Activity of Colony-Stimulating Factor-1 Receptor Kinase Inhibitor in Tenosynovial Giant Cell Tumors
In a phase I study reported in The New England Journal of Medicine, Tap et al found that a newly developed inhibitor of colony-stimulating factor-1 receptor (CSF1R) kinase showed activity in tenosynovial giant cell tumors. CSF1 gene expression is elevated in most such tumors. The structure of the inhibitor (PLX3397) was guided through x-ray co-crystallography studies; the inhibitor acts to trap the receptor kinase in an autoinhibited conformation.
Responses
In the dose-escalation phase of the study (n = 41), the agent was evaluated in solid tumors. In an extension phase, the agent was administered orally at the selected phase II dose (1,000 mg/d) to 23 patients with tenosynovial giant cell tumors.
The overall response rate was 52% (all partial responses), and the disease control rate was 83%. Response usually occurred within the first 4 months of treatment, and the median duration of response was > 8 months. At data cutoff, median progression-free survival had not been reached. A total of 17 patients remained on study, with 7 on treatment for > 1 year. Of 14 patients who had baseline and at least one postbaseline magnetic resonance imaging evaluation, 11 had a partial response, according to tumor volume score, with 3 having stable disease. The mean decrease in tumor volume score was 61%.
Adverse Events
The most common treatment-related adverse events were changes in hair color (74%), fatigue (65%), nausea (39%), dysgeusia (26%), and periorbital edema (26%). Treatment-related grade ≥ 3 adverse events included hyponatremia (9%), elevated alanine transaminase or aspartate transaminase level (9%), fatigue, diarrhea (4%), anemia (4%), and neutropenia (4%). The most common cause of dose alteration was fatigue. Treatment was discontinued in two patients (9%) due to adverse events.
The investigators concluded: “Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients.”
William D. Tap, MD, is the corresponding author of The New England Journal of Medicine article.
The study was funded by Plexxikon. For full disclosures of the study authors, visit www.nejm.org.
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