Trametinib for NRAS-mutated tumors: Results from the Drug Rediscovery Protocol

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.