Larotrectinib
| Evidence Level: L4 | Predicted Indications: 2 |
Table of Contents
Larotrectinib: From NTRK Fusion-Positive Solid Tumors to Multiple Endocrine Neoplasia
One-Sentence Summary
Larotrectinib (marketed as VITRAKVI) is a selective TRK inhibitor, an oncology drug for tumors driven by NTRK gene fusions. The supplied data lists no approved indication text, so this original indication comes from general knowledge. The TxGNN model predicts it may be effective for multiple endocrine neoplasia, but the support is thin: 1 broad precision-oncology trial that does not show a larotrectinib arm for this disease, and 2 publications that are only indirectly related.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not listed in the supplied license records (generally known as NTRK fusion-positive solid tumors) |
| Predicted New Indication | Multiple endocrine neoplasia |
| TxGNN Prediction Score | 99.24% |
| Evidence Level | L4 |
| US Market Status | ✓ Marketed |
| Number of NDAs | 7 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Larotrectinib selectively inhibits the TRK kinases (NTRK1/2/3). Detailed mechanism-of-action data is not available in the supplied record, so this description relies on general knowledge of the drug class.
Multiple endocrine neoplasia, notably MEN2, is driven mainly by RET mutations, and larotrectinib is not known to inhibit RET. There is therefore no direct mechanistic rationale. The link is indirect. The supplied literature covers kinase inhibitors in RET-driven thyroid cancer and resistance to selective RET inhibitors. Any benefit would probably be limited to rare NTRK fusion-positive tumors, and the supplied data does not show this.
The very high TxGNN score (99.24%) is a graph-based prediction, not clinical evidence. It should be treated as a hypothesis to test.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02465060 | Phase 2 | Active, not recruiting | 6,452 | NCI-MATCH: a genetically guided basket trial in advanced, refractory solid tumors, lymphomas and myeloma. The supplied data does not show that a larotrectinib arm treated multiple endocrine neoplasia patients, so it is general rather than disease-specific evidence (relevance grade C). |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31322645 | 2019 | Review | Endocrine Reviews | Kinase inhibitors for advanced thyroid cancer, including mutation-specific therapies. This gives background for RET-driven endocrine tumors but does not test larotrectinib. |
| 38438731 | 2024 | Preclinical/Mechanistic | NPJ Precision Oncology | Off-target resistance mechanisms to selective RET inhibitors (selpercatinib, pralsetinib) in RET-driven medullary thyroid carcinoma. It does not involve larotrectinib. |
US Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA210861 | VITRAKVI (Bayer HealthCare Pharmaceuticals Inc.) | Capsule | Not listed |
| NDA211710 | VITRAKVI (Bayer HealthCare Pharmaceuticals Inc.) | Solution, concentrate | Not listed |
| NDA210861 | VITRAKVI (Loxo Oncology, Inc.) | Capsule | Not listed |
| NDA211710 | VITRAKVI (Bayer HealthCare Pharmaceuticals Inc.) | Solution, concentrate | Not listed |
| NDA211710 | VITRAKVI (Loxo Oncology, Inc.) | Solution | Not listed |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (TRK kinase inhibitor) |
| 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: Larotrectinib does not target RET, the main driver of multiple endocrine neoplasia. The only trial is a broad basket study with no demonstrated larotrectinib arm for this disease, and the two publications concern other drugs or tumor types. Evidence is at the L4 level, and the high TxGNN score alone cannot justify moving forward.
To proceed, the following is needed:
- Identify any NTRK fusion-positive cases within multiple endocrine neoplasia, and check whether the NCI-MATCH data include any relevant larotrectinib-treated patients
- Preclinical or case-level evidence testing larotrectinib itself in multiple endocrine neoplasia models
- Approved indication text and mechanism-of-action data, to allow a baseline comparison
- Package insert warnings and contraindications, to complete the safety screening
- Route and dosage form compatibility assessment
Note on the second prediction (HER2-positive breast carcinoma, score 99.14%): it is supported only by a preclinical study of a different TRK inhibitor (entrectinib), with no clinical trials. This is L5-level evidence, so it also stays at Hold.
This report is for research reference only and does not constitute medical advice. Repurposing candidates require clinical validation before any application.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.