Trametinib
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Trametinib: From BRAF V600-Mutant Melanoma to Additional Melanoma Subtypes
One-Sentence Summary
Trametinib is a MEK1/2 inhibitor whose established use — evident throughout the clinical trial record in this evidence pack — is combination therapy with dabrafenib for BRAF V600 mutation-positive melanoma. TxGNN additionally flags several histological and anatomical melanoma subtypes (nodular, superficial spreading, non-cutaneous/mucosal-ocular) as candidates for the same mechanism, each supported to varying degrees by completed Phase 2/3 trials and case-level literature, while a subset of predictions (choroideremia, scrotal melanoma, CDK4-linked melanoma, balloon cell melanoma) have no clinical or mechanistic support at all. This is a multi-indication candidate pack (10 predictions, evidence levels L1–L5), so each candidate below is assessed independently rather than as a single go/no-go decision.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available in Taiwan/Germany regulatory data (0 licenses on file). Based on clinical trial descriptions in this pack, trametinib's established use is combination therapy with dabrafenib for BRAF V600E/K mutation-positive melanoma (unresectable/metastatic and adjuvant settings) |
| Best-Supported New Indications | Superficial spreading melanoma and Nodular malignant melanoma (histological subtypes of cutaneous melanoma) |
| TxGNN Prediction Score (top pick) | 99.14% (both indications, tied) |
| Evidence Level | L2 (1 completed Phase 2 trial + supporting cohort/case literature) |
| Germany Market Status | Not marketed (未上市) |
| Number of Authorizations | 0 |
| Recommended Decision | Proceed with Guardrails (for melanoma-subtype extensions, conditional on BRAF V600 testing) — see full ranking below for other candidates |
Full Predicted-Indication Ranking
| Rank | Disease | TxGNN Score | Evidence Level | Recommendation |
|---|---|---|---|---|
| 1 | Choroideremia | 99.31% | L5 | Hold |
| 2 | Non-cutaneous melanoma | 99.30% | L1 | Research Question |
| 3 | Epithelioid cell melanoma | 99.28% | L4 | Research Question |
| 4 | Eyelid melanoma | 99.26% | L4 | Research Question |
| 5 | Scrotum melanoma | 99.21% | L5 | Hold |
| 6 | Nodular malignant melanoma | 99.14% | L2 | Proceed with Guardrails |
| 7 | Balloon cell malignant melanoma | 99.14% | L5 | Hold |
| 8 | Superficial spreading melanoma | 99.14% | L2 | Proceed with Guardrails |
| 9 | CDK4-linked melanoma | 99.14% | L5 | Hold |
| 10 | Amelanotic skin melanoma | 99.14% | L4 | Research Question |
Note: Evidence level here does not track monotonically with TxGNN score — a high similarity score reflects embedding proximity in the knowledge graph, not clinical support. Rank 2 is labeled L1 in the source scoring but downgraded to "Research Question" because its listed trials are cutaneous-melanoma registration trials applied indirectly to a non-cutaneous population, not disease-specific RCTs.
Why is This Prediction Reasonable?
Detailed DrugBank mechanism-of-action text is not available in this evidence pack (data gap DG002). However, every clinical trial record in the pack consistently describes trametinib as an oral MEK1/2 inhibitor, used in combination with the BRAF inhibitor dabrafenib to block the MAPK/ERK signaling cascade downstream of BRAF V600 mutations. This combination is the backbone of the pivotal registration trials present here (e.g., NCT01245062, NCT01584648, NCT01597908), which established efficacy in BRAF V600E/K-mutant unresectable or metastatic cutaneous melanoma.
The predictions in ranks 6 and 8 (nodular and superficial spreading melanoma) are histological subtypes of cutaneous melanoma rather than distinct diseases — they share the same BRAF V600 mutation biology as the already-treated population, so the mechanistic extrapolation is close to direct rather than novel. Rank 2 (non-cutaneous melanoma) and the ocular/mucosal predictions (ranks 3, 4, 10) are biologically more distant: BRAF V600 mutation prevalence in conjunctival, eyelid, and mucosal melanoma is substantially lower than in cutaneous melanoma, so response is plausible only in the BRAF-mutant-positive subset, as illustrated by isolated case reports of conjunctival melanoma responding to BRAF/MEK inhibition (PMID 27893585, 31361915).
Conversely, choroideremia (rank 1), scrotal melanoma (rank 5), balloon cell melanoma (rank 7), and CDK4-linked melanoma (rank 9) have no clinical trials, no literature, and no plausible mechanistic link to MEK inhibition (choroideremia is a CHM/REP1 retinal degeneration unrelated to MAPK signaling; CDK4-driven melanoma acts through cell-cycle rather than MAPK pathways). These should be treated as pure knowledge-graph artifacts.
Clinical Trial Evidence
Trials below form the core evidence base underpinning trametinib's BRAF/MEK mechanism; they support the melanoma-subtype extensions (non-cutaneous, nodular, superficial spreading) as background mechanistic evidence rather than subtype-specific confirmatory trials.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01245062 | Phase 3 | Completed | 322 | Pivotal trial: trametinib monotherapy vs. chemotherapy in BRAF V600E/K-positive cutaneous melanoma |
| NCT01584648 | Phase 3 | Completed | 423 | COMBI-d: dabrafenib+trametinib vs. dabrafenib alone, unresectable/metastatic BRAF V600E/K cutaneous melanoma |
| NCT01597908 | Phase 3 | Completed | 704 | COMBI-v: dabrafenib+trametinib vs. vemurafenib, BRAF V600E/K cutaneous melanoma |
| NCT03551626 | Phase 3b | Completed | 552 | COMBI-APlus: adjuvant dabrafenib+trametinib after complete resection, Stage III BRAF V600 melanoma; pyrexia AE-management algorithm |
| NCT01072175 | Phase 1/2 | Completed | 430 | Original dose-escalation/combination trial of dabrafenib+trametinib in BRAF-mutant metastatic melanoma |
| NCT02039947 | Phase 2 | Completed | 127 | Dabrafenib+trametinib in BRAF-mutant melanoma with brain metastases (4 mutation cohorts) |
| NCT02645149 | Phase 2 | Completed | 216 | Molecular profiling with matched targeted therapy in BRAF/NRAS wild-type unresectable/metastatic melanoma progressing on immunotherapy |
| NCT02910700 | Phase 2 | Active, not recruiting | 52 | Triplet nivolumab+dabrafenib+trametinib (TRIDeNT) vs. encorafenib+binimetinib+nivolumab (TRIBECA), BRAF-mutant Stage III-IV melanoma |
| NCT05171374 | N/A | Unknown | 500 | Prospective real-world outcomes of dabrafenib+trametinib in resectable/metastatic BRAF+ melanoma |
| NCT03340506 | Phase 4 | Recruiting | 100 | Long-term safety roll-over study for patients continuing dabrafenib/trametinib after parent-study completion |
No trials in this pack specifically enroll patients with choroideremia, scrotal melanoma, balloon cell melanoma, or CDK4-linked melanoma.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 40853557 | 2025 | Review | JAMA | Overview of cutaneous melanoma epidemiology and treatment landscape, including BRAF/MEK-targeted therapy |
| 30376465 | 2019 | Cohort | Melanoma Research | Multicenter real-life study of BRAF/MEK inhibitor combination in melanoma patients with active brain metastases (n=65) |
| 31361915 | 2020 | Case Report/Review | Clin Exp Dermatol | BRAF-mutated bulbar conjunctival (epithelioid) melanoma treated with vemurafenib; literature review |
| 27893585 | 2017 | Case Report | Ophthalmic Plast Reconstr Surg | Conjunctival melanoma with BRAF V600E responsive to systemic BRAF/MEK inhibitor combination |
| 31747798 | 2019 | Case Report/Review | J Investig Med High Impact Case Rep | Lacrimal sac malignant melanoma (epithelioid type); review of 15 Japanese cases |
| 41310270 | 2025 | Case Report | Child's Nervous System | Pediatric amelanotic CNS melanoma with systemic spread, associated with congenital melanocytic naevi |
| 41209431 | 2026 | Case Report | Oncology Letters | Combined BRAF/MEK inhibition for BRAF-mutant brain metastases from superficial spreading melanoma during pregnancy |
| 37756677 | 2025 | Case Report | Retinal Cases & Brief Reports | Rapid resolution of choroidal metastasis from cutaneous melanoma after combined targeted therapy |
| 24879511 | 2014 | Case Series (safety) | Am J Dermatopathol | Panniculitis as an adverse effect of BRAF/MEK inhibitor therapy (dabrafenib, dabrafenib+trametinib) |
| 32614358 | 2020 | Case Report | La Clinica Terapeutica | PET-guided switch from immunotherapy to BRAF/MEK targeted therapy in nodular melanoma with cutaneous/skeletal metastases |
No literature was returned for choroideremia, scrotal melanoma, balloon cell melanoma, or CDK4-linked melanoma.
Germany Market Information
Trametinib is currently not marketed in Germany under this evidence pack's regulatory data source (market status: 未上市, 0 authorizations on file). No license table can be produced.
Cytotoxicity
Trametinib is an antineoplastic agent (all trial populations in this pack are oncology/melanoma patients), so this section applies.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (MEK1/2 inhibitor) — not a conventional cytotoxic chemotherapy 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
Please refer to the package insert for safety information. (TFDA/BfArM warning, contraindication, and drug-interaction data are not available in this evidence pack — flagged as a blocking data gap, DG001.)
Conclusion and Next Steps
Decision: Proceed with Guardrails (for the melanoma-subtype extensions: nodular melanoma, superficial spreading melanoma, non-cutaneous melanoma) / Hold (for choroideremia, scrotal melanoma, balloon cell melanoma, CDK4-linked melanoma) / Research Question (for epithelioid cell melanoma, eyelid melanoma, amelanotic melanoma)
Rationale:
- Nodular and superficial spreading melanoma are histological subtypes already within the biological population (BRAF V600-mutant cutaneous melanoma) that the pivotal dabrafenib+trametinib trials enrolled — the mechanistic case is strong, but subtype-specific confirmatory trials are absent, so guardrails (mandatory BRAF V600 testing, subtype-stratified monitoring) are warranted.
- Non-cutaneous, ocular, and mucosal melanoma predictions rest only on case-level evidence in a population with lower BRAF mutation prevalence, and choroideremia/scrotal/balloon-cell/CDK4-linked melanoma predictions have zero clinical or mechanistic support — these should not proceed without new primary evidence.
To proceed, the following is needed:
- TFDA/BfArM package insert (warnings, contraindications, DDI) — currently a blocking data gap (DG001)
- DrugBank-sourced mechanism of action and toxicity profile (DG002)
- BRAF V600 mutation-status stratification data for any subtype-specific trial design
- Confirmation of trametinib's approved label scope (cutaneous vs. all melanoma) from an authoritative regulatory source, since it is absent from the regulatory data provided here
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.