A phase II study of the combination of pexidartinib and sirolimus to target tumor-associated macrophages in unresectable malignant peripheral nerve sheath tumors.
Authors: Manji Gulam Abbas , Stanton Liam James , Ge Liner , Sta Ana Sarah , Chrisinger John , Titus Shiny , Labadie Brian William , May Michael S. , Lyu Yang , Sender Naomi , Tan Aik-choon , Monga Varun , Chugh Rashmi , Hirbe Angela C. , Lee Shing M , Van Tine Brian Andrew , Schwartz Gary K. 
Published: June 2024

11565 Background: Cytotoxic chemotherapy in patients (pts) with unresectable malignant peripheral nerve sheath tumors (MPNSTs) affords minimal benefit with significant toxicity. Pexidartinib, an inhibitor of colony-stimulating factor-1 receptor (CSF1R), targets infiltrating M2 macrophages which correlate with disease progression; combination with an mTOR inhibitor resulted in sustained tumor control in our xenograft MPNST model. A phase I study of pexidartinib + sirolimus suggested the combination’s safety and tumoral static activity where 2 of 6 MPNST pts experienced a progression-free survival (PFS) of >18 weeks. We conducted a phase II study of this combination in pts with unresectable MPNST. Methods: This multicenter, single-arm, investigator-initiated phase 2 trial enrolled pts with unresectable MPNST with 0-3 prior systemic therapies, excluding inhibitors of tyrosine kinases or mTOR. Pts were treated with pexidartinib 1000mg and sirolimus 2mg daily. Tumor response was assessed every 6 weeks by RECIST v1.1. With a target sample size of 25 the study had 90% power to detect a difference of 12 weeks in median PFS assuming a 6 week median PFS in historical controls. Exploratory analysis on pre- and on-treatment tumor biopsies included characterization of the tumor immune microenvironment (TIME) by multiplex immunofluorescence and transcriptional analysis. Results: Fifteen pts enrolled between 1/1/19 and 1/19/23, 14 initiated therapy and are evaluable, including 4 with Neurofibromatosis Type 1 (NF1) associated MPNST. The study was closed to enrollment on 4/12/23 due to lower-than-expected accruals during the COVID-19 pandemic. Data cutoff was 9/20/23. The median age was 39 years (range 19-72) and 28.6% were female. Ten pts had been on prior systemic therapy (median 1). Twelve pts ceased therapy due to disease progression, one died on treatment from COVID-19 before radiologic evaluation, and one stopped therapy due to rash. The median PFS and median overall survival were 6 weeks (95% CI, 6-19.1) and 21.8 weeks (95% CI, 14.6-NA), respectively. One patient achieved confirmed stable disease. Three pts experienced PFS ≥12 weeks and five pts survived >8 months, four of whom had subsequent therapy. One patient was alive at last follow up after 2.7 years. Therapy was well tolerated with grade 3 treatment-related adverse events occurring in 4 (28.6%) pts, namely leukopenia and rash. Exploratory analyses of paired biopsies performed on 8 pts using multiplex immunofluorescence and bulk RNAseq will be presented. At time of submission, no pts remained on study therapy. Conclusions: Cotreatment with pexidartinib and sirolimus has limited efficacy in pts with unresectable MPNST but may benefit a subset of pts. Exploratory analyses of TIME modulation are ongoing. Clinical trial information: NCT02584647 .