Pexidartinib Received FDA Approval for Treating Tenosynovial Giant Cell Tumor

On 2 August 2019, the US Food and Drug Administration (FDA), for adult patients with symptomatic tenosynovial giant cell tumor (TDHT) causing severe morbidity or functional limitation and not amenable to surgical removal, approved pexidartinib (Turalio) capsules. Pexidartinib is the first systemic therapy approved for patients with TDHT.

Tenosynovial giant cell tumor (TDHT) is one of the nonmalignant rare tumorsthat can be locally aggressive. TDHT affects synovium-lined joints, bursae and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility in the affected joint or limb. This condition tends to develop in young, working-age adults and can be debilitating.

Surgery is the primary / main treatment for TDHT and, in severe cases, may include multiple synovectomies, joint replacement and even amputation. Despite optimal surgical intervention, diffuse TDHT has a high likelihood of recurrence.

FDA approval of Turalio for treating tenosynovial giant cell tumor is based on an international, multicenter trial enrolling 120 patients with TDHT who were not suitable for surgery, randomized (1: 1), double-blind and placebo controlled, called ENLIVEN, and the overall response rate observed in it. The overall response rate was determined at week 25 by an independent review committee (Response Evaluation Criteria in Solid Tumors - RECIST 1.1).

After 25 weeks of treatment, the overall response rate was % 38; % 15 complete response and % 23 partial response.

No patient receiving placebo had a response at all.

Among 23 patients, 22 maintained their treatment response for at least 6 months.

Measured as a percentage, joint range of motionwas assessed using a goniometer for each affected joint. Among patients with sufficient data for analysis, a statistically significant improvement in the affected joint's range of motion at 25 weeks was observed in patients receiving pexidartinib compared with those receiving placebo.

The most common adverse effects of pexidartinib were lactate dehydrogenase (LDH), increased aspartate aminotransferase (AST), hair color changes, increased alanine aminotransferase (ALT) and increased cholesterol. Additional adverse effects included neutropenia, increased alkaline phosphatase (ALP), decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia and decreased phosphate.

The prescribing information contains a warning advising healthcare professionals and patients about the risk of serious and potentially fatal liver injury. Healthcare professionals should monitor liver tests before starting pexidartinib and weekly during the first 8 weeks, every 2 weeks during the following month, and every 3 months thereafter. In patients experiencing liver injury, the pexidartinib dose should be reduced or discontinued depending on the severity of the injury.

The recommended pexidartinib doseis 400 mg orally twice daily on an empty stomach (2 capsules). 

What Is Pexidartinib's Mechanism of Action?

Pexidartinib is a capsule formulation of a small-molecule receptor tyrosine kinase (RTK) inhibitor. Pexidartinib binds and inhibits phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSF1R) and FMS-like tyrosine kinase 3 (FLT3), which may lead to inhibition of tumor cell proliferation and of macrophages, osteoclasts and mast cells involved in osteolytic metastatic disease. FLT3, CSF1R and FLT3 are overexpressed or mutated in many cancer cell types and play important roles in tumor cell proliferation and metastasis.