Larotrectinib
| Evidence Level: L3 | Predicted Indications: 10 |
Table of Contents
- Larotrectinib
- Larotrectinib: From NTRK Fusion-Positive Solid Tumours to Multiple Endocrine Neoplasia
Larotrectinib: From NTRK Fusion-Positive Solid Tumours to Multiple Endocrine Neoplasia
One-Sentence Summary
Larotrectinib is a selective TRK inhibitor marketed in Singapore as VITRAKVI. It is used for solid tumours driven by NTRK gene fusions, although the registration records compiled for this report do not list an approved indication text. The TxGNN model predicts it may be effective for multiple endocrine neoplasia, but support is weak: 1 clinical trial (a broad basket trial with only indirect relevance) and 2 publications (a review and a mechanistic report) are currently available.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not listed in the Singapore registration records (the drug is known as a tumour-agnostic TRK inhibitor for NTRK fusion-positive solid tumours) |
| Predicted New Indication | Multiple endocrine neoplasia |
| TxGNN Prediction Score | 99.24% |
| Evidence Level | L3 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 3 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known information, larotrectinib is a selective inhibitor of the TRK receptor kinases (TRKA, TRKB and TRKC). It works against tumours driven by NTRK gene fusions, regardless of where in the body the tumour began.
Multiple endocrine neoplasia type 2 (MEN2) is mainly driven by activating germline mutations in the RET gene, not by TRK signalling. The link between the drug and this disease is therefore indirect. Any benefit would probably depend on a co-occurring NTRK fusion or on bypass-pathway signalling, not on the RET lesion that defines the condition. The available literature discusses kinase inhibitors in thyroid cancer and resistance to RET inhibitors, which gives context but does not show that larotrectinib works in this disease.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02465060 | Phase 2 | Active, not recruiting | 6452 | NCI-MATCH: a non-randomised basket trial that assigns treatment by genetic testing in advanced, refractory solid tumours, lymphomas and myelomas. It is not specific to multiple endocrine neoplasia, and the larotrectinib arm applies to NTRK-fusion tumours. It provides only indirect support. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31322645 | 2019 | Review | Endocrine Reviews | Overview of kinase-inhibitor therapy for advanced thyroid cancer, including mutation-specific approvals |
| 38438731 | 2024 | Preclinical/Mechanistic | NPJ Precision Oncology | A medullary thyroid carcinoma patient with a RET mutation developed resistance to selpercatinib through alternative oncogenes |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16827P | VITRAKVI ORAL SOLUTION 20MG/ML | Solution | Not stated in the records |
| SIN15991P | VITRAKVI HARD CAPSULE 100MG | Capsule | Not stated in the records |
| SIN15992P | VITRAKVI HARD CAPSULE 25MG | Capsule | Not stated in the records |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (TRK 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
- Drug Interactions: The interaction screening returned 100 interacting drugs. Most are Moderate. One Major interaction was identified in the first 20 listed: clarithromycin. Moderate interactions include:
- Corticosteroids: hydrocortisone, dexamethasone, betamethasone, triamcinolone, budesonide
- Gastric acid suppressants: omeprazole, cimetidine
- Others: aprepitant, pioglitazone, saxagliptin, clotrimazole, cisapride, naltrexone
Naloxegol is rated Minor. The full list should be checked before any use.
Please refer to the package insert for warnings and contraindications, which were not available in the data compiled for this report.
Conclusion and Next Steps
Decision: Hold
Rationale: The TxGNN score is high, but the only trial is a broad basket study with no result specific to multiple endocrine neoplasia. The disease is driven mainly by RET, not TRK, so the mechanistic link is indirect. Evidence is limited to a review and a mechanistic report.
To proceed, the following is needed:
- Package insert warnings and contraindications from the Singapore regulator (HSA), and the approved indication text
- Detailed mechanism of action data
- Evidence that NTRK fusions or TRK-dependent signalling occur in multiple endocrine neoplasia
- Clinical data (case series or trial arms) in NTRK fusion-positive patients with this disease
- Review of the clarithromycin interaction and other CYP-related interactions
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.