Presentation (CTI)

OBJECTIVES: Neurofibromatosis type-1 (NF1) is a rare, autosomal-dominant genetic disorder commonly associated with the development of benign nerve sheath tumours, e.g., plexiform neurofibromas (PNs), which cause significant morbidity when surgery is not feasible. In recent years, novel agents including mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) pathway inhibitors, MEK inhibitors, and targeted anti-cancer therapies have revolutionised the treatment landscape of NF1-PN. The aim of this review was to identify and summarise the clinical outcomes of MEK inhibitors and targeted anti-cancer agents in NF1-PN.
METHODS: A systematic literature search was conducted in Embase, MEDLINE, and the Cochrane Library to identify NF1-PN clinical trials ongoing or completed between 1^st January 1946 and 6^th September 2024. Supplementary searches were conducted across clinical trial registries and oncology congresses. Two reviewers independently screened the literature and extracted data from eligible trials on the study status, patient characteristics, and clinical outcomes, including change in tumour volume and response outcomes. Risk of bias was assessed using the Cochrane RoB-2 or ROBINS-I tool (PROSPERO protocol registration: CRD42024588717).
RESULTS: Of 154 records identified, 51 were selected for inclusion in the review. These reported on a total of 21 unique studies on 11 emerging therapies: 6 MEK inhibitors (selumetinib, mirdametinib, trametinib, binimetinib, FCN-159, tunlametinib) and 5 targeted anti-cancer agents (cabozantinib, tipifarnib, sorafenib, sirolimus, everolimus). Most clinical trials for these interventions were Phase 1/2 and single-arm, with <100 participants. Clinical benefits were seen with selumetinib and mirdametinib. However, tipifarnib, sorafenib, sirolimus, and everolimus failed to demonstrate significant treatment benefit.
CONCLUSIONS: The promising results of MEK inhibitors in therapeutic trials for NF1 demonstrate that targeting the MAPK/ERK pathway is an attractive therapeutic avenue for unresectable PNs. Because selumetinib is only approved for children, future reimbursement will require advanced studies establishing MEK inhibitor efficacy in adults.