Pexidartinib for Advanced Tenosynovial Giant Cell Tumors


Key Points

  • Pexidartinib produced responses in 39% of patients.
  • Mixed or cholestatic hepatotoxicity was an identified safety concern.

In the phase III ENLIVEN trial reported in The Lancet, Tap et al found that the colony-stimulating factor 1 inhibitor pexidartinib produced responses in patients with advanced tenosynovial giant cell tumors (TGCTs) not amenable to surgical resection.

Study Details

In the double-blind portion of the trial, 120 patients from 12 countries with symptomatic TGCTs were randomly assigned between May 2015 and September 2016 to receive pexidartinib (n = 61) or placebo (n = 59). Pexidartinib was given at a loading dose of 1,000 mg per day (400 mg morning, 600 mg evening) for the first 2 weeks, followed by 400 mg twice a day for 22 weeks. An open-label study of pexidartinib for all patients was to follow the randomized phase—the randomized phase is reported here.

The primary endpoint was overall response at 25 weeks on central review in the intention-to-treat population.


The finding of mixed or cholestatic hepatotoxicity prompted the data monitoring committee to stop enrollment six patients short of target. Response at week 25 was achieved in 24 (39%) of 61 patients treated with pexidartinib vs 0 (0%) of 59 patients treated with placebo (P < .0001). At median 6-month follow-up, no patients with a response to pexidartinib had progressed; after median follow-up of 22 months, median duration of response was not reached.

Adverse Events

Serious adverse events occurred in 13% of the pexidartinib group and 2% of the placebo group. The most common pexidartinib-associated adverse events of any grade were hair color changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%). Grade 3 or 4 adverse events occurred in 44% of the pexidartinib group and 12% of the placebo group; those more common with pexidartinib included increases in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, as well as hypertension. Three patients in the pexidartinib arm experienced aminotransferase elevations three or more times the upper limit of normal, with total bilirubin and alkaline phosphatase two or more times the upper limit of normal, indicating mixed or cholestatic hepatotoxicity. One biopsy-confirmed case persisted for 7 months.

The investigators concluded, “Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery.”

William D. Tap, MD, of the Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet article.

Disclosure: The study was funded by Daiichi Sankyo. For full disclosures of the study authors, visit

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