Trabectedin
| Evidence Level: L2 | Predicted Indications: 1 |
Table of Contents
Trabectedin: From Soft Tissue Sarcoma/Ovarian Cancer to Female Breast Carcinoma
One-Sentence Summary
Trabectedin (Yondelis) is a marine-derived DNA-binding agent internationally established for second-line 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, though the drug is not yet marketed in India.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available from India regulatory data (drug not marketed). Per international literature (EMA approval): second-line soft tissue sarcoma and platinum-sensitive relapsed ovarian cancer (with PLD) |
| Predicted New Indication | Female Breast Carcinoma |
| TxGNN Prediction Score | 99.73% |
| Evidence Level | L2 |
| India Market Status | ✗ Not marketed (Not marketed) |
| Number of Registrations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed, India-label-verified mechanism of action data is currently unavailable (marked as a data gap). Based on published pharmacology, trabectedin binds the DNA minor groove, interferes with transcription-coupled nucleotide excision repair (TC-NER), and induces DNA–protein crosslinks. This produces selective cytotoxicity in tumors with homologous recombination deficiency — most notably BRCA1/2-mutated cancers. Trabectedin also selectively depletes tumor-associated macrophages, giving it an additional immune-modulatory effect distinct from classic cytotoxic chemotherapy.
Ovarian cancer, one of trabectedin’s established indications, carries a ~20% BRCA1/2 mutation rate independent of family history — the same homologous-recombination-deficiency biology seen in a meaningful subset of breast cancers (particularly triple-negative and hereditary BRCA1/2-mutated breast cancer). This shared molecular vulnerability is the core rationale for extending trabectedin from ovarian cancer/sarcoma into breast cancer.
That said, breast cancer is not trabectedin’s core pharmacological target, and the absence of a formally documented original indication and MOA in the India regulatory dataset is itself a signal that this repurposing candidate needs additional foundational data before further evaluation.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00786838 | Phase 2 | Completed | 76 | Single-blind, placebo-controlled, multicenter study assessing QT/QTc effects of a single trabectedin dose in advanced solid tumor patients; the most direct randomized-design evidence available for this population. |
| NCT03470805 | Phase 2 | Completed | 9 | Olaparib maintenance following trabectedin-PLD induction in recurrent, BRCA-associated ovarian carcinoma; trabectedin used only as induction therapy, not the primary study drug — indirect relevance. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 25239225 | 2014 | RCT (Phase 2) | Clinical Breast Cancer | Multicenter randomized study of single-agent trabectedin in advanced breast cancer after anthracycline/taxane failure, comparing two dosing regimens. |
| 27266804 | 2016 | RCT (Phase 2) | Clinical Breast Cancer | Trabectedin efficacy in HR-positive/HER2-negative advanced breast cancer stratified by XPG gene expression as a predictive biomarker. |
| 24692579 | 2014 | Phase 2 (first-in-class) | Annals of Oncology | International phase II trial of trabectedin specifically in germline BRCA1/2-mutated metastatic breast cancer — the most mechanistically targeted trial identified. |
| 19114300 | 2009 | RCT (Phase 1) | European Journal of Cancer | Phase I pharmacokinetic study of trabectedin + doxorubicin in advanced soft tissue sarcoma and breast cancer; feasibility and antitumor activity evaluated. |
| 26592307 | 2016 | Review | Expert Opinion on Investigational Drugs | Comprehensive review of trabectedin’s mechanism and potential in breast cancer, including tumor-associated macrophage modulation. |
| 27710871 | 2016 | Review | Cancer Treatment Reviews | Review of trabectedin as a chemotherapy option specifically for BRCA-deficient tumors, spanning sarcoma, ovarian, and breast cancer. |
| 31994460 | 2020 | Review | Current Drug Targets | Focused review of trabectedin’s mechanism of action and genomic predictors of response (including BRCA/HR status) in gynecological and related cancers. |
| 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 diverse pathways in MCF-7 (HER2-/ER+) and MDA-MB-453 (HER2+/ER-) breast cancer cell lines. |
| 38366738 | 2024 | Case Report | Journal of Dermatology | Trabectedin effective in radiation-induced angiosarcoma of the breast refractory to multiple prior anticancer drugs. |
India Market Information
Trabectedin is not currently marketed in India — no registrations, brand names, or approved indications are on file (total_licenses: 0). No India-specific label data is available for cross-reference.
Cytotoxicity
Trabectedin is a marine-derived cytotoxic antineoplastic agent (DNA minor-groove binder / transcription-coupled repair inhibitor), consistent with its established use in sarcoma and ovarian cancer.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (DNA-binding alkylator-type agent, marine-derived) |
| Myelosuppression Risk | High — published safety literature reports grade 3–4 neutropenia in ~50% and thrombocytopenia in ~20% of treated patients |
| Emetogenicity Classification | Not specified in available data; India label not yet available (drug not marketed) |
| Monitoring Items | CBC with differential, liver function tests (hepatotoxicity reported), creatine kinase (rhabdomyolysis has been reported with this class), renal function |
| Handling Protection | Yes — cytotoxic/hazardous drug handling precautions required per standard antineoplastic handling protocols |
Safety Considerations
- Drug Interactions: 450 documented interactions on file. One Major-level interaction identified (Clarithromycin, a strong CYP3A4 inhibitor). Nineteen sampled Moderate-level interactions include other CYP3A4/CYP inhibitors (Cimetidine, Miconazole, Metronidazole), statins with myopathy risk (Rosuvastatin, Simvastatin), and diabetes medications (Acarbose, Pioglitazone, Rosiglitazone).
Key warnings and contraindications from the India label are not yet available (drug not marketed; label data gap flagged as Blocking).
Conclusion and Next Steps
Decision: Hold
Rationale: A Blocking-severity data gap (missing India label warnings/contraindications) prevents completion of the S1 safety pre-assessment, and trabectedin is not currently marketed in India. Direct clinical evidence for breast cancer remains limited to small Phase 1/2 studies (evidence level L2, TxGNN decision stage flagged as “Research Question” only) without confirmatory Phase 3 data in this indication.
To proceed, the following is needed:
- India/TFDA label PDF (warnings, contraindications) — required before any S1 safety review
- Confirmed mechanism of action from DrugBank to formalize the mechanistic rationale
- Larger, confirmatory trial data in breast cancer, ideally enriched for BRCA1/2-mutated or triple-negative subgroups
- Assessment of a market-entry pathway for trabectedin in India, since no registration currently exists
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.