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 is a marine-derived cytotoxic agent currently used internationally for advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin (PLD), for platinum-sensitive relapsed ovarian cancer. The TxGNN model predicts it may also be effective for Female Breast Carcinoma, particularly in BRCA1/2-mutated or homologous-recombination-deficient tumours, with 2 registered clinical trials and 20 publications currently identified, including two early-phase breast cancer trials. The drug is not currently marketed in Norway, and several safety data fields remain unresolved.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | No Norway license on file (drug not marketed). Per international literature, trabectedin is EU-approved for second-line soft tissue sarcoma and, combined with PLD, for platinum-sensitive relapsed ovarian cancer. |
| Predicted New Indication | Female Breast Carcinoma |
| TxGNN Prediction Score | 99.73% (rank 3480) |
| Evidence Level | L2 |
| Norway Market Status | ✗ Not marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in this evidence pack (flagged as a High-severity data gap). Based on published pharmacology literature, trabectedin is a DNA minor-groove alkylator that preferentially binds GC-rich sequences and interferes with transcription-coupled nucleotide excision repair (TC-NER). This produces selective cytotoxicity in tumours with nucleotide excision repair (NER) or homologous recombination (HR) deficiencies — most notably BRCA1/2-mutated cells — and separately modulates the tumour microenvironment by depleting tumour-associated macrophages.
This mechanism plausibly extends from sarcoma and ovarian cancer to breast cancer because a meaningful subset of breast tumours, especially triple-negative and hereditary BRCA1/2-mutated cases, share the same HR-deficient (synthetic-lethal) biology that underlies trabectedin's activity in ovarian cancer. Several identified trials and publications directly test this hypothesis, including a phase II study restricted to germline BRCA1/2-mutated metastatic breast cancer and an olaparib maintenance study following trabectedin+PLD response, reinforcing the mechanistic rationale for the TxGNN prediction rather than establishing it as a novel, unexplained signal.
It should be noted that the reported BRCA/HR-pathway rationale above is derived from external literature, not from the structured original_moa field, which remains a data gap in this evidence pack.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00786838 | Phase 2 | Completed | 76 | Single-blind, multicenter, placebo-controlled, sequential-design study evaluating trabectedin's effect on QT/QTc interval in patients with advanced solid tumor malignancies (cardiac safety study, not breast-cancer efficacy). |
| NCT03470805 | Phase 2 | Completed | 9 | Olaparib maintenance therapy after response to trabectedin + pegylated liposomal doxorubicin in recurrent ovarian carcinoma; tests the BRCA/HR-deficiency rationale relevant to breast cancer, but extremely small sample size (n=9). |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 25239225 | 2014 | Phase 2 RCT | Clinical Breast Cancer | Multicenter, randomized phase II study of single-agent trabectedin in advanced breast cancer after anthracycline/taxane failure, comparing two administration regimens. |
| 24692579 | 2014 | Phase 2 | Ann Oncol | First-in-class phase II study of trabectedin in germline BRCA1/2-mutated metastatic breast cancer; direct clinical support for the HR-deficiency mechanistic link. |
| 27266804 | 2016 | Phase 2 | Clinical Breast Cancer | Phase 2 study of trabectedin in HR-positive, HER2-negative advanced breast cancer stratified by XPG gene expression as a predictive biomarker. |
| 25722380 | 2015 | Phase 3 (exploratory) | Ann Oncol | Exploratory analysis of the phase 3 OVA-301 trial showing BRCA1/XPG mutation status predicts response to trabectedin + PLD, supporting the biomarker-driven rationale. |
| 39777457 | 2025 | Preclinical | Cancer Immunol Res | Trabectedin depletes immunosuppressive myeloid cells and enhances IL-12-driven NK-cell cytotoxicity in triple-negative breast cancer models. |
| 26592307 | 2016 | Review | Expert Opin Investig Drugs | Reviews trabectedin's investigational use in breast cancer, including its dual cytotoxic and tumour-microenvironment-modulating mechanisms. |
| 27710871 | 2016 | Review | Cancer Treat Rev | Discusses trabectedin as a chemotherapy option specifically for patients with BRCA deficiency across tumour types. |
| 23792433 | 2013 | Preclinical | Toxicology Letters | Trabectedin induces apoptosis via distinct pathways in HER2-/ER+ (MCF-7) and HER2+/ER- (MDA-MB-453) breast cancer cell lines. |
| 24941346 | 2014 | Preclinical | Eur Cytokine Netw | Demonstrates anti-angiogenic effects of trabectedin in human breast cancer cell lines and endothelial cells. |
| 19114300 | 2009 | Phase 1 | Eur J Cancer | Phase I pharmacokinetic study of trabectedin plus doxorubicin in advanced soft tissue sarcoma and breast cancer (mixed population, feasibility data). |
Norway Market Information
Trabectedin currently holds no marketing authorization in Norway (0 licenses on file). No dosage forms or authorization numbers are available for extraction.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic — marine-derived DNA minor-groove alkylator (tetrahydroisoquinoline alkaloid), interferes with transcription-coupled DNA repair |
| Myelosuppression Risk | High — literature (PMID 19496709) reports grade 3–4 neutropenia in ~50% and thrombocytopenia in ~20% of patients; hepatic transaminase elevation is also common |
| Emetogenicity Classification | Moderate (based on general oncology literature for trabectedin; not confirmed against a Norwegian/local package insert, which is currently a data gap) |
| Monitoring Items | CBC with differential, liver function tests (AST/ALT/bilirubin), renal function, creatine phosphokinase |
| Handling Protection | Yes — must follow standard cytotoxic drug handling and disposal protocols (IV infusion, closed-system transfer where available) |
Safety Considerations
Formal safety data (key warnings, contraindications, drug-drug interactions) are not yet available for this candidate — this is flagged as a Blocking data gap (DG001: TFDA/local label warnings and contraindications pending). Please refer to the package insert once available for definitive safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The mechanistic rationale (HR/BRCA-deficiency synthetic lethality) is biologically sound and supported by early-phase clinical data, but evidence for breast cancer specifically remains limited to small, single-arm or biomarker-stratified phase II studies (largest breast-cancer-specific cohort: proof-of-concept scale). Combined with the drug's non-marketed status in Norway and a Blocking safety data gap (no TFDA/local warnings or contraindications on file), this candidate is not yet ready for indication-expansion evaluation.
To proceed, the following is needed:
- Resolve DG001 (blocking): obtain TFDA/local package insert warnings and contraindications
- Resolve DG002 (high): confirm original mechanism of action from DrugBank API to validate the mechanistic rationale presented here
- Larger, randomized breast-cancer-specific trial data, ideally enriched for BRCA1/2-mutated or HR-deficient populations
- Assessment of feasibility for Norway market entry, since the drug currently holds no local authorization
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.