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| Ref Type | Journal Article | ||||||||||||
| PMID | (42361675) | ||||||||||||
| Authors | Verbeek FAJ, Martinez MP, Spiekman IAC, Verkerk K, Haj Mohammad SF, Timmer H, van Maren MA, Zeverijn LJ, Geurts BS, van der Noort V, Roepman P, Jansen AML, de Leng WWJ, Theelen WSME, Piet B, Gelderblom H, Verheul HMW, Voest EE | ||||||||||||
| Title | Trametinib for NRAS-mutated tumors: Results from the Drug Rediscovery Protocol. | ||||||||||||
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| Abstract Text | NRAS-mutations occur in about 3% of all cancers. Currently, no Food and Drug Administration- (FDA) or European Medicines Agency- (EMA)-approved therapy exists for patients harboring NRAS-mutated malignancies. Trametinib, a MEK1/2 inhibitor, could elicit clinical benefit (CB) in patients harboring NRAS mutations by blocking the MAPK pathway. In the Drug Rediscovery Protocol (DRUP; NCT02925234), we evaluated the clinical efficacy and safety of trametinib monotherapy for the treatment of NRAS-mutated cancers.Patients with progressive, advanced and/or metastatic solid malignancies harboring NRAS mutations, who had exhausted all standard treatment options, received trametinib monotherapy. Primary endpoints were CB, defined by RECIST v1.1 as confirmed complete response (CR), partial response (PR), or stable disease (SD) ≥ 16 weeks, and safety. Whole-genome sequencing was performed on pre-treatment biopsies for biomarker analysis.Between January 2017 and February 2024, 24 evaluable patients were included for trametinib monotherapy. CB was observed in nine patients (37.5%), including one partial responder (4.2%). Median overall survival and progression-free survival were 9.0 (95% CI: 5.6 - 13.5) and 3.7 months (95% CI: 3.3 - 5.3), respectively. Response or survival outcomes did not vary between patients with NRAS mutations at codon Q61 versus codon G12/13, nor between patients with non-small cell lung cancer (NSCLC) versus other tumors. No unexpected toxicities were observed. Biomarker analysis did not identify genomic markers for (non)response.Trametinib monotherapy offers limited CB in patients harboring NRAS-mutant malignancies. Future research should further explore the biological and clinical significance of specific NRAS codon mutations to identify biomarkers and optimize treatment approaches. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| NRAS Q61X | Advanced Solid Tumor | no benefit | Trametinib | Phase II | Actionable | In a Phase II trial (DRUP), treatment with Mekinist (trametinib) was well tolerated but demonstrated limited efficacy with a clinical benefit rate of 37.5% (9/24), an objective response rate of 4.2% (1/24, 1 partial response), median time on treatment of 3.2 months, median overall survival of 8.9 months, and median progression-free survival of 3.7 months in patients with advanced solid tumors harboring NRAS Q61X or G12/G13X (PMID: 42361675; NCT02925234). | 42361675 |