA-repair-deficiency-driven treatment rationale with a subset of BRCA1/2-mutated breast cancers. The mechanistic link to breast cancer is therefore a reasonable extrapolation supported by preclinical and early-phase clinical signal, rather than a directly validated indication.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00786838 | Phase 2 | Completed | 76 | Single-blind, placebo-controlled, sequential-design QT/QTc interval study of single-dose trabectedin in advanced solid tumor malignancies; directly evaluates trabectedin cardiac safety at therapeutic dose (Relevance grade A). |
| NCT03470805 | Phase 2 | Completed | 9 | Olaparib maintenance after response to trabectedin + pegylated liposomal doxorubicin (PLD) induction in recurrent BRCA-mutated ovarian carcinoma; trabectedin-PLD serves as induction regimen, not the primary study arm (small n=9, Relevance grade B). |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 25239225 | 2014 | RCT | Clinical Breast Cancer | Multicenter, randomized Phase 2 study of single-agent trabectedin (2 dosing regimens) in advanced breast cancer after prior anthracycline and taxane treatment. |
| 27266804 | 2016 | RCT | Clinical Breast Cancer | Phase 2 study of trabectedin in HR+/HER2- advanced breast cancer, efficacy assessed by tumor XPG mRNA expression as predictive biomarker. |
| 24692579 | 2014 | Phase 2 Trial | Annals of Oncology | International first-in-class Phase 2 trial showing trabectedin activity in germline BRCA1/2-mutated metastatic breast cancer. |
| 19114300 | 2009 | Phase 1 Trial | European Journal of Cancer | Phase I/PK study of trabectedin + doxorubicin combination in advanced soft tissue sarcoma and breast cancer, feasibility and antitumor activity assessed. |
| 26592307 | 2016 | Review | Expert Opinion on Investigational Drugs | Reviews trabectedin's mechanism (transcription regulation, TAM reduction) and its investigational potential in breast cancer. |
| 27710871 | 2016 | Review | Cancer Treatment Reviews | Reviews trabectedin as a chemotherapy option in patients with BRCA deficiency, including breast cancer. |
| 39777457 | 2025 | Preclinical | Cancer Immunology Research | Trabectedin depletes immunosuppressive myeloid cells and enhances IL-12-driven NK-cell cytotoxicity in triple-negative breast cancer models. |
| 23792433 | 2013 | Preclinical | Toxicology Letters | Trabectedin induces apoptosis via death-receptor pathway in MCF-7 (HER2-/ER+) and MDA-MB-453 (HER2+/ER-) breast cancer cell lines. |
| 24941346 | 2014 | Preclinical | European Cytokine Network | Demonstrates anti-angiogenic effects of trabectedin on HUVECs and breast cancer cell lines via angiogenic cytokine modulation. |
| 18410797 | 2008 | Review | Seminars in Oncology | Reviews emerging agents, including trabectedin, for anthracycline- and taxane-refractory metastatic breast cancer. |
Germany Market Information
Trabectedin currently has no marketing authorization record in this jurisdiction (0 licenses on file); market status is Not Marketed.
Cytotoxicity
Trabectedin is a conventional cytotoxic chemotherapeutic agent (marine-derived, DNA minor-groove-binding alkylating-type agent), so this section applies.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic — DNA minor-groove binder / transcription-coupled repair inhibitor (marine-derived alkylating-type agent) |
| Myelosuppression Risk | High — literature reports grade 3–4 neutropenia in ~50% and grade 3–4 thrombocytopenia in ~20% of patients (Boudou et al., 2009) |
| Emetogenicity Classification | Moderate (based on known clinical profile; specific formal classification not provided in this evidence pack) |
| Monitoring Items | CBC with differential, liver function tests (hepatotoxicity reported), creatine kinase (rhabdomyolysis risk), renal function, and cardiac monitoring (QT/QTc, per NCT00786838) |
| Handling Protection | Requires handling per standard cytotoxic/hazardous drug handling regulations |
Safety Considerations
Please refer to the package insert for safety information. (Key warnings, contraindications, and drug interaction data are not currently available in this evidence pack — flagged as a blocking data gap, DG001.)
Conclusion and Next Steps
Decision: Hold
Rationale: The drug is not currently marketed/licensed in this jurisdiction, and package-insert-level safety data (warnings, contraindications) is a blocking data gap (DG001), preventing a full S1 safety pre-assessment. While evidence level L2 (one supportive comparative QT-safety trial plus multiple early-phase/preclinical breast cancer studies) is mechanistically plausible and biomarker-directed (BRCA1/2, XPG), it is not yet strong enough on its own to justify progression without safety substantiation.
To proceed, the following is needed:
- Local safety labeling data (TFDA/BfArM package insert: warnings, contraindications, DDI) to close DG001
- Confirmed structured MOA documentation from DrugBank to close DG002 (partially supported by literature mechanistic rationale above)
- Additional larger Phase 2/3 breast-cancer-specific RCT data (current dedicated breast cancer trials are small/early-phase)
- Formal drug-drug interaction (DDI) profile, currently returns no results
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.