(P 48) PRECLINICAL ACTIVITY OF MEK INHIBITION IN COMBINATION WITH CHEMOTHERAPY IN MALIGNANT PERIPHERAL NERVE SHEATH TUMOR

Objective: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma most commonly occurring in individuals with neurofibromatosis 1 (NF1) and associated with poor prognosis despite conventional therapy. MEK inhibitors have emerged as promising agents for NF1-associated tumors. Mirdametinib is a selective MEK1/2 inhibitor with improved potency and bioavailability compared to earlier MEK inhibitors and is FDA approved for NF1 plexiform neurofibromas in adults and children. We evaluated the preclinical activity of mirdametinib in combination with chemotherapy in MPNST patient-derived xenografts (PDXs).

Methods: Clinically relevant dosing of mirdametinib monotherapy (0.5 mg/kg PO BID x 21 days) and in combination with conventional soft tissue sarcoma-based chemotherapy (ifosfamide/doxorubicin) were administered to nude mice to assess tolerability. After confirmation of dose and schedule, an MPNST PDX model (NF1 null) was propagated and treated with vehicle, trametinib, or mirdametinib with each MEK inhibitor administered as monotherapy or in combination with chemotherapy. Differences in tumor volume and progression-free survival (PFS) were assessed across treatment arms.

Results: Administration of mirdametinib singly and in combination with chemotherapy were tolerated at clinically relevant dosing of each drug with no appreciable toxicity observed when given with supportive care (daily saline infusion and wet food). While significant tumor volume control is observed with mirdametinib monotherapy or chemotherapy (p=0.02 for both, AUC comparison) relative to vehicle control, the combination of mirdametinib with chemotherapy was significantly improved compared to mirdametinib alone (p=0.03) and chemotherapy alone (p=0.02). Mirdametinib with chemotherapy is superior to trametinib alone (p=0.04) and with a trend to improved activity compared to trametinib with chemotherapy though not currently significant (p=0.07). Similarly, mirdametinib with chemotherapy improves PFS compared to chemotherapy alone (p=0.008, log-rank) but not significantly different when compared with trametinib with chemotherapy (p=0.07).

Conclusion: MEK inhibition in combination with chemotherapy results in superior tumor volume control and PFS in preclinical models of MPNST and supports future investigation of this combination strategy in patients with MPNST.