Abstract: Pexidartinib (PLX3397) is a novel, orally bioavailable small-molecule tyrosine kinase inhibitor that selectively targets the colony-stimulating factor 1 receptor (CSF-1R), c-KIT, and FMS-like tyrosine kinase 3 (FLT3). It is the first systemic therapy approved by the US Food and Drug Administration (FDA) for the treatment of symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations. Beyond its primary indication, pexidartinib has garnered significant attention in oncology for its profound immunomodulatory effects within the tumor microenvironment (TME). By inhibiting the CSF-1/CSF-1R signaling axis, pexidartinib effectively depletes immunosuppressive M2-like tumor-associated macrophages (TAMs) and promotes a shift toward the anti-tumorigenic M1 phenotype. This literature review synthesizes current research on pexidartinib, detailing its pharmacological activity, molecular mechanism of action, structure-activity relationships, current clinical limitations—particularly hepatotoxicity—and future perspectives in combination cancer immunotherapy.
1. Introduction
Pexidartinib (marketed as TURALIO™) represents a significant breakthrough in targeted oncology, particularly for rare joint tumors. In August 2019, it became the first FDA-approved systemic treatment for adult patients with symptomatic tenosynovial giant cell tumor (TGCT) that is not amenable to surgical resection [3][9]. TGCT is a locally aggressive neoplasm driven by the overexpression of colony-stimulating factor 1 (CSF-1), which recruits CSF-1R-expressing macrophages that form the bulk of the tumor mass and drive severe joint inflammation and destruction [1][6].
While its clinical approval is currently limited to TGCT, the therapeutic potential of pexidartinib extends to a wide array of solid and hematologic malignancies. The CSF-1/CSF-1R pathway is a critical regulator of the tumor microenvironment (TME), primarily responsible for the recruitment, differentiation, and survival of tumor-associated macrophages (TAMs) [4][7]. Because TAMs frequently adopt an immunosuppressive phenotype that facilitates tumor progression, angiogenesis, and therapy resistance, targeting this axis with pexidartinib has emerged as a highly promising strategy in modern cancer immunotherapy [1][7].
2. Pharmacological Activity
The primary pharmacological activity of pexidartinib revolves around its ability to reprogram the immunological landscape of the TME. In many cancers, the TME is dominated by M2-polarized TAMs, which secrete immunosuppressive cytokines (such as IL-10 and TGF-β) and promote immune evasion [4][7]. Pexidartinib disrupts the CSF-1/CSF-1R signaling cascade, leading to the depletion of these M2-like TAMs and inducing a favorable shift in the M1/M2 macrophage ratio toward the pro-inflammatory, anti-tumor M1 phenotype [2][7].
Preclinical and clinical studies have demonstrated the broad pharmacological utility of pexidartinib across various malignancies. In osteosarcoma and breast cancer models, pexidartinib treatment significantly reduced TAMs and FOXP3+ regulatory T cells while simultaneously increasing the infiltration of CD4+ and CD8+ cytotoxic T cells into the tumor bed [2][6]. In glioblastoma, pexidartinib prevented radiation-recruited monocytes from differentiating into pro-angiogenic TAMs, thereby delaying tumor recurrence and potentiating the effects of radiotherapy [1]. Furthermore, in prostate cancer models with bone metastases, pexidartinib attenuated skeletal pain, reduced tumor-induced bone remodeling, and decreased disease progression by targeting myeloid lineage cells [1].
3. Molecular Mechanism of Action
Pexidartinib is a highly selective, orally bioavailable small-molecule tyrosine kinase inhibitor. It primarily targets three receptor tyrosine kinases: CSF-1R, the KIT proto-oncogene receptor tyrosine kinase (c-KIT), and FMS-like tyrosine kinase 3 (FLT3), particularly those harboring an internal tandem duplication (ITD) mutation [3][9].
At the molecular level, pexidartinib functions as a type 2 kinase inhibitor. It is prospectively designed to bind to the juxtamembrane region of the CSF-1R [1][5]. This binding stabilizes the receptor in an auto-inhibited state, effectively folding and inactivating the kinase domain. Consequently, it prevents the binding of both the CSF-1 ligand and adenosine triphosphate (ATP) to the receptor [1][6]. Without ligand binding and ATP availability, CSF-1R cannot undergo ligand-induced auto-phosphorylation, which halts downstream oncogenic and survival signaling pathways, including the ERK and PI3K/Akt cascades [2][6].
4. Structure-Activity Relationship (SAR)
The structural design of pexidartinib allows for potent and highly selective kinase inhibition compared to earlier generation inhibitors like imatinib. Biochemical assays reveal that pexidartinib inhibits CSF-1R with a half-maximal inhibitory concentration (IC50) of approximately 0.013 to 0.020 μM (13-20 nM) [3][6]. It also demonstrates high potency against c-KIT (IC50 of 0.010 to 0.027 μM) and FLT3-ITD (IC50 of 0.009 to 0.018 μM) [1][3].
Importantly, pexidartinib exhibits limited cross-reactivity with other kinases. In comprehensive screens, it showed IC50 values greater than 0.1 μM for kinases such as CDK19, KDR, LCK, and TRK3, and greater than 1 μM for most other tested kinases [6]. Its ability to specifically engage the juxtamembrane region of CSF-1R is the structural basis for its superior potency and selectivity over conventional type 2 inhibitors [3]. Pharmacokinetically, pexidartinib is highly protein-bound (>99%) and is metabolized primarily in the liver by cytochrome P450 3A4 (CYP3A4) and UDP-glucuronosyltransferase 1A4 (UGT1A4) [5][9].
5. Current Limitations
Despite its clinical efficacy, the use of pexidartinib is constrained by a significant toxicity profile, most notably severe hepatotoxicity. Pexidartinib carries a boxed warning for potentially fatal liver injury, characterized by mixed or cholestatic hepatotoxicity with elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and alkaline phosphatase (ALP) [2][11]. This hepatotoxicity is mechanistically attributed to the drug's on-target inhibition of CSF-1R on Kupffer cells—the resident macrophages of the liver responsible for clearing transaminases and other enzymes [1][2]. Due to these risks, pexidartinib is only available in the US through a restricted Risk Evaluation and Mitigation Strategy (REMS) program, requiring rigorous and frequent liver function monitoring [3][6].
Other common adverse events include hair color changes (depigmentation), which are likely linked to the off-target inhibition of c-KIT, as well as fatigue, nausea, dysgeusia, and periorbital edema [1][6]. Furthermore, pexidartinib exposure is significantly increased when taken with high-fat meals or in patients with renal impairment, necessitating strict dosing modifications and dietary guidelines [6][9].
6. Future Perspectives
The future of pexidartinib lies in its integration into combination treatment regimens to overcome therapeutic resistance and enhance anti-tumor immunity. Because cytotoxic therapies (like paclitaxel and radiation) often induce macrophage recruitment and upregulate CSF-1 expression, combining these treatments with pexidartinib has shown synergistic effects in preclinical and early clinical trials [1][10]. Ongoing Phase I/II trials are evaluating pexidartinib in combination with immune checkpoint inhibitors (e.g., pembrolizumab, durvalumab), MEK inhibitors (e.g., binimetinib), and mTOR inhibitors (e.g., sirolimus) across various solid tumors, including melanoma, glioblastoma, and gastrointestinal stromal tumors (GIST) [1][2][3].
Additionally, novel drug delivery systems are being explored to maximize efficacy while minimizing systemic toxicities like hepatotoxicity. For instance, conjugating pexidartinib to M2pep-coated nanoparticles has been shown to facilitate targeted uptake by TAMs, bolstering anti-tumorigenic effects relative to the administration of the free drug [2]. As our understanding of macrophage plasticity deepens, pexidartinib will likely play a foundational role in next-generation TME-targeted immunotherapies.
