Larotrectinib
| 證據等級: L5 | 預測適應症: 2 個 |
目錄
Larotrectinib: A Predicted New Indication — Multiple Endocrine Neoplasia
One-Sentence Summary
Larotrectinib is not currently marketed in Taiwan, and no original-indication data is on file for this evidence pack. The TxGNN model predicts it may be effective for Multiple Endocrine Neoplasia (MEN), but this direction is currently supported by only 1 clinical trial (a broad genomic basket trial, not MEN-specific) and 2 review-type publications, none of which directly test larotrectinib in MEN patients.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available (no original indication or Taiwan license data on file) |
| Predicted New Indication | Multiple Endocrine Neoplasia |
| TxGNN Prediction Score | 99.24% |
| Evidence Level | L4 |
| US Market Status | ✗ Not Marketed (Taiwan) |
| Number of NDAs | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed original-indication and formal mechanism-of-action records are not available in this evidence pack (DrugBank MOA lookup flagged as a data gap, severity High). Based on the mechanistic notes attached to this prediction, larotrectinib is known to be a highly selective pan-TRK (NTRK1/2/3) kinase inhibitor.
The predicted new indication, Multiple Endocrine Neoplasia (MEN, including MEN2A/2B), is driven primarily by germline RET mutations — a different oncogenic driver than the NTRK fusions larotrectinib targets. The supporting literature actually discusses RET-directed kinase inhibitors (selpercatinib, pralsetinib) and general thyroid-cancer kinase-inhibitor therapy, not larotrectinib itself. The mechanistic overlap is therefore indirect: it would only be relevant in the rare subset of endocrine tumors that happen to carry an NTRK fusion rather than a RET alteration, which the current evidence does not confirm.
A second, lower-ranked candidate from the same model run — HER2-positive breast carcinoma (TxGNN score 99.14%) — shows a similarly indirect link: the supporting study used entrectinib (a different pan-TRK inhibitor) combined with a JAK2 inhibitor in preclinical models, not larotrectinib. Both predictions are best characterized as plausible drug-class hypotheses rather than drug-specific findings at this stage.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02465060 | Phase 2 | Active, not recruiting | 6,452 | MATCH is a genomic-marker-directed basket trial across refractory advanced solid tumors, lymphomas, and myelomas. It includes an NTRK-fusion-positive treatment arm, but is not designed for MEN or for a larotrectinib+MEN combination — relevance graded C (architectural co-occurrence only, not direct causal evidence). |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31322645 | 2019 | Review | Endocrine Reviews | Reviews kinase-inhibitor therapy (vandetanib, cabozantinib, sorafenib, lenvatinib, and mutation-specific agents) for advanced thyroid cancer; general oncology-kinase-inhibitor context, not larotrectinib-specific. |
| 38438731 | 2024 | Review | NPJ Precision Oncology | Discusses acquired resistance to RET-targeted TKIs (selpercatinib, pralsetinib) in RET-driven medullary thyroid carcinoma; does not address larotrectinib or MEN directly. |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (selective pan-TRK/NTRK1-3 kinase inhibitor) — not a conventional cytotoxic agent |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Please refer to the package insert warnings and precautions |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
Please refer to the package insert for safety information.
Conclusion and Next Steps
Decision: Hold
Rationale:
- The mechanistic link between larotrectinib (pan-TRK inhibitor) and MEN (predominantly RET-driven) is indirect, and the sole clinical trial is a non-indication-specific basket trial with only C-grade relevance. Evidence level is L4 (mechanism/preclinical-level), and the model’s own recommendation for this candidate is already “Hold.”
- TFDA labeling data (Blocking gap) is missing, which prevents even an initial S1 safety screen from starting.
To proceed, the following is needed:
- TFDA package insert / label data (warnings, contraindications) — currently blocking
- Confirmed DrugBank mechanism-of-action record
- MEN-subgroup or NTRK-fusion-stratified outcome data from the MATCH trial (or a dedicated larotrectinib+MEN study)
- Confirmation of larotrectinib’s original approved indication(s) and Taiwan regulatory/market status, since none is currently on file
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.