Phase II Study of Pexidartinib Plus Sirolimus in Unresectable Malignant Peripheral Nerve Sheath Tumors Identifies M2 Macrophage Activation.

PURPOSE: To evaluate the preliminary efficacy and safety of the combination of pexidartinib, an inhibitor of colony-stimulating factor-1 receptor (CSF1R), and sirolimus, a mammalian target of rapamycin inhibitor, to target infiltrating M2 macrophages in malignant peripheral nerve sheath tumors (MPNSTs). PATIENTS AND METHODS: This investigator-initiated, phase II, multicenter, single-arm trial enrolled patients with unresectable MPNSTs. Patients were treated with pexidartinib 1000 mg and sirolimus 2 mg orally daily. The primary end point was progression-free survival (PFS). Secondary end points included objective response, safety profile, and overall survival (OS). Pretreatment and on-treatment tumor biopsies were obtained to evaluate changes in the tumor microenvironment (TME) using multiplex immunofluorescence and differential transcriptional profiling. RESULTS: Fifteen patients with MPNSTs were enrolled and 14 initiated therapy. Eight had neurofibromatosis type 1, five were sporadic, and one was undetermined. Although the target sample size was 25, because of the lower-than-expected accrual during the COVID-19 pandemic, enrollment was halted on April 12, 2023. The median PFS and median OS were 6 weeks (95% CI, 6 to 19.1) and 17.9 weeks (95% CI, 13.7 to not applicable), respectively. One patient achieved confirmed stable disease. Three patients experienced PFS ≥12 weeks. Grade 3 treatment-related toxicities (rash and leukopenia) occurred in four (28.6%) patients. Although the study did not meet its primary end point, correlative analysis demonstrated that four of the five long-term survivors had an immune-rich pretreatment TME, three of whom had a reduction in M2-tumor-associated macrophage signal with treatment. CONCLUSION: Further studies of combination of pexidartinib and sirolimus and/or immunotherapy should be performed in the subset of patients with advanced MPNST with an immune-rich TME.