Pexidartinib in the Management of Advanced Tenosynovial Giant Cell Tumor: Focus on Patient Selection and Special Considerations

Abstract

Tenosynovial giant cell tumor (TGCT) is a neoplasm of the joint synovium that can have severe impacts on joint mobility, function, and quality of life. Traditionally, treatment modalities included partial or complete surgical synovectomy, radiotherapy (typically as an adjunct to surgery), and watchful monitoring (no medical or surgical intervention). However, these approaches have been met with varying degrees of success and high recurrence rates, as well as onerous complications and clinical sequelae. Pexidartinib, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, presents a promising molecular approach that targets a neoplastic driver of TGCT. While the introduction of pexidartinib allows clinicians to avoid the significant morbidity associated with traditional treatment options, there are also defined risks associated with pexidartinib treatment. Therefore, patient selection is critical in optimizing treatment modalities in TGCT. The purpose of this literature review is to identify the TGCT patient population that would derive maximal benefit with minimal risk from pexidartinib, and to determine the specific indications and contraindications for selecting pexidartinib over other therapeutic approaches. Specifically, this paper compares the efficacy and safety profile of pexidartinib across clinical and preclinical studies to that of surgery, radiotherapy, and watchful monitoring. Rates of improvement in joint mobility, pain, and recurrence-free survival across studies of pexidartinib have been encouraging. The most common adverse events are mild (hypopigmentation of the hair) or reversible (transient aminotransferase elevation). Severe or permanent adverse events (notably cholestatic hepatotoxicity) are rare. While the optimal treatment strategy remains highly dependent on a patient's clinical circumstances and treatment goals, pexidartinib has surfaced as a promising therapeutic in cases where the morbidity of surgery or radiotherapy outweighs the benefits.

Diagnostic Value, Prognostic Value, and Immune Infiltration of LOX Family Members in Liver Cancer: Bioinformatic Analysis

“…CSF-1R plays critical roles in regulating tumorassociated macrophages in TME, and targeted inhibition of the CSF-1/CSF-1R signal axis has broad application prospects in immunotherapy of malignant tumors (74). Pexidartinib is an orally administered small-molecule tyrosine kinase inhibitor that selectively inhibits CSF1R, and is currently being assessed for other types of cancer (75). Another kinase inhibitor, Derazantinib, also found to have activity against CSF1R and is under investigation for cholangiocarcinoma (76).…”

Complementary Effects of Surgery and Pexidartinib in the Management of Patients with Complex Diffuse-Tenosynovial Giant Cell Tumor

“…However, a patient can continue systemic treatment if symptomatic improvement (pain, swelling, stiffness, and range of motion) has been achieved, if the tumor remains unresectable, and if the drug is tolerable. The combination of neoadjuvant pexidartinib therapy and surgical resection can be implemented to reduce the likelihood of recurrence in cases either having a large volume of disease or having anatomic constraints that preclude complete tumor resection [ 22 ]. In the ENLIVEN study, 32/61 (52.4%) of pexidartinib-treated patients had received ≥1 prior surgery [ 18 ].…”

“…As such, and to mitigate potential risks, the three patients summarized here started at a daily dose of 400 mg pexidartinib which is half of the approved dose of 800 mg daily [ 19 ]. It is critical to weigh the risks and benefits of drug treatment and closely monitor patients on the drug in cases in which dose reduction or discontinuation becomes necessary [ 22 ]. As demonstrated in the 3 cases reported here, pexidartinib treatment was effective in decreasing tumor size and improving symptoms, dose reductions and temporary discontinuation of the drug occurred due to adverse reactions, and highlighting the flexibility that can be used in dosing the drug based on the clinical response and how well the patient tolerates the drug.…”

Sarcoma care in the era of precision medicine

“…For the latter, prognosis has been improved since precision medicine has led to identification of the novel tyrosine kinase inhibitor, avapritinib [84]. Moreover, patients with benign tenosynovial giant cell tumors with elevated levels of CSF1-caused by translocation/fusion and other not fully known mechanisms-can often be offered pexidartinib or vimseltinib [85][86][87], an example of an emerging molecular marker for sarcoma treatment.…”