Pexidartinib Reduces Tumor Size in Symptomatic Tenosynovial Giant Cell Tumor

Pexidartinib met its primary endpoint of tumor response as measured by tumor size reduction in patients with symptomatic tenosynovial giant cell tumor (TGCT) where surgical resection is contraindicated, according to results from the phase III ENLIVEN trial.

Daiichi Sankyo, the manufacturer of pexidartinib, announced the findings in a press release. The data have not yet been presented or published.

TGCT is a rare, potentially destructive tumor of the joint or tendon sheath that can lead to significant pain, joint destruction, frequent surgery, and loss of mobility. At this time, there are not currently any therapies approved specifically for TGCT.

Pexidartinib is an oral small molecule inhibitor of the CSF1 receptor and Kit kinases, which regulate key components of the tumor and its microenvironment. The CSF1 gene is elevated in most TGCTs.

The ENLIVEN trial is an ongoing global, multicenter, pivotal two-part phase III study. The first part of the study, which is the double-blind phase, is designed to evaluate the efficacy and safety of pexidartinib versus placebo. The second part of the study is a longer-term, open-label study of pexidartinib.

In November 2015, the FDA granted breakthrough therapy status to pexidartinib, based on findings from a phase I study. In an expansion cohort of the study, the objective response rate with pexidartinib was 52.2% (95% CI, 32-73).

In the 2-part phase I study, 41 patients were treated with pexidartinib in a dose-escalation cohort, with an additional 23 patients enrolled in an extension study.

The mean duration of treatment for patients in the dose-escalation arm was 70.7 days (range, 3-575). In patients who completed at least 1 cycle of pexidartinib (n = 35), the stable disease rate was 23% and there was 1 patient with a partial response (3%). Overall, this portion of the study identified a 1000 mg/day dose of pexidartinib for future study.

In the extension arm, which utilized the 1000 mg/day dose, the mean age of patients was 46 years. The most common site of disease was the knee. Eighteen patients had undergone previous surgery and 4 had received prior therapy with imatinib (Gleevec) or nilotinib (Tasigna). The median duration of treatment with pexidartinib was 8 months.

Overall, 30.4% of patients treated with pexidartinib had stable disease, for a disease control rate of 83% (95% CI, 67-98). At the time of the analysis, the median progression-free survival had not been reached, with 17 patients remaining on the study, 7 of whom had received pexidartinib for longer than 12 months.

The authors of the study noted that responses seen with pexidartinib were significantly better than traditionally experienced by patients treated with imatinib. In previous studies, imatinib has demonstrated an objective response rate of 19%.

In the expansion arm, dose reductions were required for 61% of patients, with 30% requiring a temporary treatment withdrawal. The most common reason for dose alteration was fatigue.

The most common pexidartinib-related all-grade adverse events (AEs) were changes in hair color (74%), fatigue (65%), nausea (39%), dysgeusia (26%), and periorbital edema (26%). The most frequent grade ≥3 AEs were hyponatremia (9%), elevated aspartate aminotransferase or alanine aminotransferase level or both (9%), fatigue (4%), diarrhea (4%), anemia (4%), and neutropenia 4%.

Tap WD, Wainberg ZA, Anthony SP, et al. Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. N Engl J Med. 2015;373:428-437.