Selumetinib
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Selumetinib: Familial generalized lentiginosis
One-Sentence Summary
Selumetinib is an oral MEK inhibitor originally used to treat neurofibromatosis. The TxGNN model ranks familial generalized lentiginosis as its top prediction, but there are currently no clinical trials and no publications supporting this specific indication. The best-supported predicted indication in the data compiled for this report is peripheral nerve schwannoma (3 clinical trials, 6 publications), which is discussed below.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Familial generalized lentiginosis |
| TxGNN Prediction Score | 0.9996 |
| Evidence Level | L5 |
| Australia Market Status | Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 1 (valid: 1) |
| Recommended Decision | Hold |
Of the ten predicted indications, only two have any supporting evidence: peripheral nerve schwannoma (L3, 0.9995) and rhabdoid tumour (L4, 0.9996). The other eight are model predictions only (L5).
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available for selumetinib in the data compiled for this report. Based on known information, selumetinib is a MEK inhibitor, and its efficacy in neurofibromatosis (NF1 plexiform neurofibromas) has been established. Mechanistically, it may be applicable to other conditions driven by RAS/MAPK pathway dysregulation.
For familial generalized lentiginosis, the prediction is not backed by trials or literature. Lentiginoses of this type are often linked to RAS/MAPK pathway dysregulation, which a MEK inhibitor could plausibly modulate. The similarity to the original indication has not yet been assessed. Several other top-ranked predictions (gastrocutaneous syndrome, café-au-lait macule syndromes, acromelanosis, Moynahan syndrome) come from the TxGNN model (deep learning), and their scores may reflect similarities the model learned between related diseases, not biological evidence.
The two predictions with real supporting data are more informative:
- Peripheral nerve schwannoma: Loss of NF2 and interactions between the NF1 and NF2 tumour suppressors drive Schwann cell tumours through RAS/MAPK signalling, making MEK inhibition plausible. Evidence is limited to early-phase trials and a case report.
- Rhabdoid tumour: Preclinical work in atypical teratoid rhabdoid tumours suggests dependence on the MAPK pathway.
Clinical Trial Evidence
No clinical trials are registered for the top-ranked indication, familial generalized lentiginosis. The trials below relate to the better-supported predictions.
Peripheral nerve schwannoma
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT03095248 | Phase 2 | Terminated | 10 | Selumetinib in NF2-related tumours, assessing tumour growth and hearing changes. Terminated early and underpowered, but the most direct evidence. |
| NCT07707947 | Phase 2 | Not yet recruiting | 20 | Single-arm study of a MEK1/2 inhibitor (selumetinib) in NF2-related schwannomatosis, in adults and children with inoperable or progressive tumours. No results yet. |
| NCT07713745 (PRIME-NF2) | Phase 2 | Not yet recruiting | 200 | Adaptive platform-basket trial in NF2-related schwannomatosis across four tumour types. Selumetinib’s inclusion as an arm is not confirmed. |
Rhabdoid tumour
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT03155620 | Phase 2 | Active, not recruiting | 1377 | NCI-COG Pediatric MATCH screening protocol assigning targeted therapy by genetic testing. Selumetinib is one arm for MAPK-pathway alterations, and no rhabdoid-specific efficacy data are shown. |
Literature Evidence
No publications are available for familial generalized lentiginosis. The publications below relate to the better-supported predictions.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37906356 | 2023 | Review | Current Oncology Reports | Management of nervous system tumours in neurofibromatosis and schwannomatosis. MEK inhibitors have shown promise. |
| 37046591 | 2023 | Review / expert recommendations | Cancers | EURACAN recommendations on peripheral and cranial nerve tumours. Evidence is low because of rarity. |
| 38058737 | 2023 | Case report | Mol Ther Methods Clin Dev | Partial response to selumetinib in a patient with an NF2-associated ependymoma. |
| 38216572 | 2024 | Preclinical | Nature Communications | NF1 and NF2 tumour suppressors interact to drive Schwann cell tumour de-differentiation and treatment resistance. |
| 25638158 | 2015 | Preclinical | Oncotarget | In atypical teratoid rhabdoid tumours, LIN28 disruption reveals the MAPK pathway as a therapeutic target. |
| 33835000 | 2020 | Case report | Acta Dermatovenerol Croat | Plexiform neurofibroma without NF1. |
| 40861330 | 2025 | Case report | Surgical Case Reports | Surgical management of a giant mediastinal schwannoma in NF1. Not related to selumetinib therapy. |
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 14236G | Koselugo | Capsule 10 mg (oral) | Not available in the data compiled for this report |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (MEK inhibitor) |
| Myelosuppression Risk | Please refer to the Product Information (PI) warnings and precautions |
| Emetogenicity Classification | Please refer to the Product Information (PI) warnings and precautions |
| Monitoring Items | Please refer to the Product Information (PI) warnings and precautions |
| Handling Protection | Please refer to the Product Information (PI) warnings and precautions |
Safety Considerations
Warning and contraindication data were not available for this report. Please refer to the TGA-approved Product Information (PI) for safety information.
Drug Interactions: 84 interactions were identified. Those with Major severity in the listed data:
- Aprepitant
- Dexamethasone
- Clarithromycin
- Cobicistat
Examples with Moderate severity include acetylsalicylic acid, cimetidine, clotrimazole, deferasirox, and a group of anticoagulants and antiplatelets (apixaban, betrixaban, bivalirudin, cangrelor, caplacizumab, cilostazol, dipyridamole, abciximab, antithrombin III). Only 20 of the 84 interactions were available for review, so the full list should be checked.
Conclusion and Next Steps
Decision: Hold (for familial generalized lentiginosis)
Rationale: The top-ranked prediction is based on the model score alone, with no trials or literature. Selumetinib is already marketed in Australia, but the safety data needed for screening are missing. Peripheral nerve schwannoma (NF2-related) is the most promising candidate. It has L3 evidence and one directly relevant Phase 2 trial, which was terminated with only 10 patients, so it is best treated as a research question rather than a Go decision.
To proceed, the following is needed:
- Product Information warnings and contraindications for Koselugo from the TGA or PBS
- Detailed mechanism of action data
- The approved indication text for ARTG 14236G
- For familial generalized lentiginosis: any mechanistic, preclinical or case-level evidence
- For NF2-related schwannoma: results from NCT03095248 and the outcomes of the not-yet-recruiting NCT07707947 and NCT07713745, including confirmation of whether selumetinib is an arm in PRIME-NF2
- A review of the full list of 84 drug interactions, particularly with CYP3A4 inhibitors and anticoagulants
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.