Trabectedin
| Evidence Level: L5 | Predicted Indications: 1 |
Table of Contents
Trabectedin: Female breast carcinoma
One-Sentence Summary
Trabectedin is a marine-derived cytotoxic agent, originally used to treat ovarian cancer (in combination with pegylated liposomal doxorubicin for relapsed disease). The TxGNN model predicts it may be effective for female breast carcinoma, with 1 clinical trial (a QT-interval safety study, not an efficacy trial) and 20 publications compiled for this direction, including Phase 2 breast cancer studies.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Female breast carcinoma |
| TxGNN Prediction Score | 0.9973 |
| Evidence Level | L5 |
| Australia Market Status | Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 1 (valid: 1) |
| Recommended Decision | Hold (research question; see the conclusion) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the source database. From the published literature compiled for this report, trabectedin binds the DNA minor groove and triggers transcription-coupled nucleotide excision repair-dependent DNA double-strand breaks. It is particularly active in homologous recombination-deficient tumours, such as those with BRCA1/2 mutations.
This overlaps with a subset of breast cancers, and BRCA1/2-associated disease is a shared feature of breast and ovarian cancer. Preclinical data also suggest trabectedin reduces tumour-associated macrophages and enhances the antitumour effect of IL-12 in triple-negative breast cancer. The high TxGNN score is consistent with this biology.
Caution is warranted: the Phase 2 data in breast cancer are limited, and the model score alone does not establish efficacy.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT00786838 | Phase 2 | Completed | 76 | Single-blind, placebo-controlled study of the effect of a single trabectedin dose on QT intervals in advanced solid tumours. It is a cardiac safety study, not a breast cancer efficacy trial |
No ANZCTR trial identifiers were available in the data compiled for this report.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 25239225 | 2014 | Phase 2 trial (randomised, two regimens) | Clin Breast Cancer | Single-agent trabectedin in advanced breast cancer after anthracycline and taxane; compared two administration regimens |
| 24692579 | 2014 | Phase 2 trial | Ann Oncol | Activity of trabectedin in germline BRCA1/2-mutated metastatic breast cancer |
| 27266804 | 2016 | Phase 2 trial | Clin Breast Cancer | Trabectedin in HR-positive, HER2-negative advanced breast cancer, according to XPG mRNA expression |
| 26592307 | 2016 | Review | Expert Opin Investig Drugs | Overview of trabectedin in breast cancer; its mechanism may suit breast cancer, including effects on tumour-associated macrophages |
| 27710871 | 2016 | Review | Cancer Treat Rev | Trabectedin as a chemotherapy option in BRCA-deficient patients |
| 18410797 | 2008 | Review | Semin Oncol | Emerging agents for anthracycline- and taxane-refractory metastatic breast cancer |
| 19114300 | 2009 | Phase 1 trial | Eur J Cancer | Trabectedin plus doxorubicin in soft tissue sarcoma and breast cancer (9 breast patients) |
| 39777457 | 2025 | Preclinical | Cancer Immunol Res | Trabectedin enhances IL-12 antitumour effects in triple-negative breast cancer |
| 24941346 | 2014 | Preclinical | Eur Cytokine Netw | Anti-angiogenic effects of trabectedin on human breast cancer cells |
| 23792433 | 2013 | Preclinical | Toxicol Lett | Trabectedin induced apoptosis in MCF-7 and MDA-MB-453 breast cancer cells |
The abstracts available for this report were truncated, so efficacy results (response rates, survival) for the Phase 2 trials are not summarised here and should be checked in the full papers.
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 13340D | Yondelis | Powder for I.V. infusion 1 mg | Not stated in the data compiled for this report |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (marine-derived DNA minor groove binder) |
| Myelosuppression Risk | High. Literature reports grade 3-4 neutropenia in about 50% and thrombocytopenia in about 20% of patients with soft tissue sarcoma; hepatic toxicity is also common |
| Emetogenicity Classification | Please refer to the Product Information (PI) |
| Monitoring Items | FBC with differential, liver function tests (including transaminases and bilirubin), and ECG/cardiac monitoring as per the PI |
| Handling Protection | Follow cytotoxic drug handling regulations |
Safety Considerations
- Drug Interactions: 100 interactions were identified in the interaction database. Of the 20 listed in the data compiled for this report, one is Major: clarithromycin (a strong CYP3A4 inhibitor, which warrants caution). The remainder are Moderate, including aprepitant, dexamethasone, cimetidine, metronidazole, miconazole, levofloxacin, minocycline, rosuvastatin and simvastatin. Review the complete list before prescribing.
Warnings and contraindications were not available in the data compiled for this report. Please refer to the TGA-approved Product Information (PI) for these.
Conclusion and Next Steps
Decision: Hold
Rationale: The mechanistic link to BRCA-deficient breast cancer is plausible and Phase 2 studies exist. However, the only registered trial in the compiled data is a QT safety study, and efficacy results from the Phase 2 breast cancer studies were not available in the compiled abstracts. The model score alone is not enough to support a change in practice. The evidence is best treated as a research question.
To proceed, the following is needed:
- Full-text review of the Phase 2 breast cancer trials (PMIDs 25239225, 24692579, 27266804) to extract response and survival outcomes
- Detailed mechanism of action data and TGA PI warnings and contraindications (not available in the compiled data)
- The approved indication text from the Australian ARTG entry
- A defined target population (for example, germline BRCA1/2-mutated or triple-negative disease) and a safety monitoring plan, given the haematological and hepatic toxicity and interaction risks
- A search of ANZCTR and other registries for ongoing breast cancer trials
Other predicted indications: The remaining predictions (ranks 2-10) are mostly L5 (model prediction only), and several overlap closely with the existing ovarian cancer indications (for example germ cell tumours and BRCA1-associated ovarian cancer susceptibility). Ovarian malignant mesothelioma has only indirect preclinical evidence from pleural mesothelioma. None is supported well enough to advance beyond Hold at this stage.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.