Selumetinib
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Selumetinib: From Neurofibromatosis to Familial Generalized Lentiginosis
One-Sentence Summary
Selumetinib is a MEK1/2 inhibitor marketed in Singapore as KOSELUGO and originally used for neurofibromatosis. The TxGNN model predicts it may be effective for familial generalized lentiginosis with a very high score, but no clinical trials and no publications currently support this specific prediction. The strongest evidence among the top 10 predictions is for a related condition, peripheral nerve schwannoma (3 Phase 2 trials, 6 publications), which is described in the notes below.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Neurofibromatosis (the Singapore licence records list no approved indication text) |
| Predicted New Indication | Familial generalized lentiginosis |
| TxGNN Prediction Score | 99.96% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Selumetinib is known as a MEK1/2 inhibitor that blocks the RAS/MAPK signalling pathway. It is marketed for neurofibromatosis, a condition in which this pathway is over-activated.
Lentiginosis syndromes are often linked to RASopathies, a group of disorders caused by RAS/MAPK pathway activation. This makes MEK inhibition mechanistically plausible. However, this is a prediction based on the knowledge graph only. No trial or literature evidence was found for this specific condition, and similarity to the original indication has not yet been assessed.
Other predictions in the top 10 (for context):
- Peripheral nerve schwannoma (rank 9, L3): The most developed candidate. NF2-related schwannomas show loss of merlin with downstream RAS/RAF/MEK/ERK activation, so MEK inhibition is plausible.
- Rhabdoid tumor (rank 3, L4): Preclinical work suggests that atypical teratoid rhabdoid tumors depend on LIN28 and MAPK signalling.
- Trigeminal schwannoma (rank 10, L5): Plausible by extension from other schwannomas, but no direct evidence.
- Gastrocutaneous syndrome, acromelanosis, congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome, Moynahan syndrome, leukonychia totalis-acanthosis-nigricans-like lesions-abnormal hair syndrome, and osteopathia striata-pigmentary dermopathy-white forelock syndrome (ranks 2, 4, 5, 6, 7, 8, all L5): Prediction only, with unclear or phenotype-based rationale.
Clinical Trial Evidence
Currently no related clinical trials are registered for familial generalized lentiginosis.
For reference, trials linked to other top-ranked predictions:
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03095248 | Phase 2 | Terminated | 10 | Selumetinib in NF2-related tumors (schwannoma). Terminated early, so data are too limited to establish efficacy. |
| NCT07707947 | Phase 2 | Not yet recruiting | 20 | Single-arm study of a MEK1/2 inhibitor (selumetinib) in NF2-related schwannomatosis. No results yet. |
| NCT07713745 | Phase 2 | Not yet recruiting | 200 | PRIME-NF2 platform-basket trial in NF2-related schwannomatosis. Selumetinib's inclusion is not confirmed. |
| NCT03155620 | Phase 2 | Active, not recruiting | 1377 | NCI-COG Pediatric MATCH, a tumour-agnostic genetic-matching screening trial that includes rhabdoid tumor. Not specific to selumetinib in this tumor type. |
Literature Evidence
Currently no related literature is available for familial generalized lentiginosis.
For reference, publications linked to other top-ranked predictions:
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37906356 | 2023 | Review | Current Oncology Reports | Management of central and peripheral nervous system tumors in neurofibromatosis; MEK inhibitors have shown promise. |
| 37046591 | 2023 | Expert guideline | Cancers | EURACAN expert recommendations for peripheral and cranial nerve tumors; evidence is limited by rarity. |
| 38058737 | 2023 | Case report | Mol Ther Methods Clin Dev | Partial response to selumetinib in an NF2-associated ependymoma. |
| 38216572 | 2024 | Preclinical | Nature Communications | Interactions between NF1 and NF2 tumor suppressors in Schwann cell tumor de-differentiation and treatment resistance. |
| 25638158 | 2015 | Preclinical | Oncotarget | LIN28 disruption in atypical teratoid rhabdoid tumors highlights MAPK as a therapeutic target. |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16275P | KOSELUGO Hard Capsules 10 mg | Capsule | Not recorded in the licence data |
| SIN16276P | KOSELUGO Hard Capsules 25 mg | Capsule | Not recorded in the licence data |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (MEK1/2 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
- Drug Interactions: The interaction screen identified 84 potential interactions. Examples of major interactions: aprepitant, dexamethasone, clarithromycin, and cobicistat. Examples of moderate interactions: acetylsalicylic acid, cimetidine, clotrimazole, deferasirox, and several anticoagulants and antiplatelet agents (apixaban, dipyridamole, cilostazol, bivalirudin, cangrelor, and others).
For warnings and contraindications, please refer to the package insert.
Conclusion and Next Steps
Decision: Hold
Rationale: The prediction for familial generalized lentiginosis rests on the model score alone (L5), with no trial or literature support. The mechanistic link through RAS/MAPK is plausible but unverified.
To proceed, the following is needed:
- Evidence specific to familial generalized lentiginosis (case reports, preclinical data, or trials)
- Detailed mechanism of action data and a mechanistic comparison with the original indication
- Package insert warnings and contraindications from the HSA, which are required before safety screening
- A dosing-route and formulation review (only oral capsules are currently registered)
- Consideration of peripheral nerve schwannoma as a better-supported candidate (L3). It would need results from the ongoing NF2 Phase 2 trials, since the one completed trial was terminated after 10 patients.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.