The FDA has now approved pexidartinib (TuralioTM, Daiichi Sankyo, Inc.) for adults with symptomatic tenosynovial giant cell tumor (TGCT) that does not respond to surgery and is associated with severe morbidity or functional limitations. This is the first FDA approval for TGCT.
A locally aggressive neoplasm of the synovium of joints and tendon sheaths, TGCT is a rare disease that causes inflammation, pain, swelling, and the destruction of joints. Symptoms result in part from colony-stimulating factor 1 (CSF1) receptor-bearing macrophages. These are drawn to the tumor by CSF1, which is overexpressed in TGCT. Pexidartinib is a CSF1 receptor inhibitor.
The approval was based on ENLIVEN (NCT02371369), a phase 3 trial involving 120 patients with symptomatic, advanced TGCT not recommended for surgery. For the first part of the trial, patients were randomized to receive pexidartinib (61 patients) or placebo (59 patients). Those in the pexidartinib arm received 1,000 mg orally per day—400 mg in the morning and 600 mg in the evening—for two weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. The trial's second part consisted of an open-label study of pexidartinib for all patients. The study's primary end point was overall response at week 25 according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
Pexidartinib produced an overall response rate of 39%, with a complete response rate of 15% and a partial response rate of 23%. Of responders followed for at least six months after initial response, 22 of 23 maintained a response of six months or more; of responders followed for at least 12 months, 13 of 13 maintained a response lasting for at least the duration of that time.
The data monitoring committee discontinued enrollment six patients short of target due to the occurrence of mixed or cholestatic hepatotoxicity. Three patients receiving pexidartinib had elevations of aminotransferase that were at least three times the upper limit of normal, with total bilirubin and alkaline phosphatase at least twice the upper limit of normal, indicating mixed or cholestatic hepatotoxicity. For one patient, the hepatotoxicity lasted seven months and was confirmed by biopsy.
Nine patients withdrew from treatment in the pexidartinib group, compared with 11 in the placebo group. Serious adverse events were experienced by 13% of patients taking pexidartinib, compared with 2% (one patient) of those taking placebo. The most common adverse events associated with pexidartinib included hair color changes (67%), fatigue (54%), aspartate aminotransferase elevation (39%), nausea (38%), alanine aminotransferase elevation (28%), and dysgeusia (25%). Additional adverse effects of pexidartinib include increased cholesterol, neutropenia, decreased lymphocytes, eye edema, decreased hemoglobin, rash, and decreased phosphate.
"Pexidartinib is the first systemic therapy to show a robust tumor response in TGCT with improved patient symptoms and functional outcomes," write the researchers, led by first author William D. Tap, MD, Chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center, in their publication in The Lancet. "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."
The prescribing information includes a boxed warning concerning the risk of serious and potentially fatal liver injury. Liver tests should be monitored prior to treatment and at specified intervals during treatment. Pexidartinib is only available through the TuralioTM Risk Evaluation and Mitigation Strategy (REMS) Program.
Pexidartinib can harm a newborn infant or a developing fetus and is contraindicated for women who are pregnant or breastfeeding. Women who are of reproductive age and men with a female partner of reproductive potential should use effective contraception during pexidartinib treatment.
For More Information
Tap WD, Gelderblom H, Palmerini E, et al (2019). Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet. [Epub ahead of print] PII:S0140-6736(19)30764-0. DOI:10.1016/S0140-6736(19)30764-0
TuraliaTM (pexidartinib) prescribing information (2019). Daiichi Sankyo, Inc. Available at: https://www.turaliohcp.com/?gclsrc=aw.ds&&gclid=Cj0KCQjwp5_qBRDBARIsANxdcimH3hC8e3ZUCP8eTW_yJ632c2sp4vGcDm9GEMellMrBV_24zH2wBo4aAjdlEALw_wcBImage credit: KGH. Licensed under CC BY-SA 3.0