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Trametinib for NRAS-mutated tumors: Results from the Drug Rediscovery Protocol
Florentine A J Verbeek1, Miguel P Martinez1, Ilse A C Spiekman2
1Department of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands.
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.
Insights
Trametinib monotherapy showed limited clinical benefit in patients with NRAS-mutated cancers. Further research is needed to identify biomarkers and optimize treatment for these challenging malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- NRAS mutations are found in approximately 3% of all cancers.
- No FDA- or EMA-approved therapies currently exist for NRAS-mutated cancers.
- Trametinib, a MEK1/2 inhibitor, targets the MAPK pathway, offering potential benefit for NRAS-mutant tumors.
Purpose of the Study:
- To evaluate the clinical efficacy and safety of trametinib monotherapy in patients with NRAS-mutated advanced solid malignancies.
- To assess clinical benefit (CB) and identify potential biomarkers for treatment response.
Main Methods:
- Patients with progressive, advanced/metastatic NRAS-mutated solid tumors received trametinib monotherapy.
- Clinical benefit was defined as confirmed complete response, partial response, or stable disease for at least 16 weeks (RECIST v1.1).
- Whole-genome sequencing was performed on pre-treatment biopsies for biomarker analysis.
Main Results:
- Twenty-four patients were evaluable; clinical benefit was observed in 37.5% (9/24), including one partial response (4.2%).
- Median overall survival was 9.0 months, and median progression-free survival was 3.7 months.
- No significant differences in outcomes were noted based on NRAS codon mutation site or tumor type (NSCLC vs. others). Biomarker analysis did not reveal predictive markers.
Conclusions:
- Trametinib monotherapy provides limited clinical benefit for patients with NRAS-mutant malignancies.
- Further investigation into the biological and clinical significance of specific NRAS codon mutations is warranted.
- Identifying biomarkers and optimizing treatment strategies are crucial for improving outcomes in this patient population.
