Tenosynovial giant cell tumor (TGCT) is a rare (43 cases per 1 million adults) and aggressive tumor type that originates in the joints. Some of the cells within TGCT express colony-stimulating factor 1 (CSF1) due to genomic alterations of the gene on chromosome 1p13. These cells make up the majority of the tumor. Surgery is the standard of care for TGCT; however, these procedures have long-term effects on joint mobility and can cause bone erosion if the tumor is not treated. Treatment options, therefore, are needed.      

Pexidartinib, a CSF1 inhibitor, was approved for patients with TGCT. It is the first systemic therapy available for TGCT, as surgery is the primary treatment option. Pexidartinib is an oral tyrosine kinase inhibitor that inhibits FLT3 and KIT in addition to CSF1. 

A phase lll trial (ENLIVEN) was conducted to evaluate the use of this drug for TGCT in patients who were not candidates for surgery. The trial was conducted between May 11, 2015, and September 30, 2016, enrolling a total of 120 patients. In the first part of this multinational, double-blind study, patients were randomly assigned to either placebo or pexidartinib at a 1:1 ratio. Baseline characteristics were similar in both groups, and the most common disease site was the knee. Inclusion criteria were age 18 years or  older, confirmed diagnosis of TGCT, symptomatic TGCT characterized by worsening pain and stiffness of joints using a numeric rating scale with a score of at least 4, and measurable disease with a tumor size of at least 2 cm. Patients were excluded if they had previous treatment with any CSF1 inhibitor.

Patients in the pexidartinib group received pexidartinib 1,000 mg orally per day as a loading dose (400 mg in the morning and 600 mg in the evening) for 2 weeks and then 800 mg per day (400 mg twice daily) for 22 weeks. The second part of the study was an open-label trial, and the primary endpoint was overall response rate at week 25.

The overall response rate was better in the pexidartinib group versus placebo (38% vs. 0%, respectively). The main side effects were hair-color changes, fatigue, nausea, and increases in aspartate aminotransferase and alanine aminotransferase. Nine of the 61 patients in the pexidartinib group were discontinued early due to adverse events and consent withdrawal versus 11 of the 59 patients in the placebo group, who discontinued due to disease progression, consent withdrawal, and noncompliance.

When patients are taking pexidartinib, liver-function tests should be monitored weekly and dose adjustments should be made as needed based on liver-injury severity. Providers should refer to the package-insert recommendations.

ENLIVEN is a landmark trial for the treatment of TGCT, as it opens doors to exploring practice-changing systemic therapy options. Hepatotoxicity, however, is a significant side effect of this medication and should be taken into consideration for treatment recommendations.

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