NFS-02. Efficacy of the RAF/MEK clamp avutometinib in combination with the mTOR inhibitor everolimus in NF1-associated malignant peripheral nerve sheath tumor models

Neurofibromatosis type 1- associated malignant peripheral nerve sheath tumor (NF1-MPNST) is the leading cause of death in patients with NF1 syndrome. A hallmark manifestation of NF1 tumors, including MPNST, is acquisition of somatic inactivation of the second NF1 allele and loss of NF1 protein function. The loss of NF1 function leads to hyperactive RAS oncoproteins and hyperactivation of downstream RAS-effector pathways, of which the RAF-MEK1/2-ERK1/2 (MAPK) signaling cascade plays a critical role. In this study, we evaluated the antitumor activity of the RAF/MEK clamp avutometinib in cell- and patient-derived NF1-MPNST xenograft models. Since avutometinib inhibits MEK activity and induces inactive complexes of MEK with the RAF kinases, potentially blocking RAF-mediated feedback, we hypothesized that avutometinib would have improved activity in NF1-MPNST compared to MEK-only inhibitors. As compared to MEK-only inhibitors trametinib or selumetinib, avutometinib inhibited RAF-mediated MEK phosphorylation in NF1-MPNST cells. In cell- and patient-derived NF1-MPNST xenograft models, avutometinib showed significantly better activity than trametinib or selumetinib in inhibiting tumor growth. In vivo pharmacodynamic assays indicated that avutometinib inhibited more potently the MAPK pathway than trametinib or selumetinib. Additionally, we evaluated the antitumor potency of combining avutometinib with the mTOR inhibitor everolimus. The combination of avutometinib with everolimus resulted in improved inhibition of cell proliferation in NF1-MPNST cells. Furthermore, the combination led to enhanced inhibition of ribosomal protein S6 phosphorylation and an improved antitumor efficacy as compared to single agent treatments in xenograft models. We conclude that avutometinib in combination with mTOR inhibition could have clinical implications in NF1-MPNST.