Pexidartinib, a Novel Small Molecule CSF-1R Inhibitor in Use for Tenosynovial Giant Cell Tumor: A Systematic Review of Pre-Clinical and Clinical Development

Abstract

Tenosynovial giant cell tumor (TGCT) is a rare benign tumor that involves the synovium, bursa, and tendon sheath, resulting in reduced mobility of the affected joint or limb. The current standard of care for TGCT is surgical resection. However, some patients have tumor recurrence, present with unresectable tumors, or have tumors that are in locations where resection could result in amputations or significant debility. Therefore, the development of systemic agents with activity against TGCT to expand treatment options is a highly unmet medical need. Pathologically, TGCT is characterized by the overexpression of colony-stimulating factor 1 (CSF-1), which leads to the recruitment of colony-stimulating factor-1 receptor (CSF-1R) expressing macrophages that make up the primary cell type within these giant cell tumors. The binding of CSF-1 and CSF-1R controls cell survival and proliferation of monocytes and the switch from a monocytic to macrophage phenotype contributing to the growth and inflammation within these tumors. Therefore, molecules that target CSF-1/CSF-1R have emerged as potential systemic agents for the treatment of TGCT. Given the role of macrophages in regulating tumorigenesis, CSF1/CSF1R-targeting agents have emerged as attractive therapeutic targets for solid tumors. Pexidartinib is an orally bioavailable and potent inhibitor of CSF-1R which is one of the most clinically used agents. In this review, we discuss the biology of TGCT and review the pre-clinical and clinical development of pexidartinib which ultimately led to the FDA approval of this agent for the treatment of TGCT as well as ongoing clinical studies utilizing pexidartinib in the setting of cancer.

Keywords: colony-stimulating factor 1 receptor; pexidartinib; pigmented villonodular synovitis; tenosynovial giant cell tumors.

Figure 1

Pexidartinib mechanism of action^a. The proliferation and survival of cancer cells and macrophages are regulated by colony-stimulating factor-1 (CSF-1). Pexidartinib is a selective CSF-1R inhibitor that stimulates the auto-inhibited state of CSF-1R by interacting with the juxtamembrane region of CSF-1R, responsible for folding and inactivating the kinase domain, and prevents the binding of CSF-1 and ATP to the region. Without the binding of CSF-1 to the receptor, CSF1-R cannot undergo ligand-induced auto-phosphorylation. Thus, inhibiting the CSF-1/CSF-1R pathway, resulting in the inhibition of tumor cell proliferation and other cells populations such as macrophages. Pexidartinib has also been shown to inhibit cKIT, FMS-like tyrosine kinase 3 (FLT3), and platelet-derived growth factor receptor (PDGFR)-β, all receptor tyrosine kinases that regulate cellular processes such as cell proliferation and survival. This illustration was created with BioRender.com. ^aData from Plexxikon Inc. Abbreviations: PI3K, phosphatidylinositol 3-kinase; pAKT, phospho-protein kinase B.

Figure 2

Chemical structure of pexidartinib (Turalio).