Safety & Efficacy of Pexidartinib+Sirolimus in MPNST

Cytotoxic chemotherapy in patients (pts) with unresectable malignant peripheral nerve sheath tumor (MPNST) affords minimal benefit with significant toxicity. Combination with an mTOR inhibitor resulted in sustained tumor control in our phase I study and administration of pexidartinib+sirolimus suggested the safety of the and tumoral static activity where 2 of 6 MPNST pts experienced a progression-free survival (PFS) of >18 weeks.

Gulam Abbas Manji and the team aimed to further evaluate the safety and efficacy of pexidartinib+sirolimus in pts with unresectable MPNST. The initial results from the phase I study were promising, indicating potential benefits in terms of disease stabilization and PFS, thus warranting further exploration in a larger cohort of pts.

Researchers utilized a multicenter, single-arm and initiated a phase 2 trial to enroll pts with unresectable MPNST who had 0-3 prior systemic therapies, excluding inhibitors of tyrosine kinases or mTOR. Selected pts were administered with pexidartinib+sirolimus (1000mg+2mg, respectively) and tumor response was assessed every 6 weeks by RECIST v1.1.

About 25 pts were enrolled in the study, with a statistical power 90% to detect a median PFS difference of 12 weeks, under the assumption of a 6-week median PFS in historical controls. Exploratory analysis of both pre-treatment and on-treatment tumor biopsies involved characterizing the tumor immune microenvironment (TIME) using multiplex immunofluorescence and transcriptional analysis methods.

They enrolled 15 pts between January 1, 2019, and January 19, 2023, for the study, with 14 initiating therapy and being evaluable of those 4 had Neurofibromatosis Type 1 (NF1) associated MPNST . Enrollment was stopped due to a lower enrollment rate during the COVID-19 pandemic on April 12, 2023, with a data cutoff on September 20, 2023.

The data indicated median age of participants was 39 years (range 19-72), with 28.6% being female. Ten pts had received prior systemic therapy, with a median of 1 regimen. Twelve pts discontinued therapy due to disease progression, 1 patient died from COVID-19 during treatment before radiologic evaluation, and 1 ceased therapy due to rash. The study was designed with a statistical power of 90% to detect clinically significant outcomes.

The median PFS was 6 weeks (95% CI, 6-19.1), and the median overall survival (OS) was 21.8 weeks (95% CI, 14.6-NA). Three pts had PFS ≥12 weeks, and 5 survived more than 8 months, with 4 receiving subsequent therapy. Only 1 patient remained alive after 2.7 years of follow-up. Therapy was generally well tolerated, with grade 3 treatment-related adverse events observed in 4 pts (28.6%), primarily leukopenia and rash. Exploratory analyses, including multiplex immunofluorescence and bulk RNAseq on paired biopsies from 8 pts, will be presented.

The study concluded that pexidartinib+sirolimus co-treatment shows limited efficacy in unresectable MPNST pts but may benefit some. Further exploration of TIME modulation is still ongoing.

The trial was sponsored by Gulam Abbas Manji from Columbia University.

Source: https://meetings.asco.org/abstracts-presentations/233343

Clinical Tiral: https://www.clinicaltrials.gov/study/NCT02584647

Manji G A, Stanton L J, Ge L, et al. (2024). “A phase II study of the combination of pexidartinib and sirolimus to target tumor-associated macrophages in unresectable malignant peripheral nerve sheath tumors.” Presented at ASCO 2024. J Clin Oncol 42, 2024 (suppl 16; abstr 11565), 10.1200/JCO.2024.42.16_suppl.11565