Trametinib
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Trametinib: From Metastatic Melanoma to Choroideremia
One-Sentence Summary
Trametinib is a MEK1/2 inhibitor originally used to treat BRAF V600-mutant metastatic melanoma. The TxGNN model's top-ranked prediction is Choroideremia, but no clinical trials and no publications support it. Among the other predictions, non-cutaneous melanoma has the strongest support, with 10 listed clinical trials (a mix of cutaneous and non-cutaneous populations; no outcome data were supplied).
Note on the top prediction: The rank 1 prediction (choroideremia) is a computational output only. The sections below report its evidence as it stands and flag the stronger alternative (non-cutaneous melanoma) for context.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Metastatic melanoma (the Singapore licence records contain no approved indication text) |
| Predicted New Indication | Choroideremia |
| TxGNN Prediction Score | 99.31% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 3 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Trametinib is a MEK1/2 inhibitor. It blocks MAP2K1 and MAP2K2, which act downstream of BRAF in the MAPK signalling pathway. Detailed mechanism-of-action text is not available beyond this target information. It is used with dabrafenib for BRAF V600-mutant melanoma and other BRAF V600E tumours.
For choroideremia, a mechanistic link is hard to establish. It is an X-linked retinal degeneration caused by loss of the CHM (REP1) gene. No connection to MEK/MAPK inhibition is evident in the data compiled for this report. The very high score (99.31%) is therefore best read as a model artefact rather than a biologically supported hypothesis.
By contrast, the lower-ranked melanoma-related predictions are mechanistically coherent. Non-cutaneous melanomas (uveal, mucosal) can carry MAPK-activating alterations. Mucosal melanoma also has preclinical evidence of sensitivity to MEK inhibitor combinations. BRAF frequency differs from cutaneous melanoma, though.
Clinical Trial Evidence
Choroideremia (rank 1): Currently no related clinical trials registered.
For reference, the strongest trial data belong to the rank 2 prediction, non-cutaneous melanoma. The table below lists the most relevant of the 10 trials. Several enrol cutaneous or tumour-agnostic populations, so fit to non-cutaneous disease must be confirmed.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02296112 | Phase 2 | Completed | 9 | Trametinib in melanoma with BRAF non-V600 mutations; small, direct trametinib evidence |
| NCT02872259 | Phase 1/2 | Completed | 74 | BGB324 plus pembrolizumab or dabrafenib/trametinib in advanced melanoma; trametinib is part of a combination backbone |
| NCT04439292 | Phase 2 | Active, not recruiting | 44 | NCI-MATCH Subprotocol H: dabrafenib + trametinib in BRAF V600-mutant tumours (excluding melanoma, thyroid, colorectal, NSCLC) |
| NCT02974725 | Phase 1 | Terminated | 241 | LXH254-centric combinations, including trametinib, in KRAS/BRAF-mutant NSCLC or NRAS-mutant melanoma |
| NCT05907304 | Phase 1 | Active, not recruiting | 86 | Naporafenib plus trametinib in RAS Q61X solid tumours; no results yet |
| NCT02410863 | Phase 2 | Terminated | 10 | Biopsy-driven targeted therapy in BRAF-mutant metastatic melanoma; ended early |
| NCT07440290 | Phase 2/3 | Recruiting | 30 | DETERMINE platform: dabrafenib + trametinib in BRAF V600-mutant cancers |
| NCT03944356 | N/A | Completed | 232 | Observational study of adjuvant dabrafenib + trametinib in melanoma |
| NCT03340506 | Phase 4 | Recruiting | 100 | Roll-over study for long-term safety; no efficacy data |
| NCT05275374 | Phase 1/2 | Not yet recruiting | 221 | XP-102 plus trametinib in BRAF V600 solid tumours; no data yet |
Literature Evidence
Choroideremia (rank 1): Currently no related literature available.
For context, the highest-ranked literature relates to malignant melanoma of the mucosa (rank 6), which is mostly preclinical or case-level:
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 29650281 | 2018 | Review | Crit Rev Oncol Hematol | Recent developments and obstacles in treating melanoma with BRAF and MEK inhibitors |
| 32943547 | 2020 | Preclinical | Mol Cancer Ther | Combined MEK and dual mTORC1/2 inhibition in a canine mucosal melanoma model |
| 28092667 | 2017 | Preclinical/translational | Oncogene | Oncogenic BRAF fusions in mucosal melanoma activate MAPK and respond to MEK/PI3K or MEK/CDK4/6 inhibition |
| 27463366 | 2016 | Preclinical | Pigment Cell Melanoma Res | Synergy of MEK and PI3K/mTOR inhibition in canine melanoma, a model for human mucosal melanoma |
| 40445056 | 2025 | Case report | Stomatologiia | Maxillary sinus melanoma with BRAF mutation treated with adjuvant dabrafenib + trametinib |
| 42675868 | 2026 | Genomic profiling | J Pathol | Mucosal melanoma shows dysregulated cell-cycle, MAPK and PI3K pathways |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN15182P | MEKINIST Film-Coated Tablets 2 mg | Film-coated tablet | Not specified in the data compiled |
| SIN15181P | MEKINIST Film-Coated Tablets 0.5 mg | Film-coated tablet | Not specified in the data compiled |
| SIN17018P | MEKINIST Powder for Oral Solution 4.7 mg | Powder for solution | Not specified in the data compiled |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (MEK1/2 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
Drug Interactions: 15 drug-drug interactions were identified, all graded Moderate. They include:
- Dabrafenib and encorafenib (other BRAF inhibitors)
- Enzalutamide and apalutamide
- Brigatinib, erdafitinib, gilteritinib, midostaurin and tucatinib
- Idelalisib, isavuconazonium, fostamatinib, elagolix, lasmiditan and sarecycline
Dabrafenib is the usual combination partner, so that interaction should be reviewed in context.
For warnings and contraindications, please refer to the package insert for safety information.
In the literature retrieved for nodular melanoma, panniculitis was reported with BRAF/MEK inhibitor therapy (including dabrafenib + trametinib). This is a case-level safety signal.
Conclusion and Next Steps
Decision: Hold
Rationale: The choroideremia prediction rests on a computational score alone (evidence level L5). No trials or publications support it, and no plausible link between MEK/MAPK inhibition and CHM-related retinal degeneration is evident. Trametinib is already marketed in Singapore, but that does not support this new indication.
To proceed, the following is needed:
- A mechanistic rationale connecting MEK inhibition to choroideremia, plus preclinical data in relevant retinal models
- Package insert warnings and contraindications (not available in the data compiled, and a blocking gap for safety screening)
- Detailed mechanism-of-action data
- Consideration of redirecting effort to non-cutaneous melanoma (rank 2, L2, Proceed with Guardrails). Its trial outcomes, the cutaneous/non-cutaneous split of enrolled patients, and BRAF/NRAS mutation status would first need to be clarified.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.