Pexidartinib for the treatment of adult symptomatic patients with tenosynovial giant cell tumors

ABSTRACT

Introduction

Tenosynovial giant cell tumor (TGCT) is a benign mesenchymal tumor arising from the synovium of tendon sheats and joints, driven by colony-stimulating factor 1 (CSF1) over-expression. Standard treatment is surgery, but local recurrences are frequent, especially in diffuse TGCT subtype, rarely cured with surgery. When TGCT becomes a chronic condition, which may severely compromise joint function and quality of life, patients may need a systemic therapy.

Areas covered: We reviewed the drugs on clinical development in TGCT, focusing on the pharmacodynamics, pharmacokinetics, efficacy, and toxicity profile of pexidartinib, the first drug approved in the US for TGCT, and on the open questions about its optimal use in clinical practice.

Expert opinion

CSFR1 inhibitors have opened a new avenue for treatment of TGCT patients. Pexidartinib is the first-in-class FDA approved agent for symptomatic locally advanced TGCT, based on a phase III study where pexidartinib showed high anti-tumor activity, improved patient symptoms, and functional outcome. A few cases of potentially life-threatening hepatic toxicity were observed. TGCT patients candidate to pexidartinib need to be carefully selected by the multidisciplinary board of center of expertise, balancing the expected risk-benefit ratio. Close monitoring of liver function and adequate education on the approved indication is warranted.

KEYWORDS:

• CSF1R-inhibitors
• hepatic toxicity
• pexidartinib
• quality of life
• tenosynovial giant cell tumor
• sarcoma

Article highlights

• Pexidartinib is a small molecule tyrosine-kinase inhibitor of colony-stimulating factor 1 (CSF1) receptor, typically activated by CSF1 over-expression in TGCT, which is a benign mesenchymal tumour, usually treated with surgery.

• Relapses are local and often multifocal and may compromise joint function; in these cases, a macroscopically complete surgery is no longer feasible and a medical treatment is needed.

• Pexidartinib received its first approval by FDA in the US on 2^nd August of 2019 in adult patients with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to surgery. After the approval of pexidartinib, many questions are still unanswered among which its long-term therapeutic effects, long-term safety and the optimal treatment duration.

Declaration of interest

S. Stacchiotti has previously acted as an advisor to Daiichi Sankyo Pharma and received institutional research funding from Daiichi Sankyo Pharma and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Information sources

1. http://www.accessdata.fda.gov/

2. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=389

3. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24c5a6f1-b640-4d14-b44b-dd293ed002b1

Additional information

Funding

This paper was not funded.