Pexidartinib Granted Priority Review by FDA for Treatment of Tenosynovial Giant Cell Tumor

Based on findings from the phase III ENLIVEN study, a new drug application for the investigational, small molecule, CSF1R receptor inhibitor pexidartinib has been granted a priority review by the FDA for the treatment of adult patients with symptomatic tenosynovial giant cell tumor.

Based on findings from the phase III ENLIVEN study, a new drug application (NDA) for the investigational, small molecule, CSF1R receptor inhibitor pexidartinib has been granted a priority review by the FDA for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT).1

Findings from the trial showed a 39.3% overall response rate with pexidartinib versus 0% with placebo after 24 weeks of treatment based on central review of magnetic resonance imaging scans.2Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the approval by August 3, 2019.

"We are pleased to announce that the FDA has accepted our application for pexidartinib with priority review designation, potentially bringing a treatment option to patients for whom there is no approved therapy," said Dale Shuster, PhD, executive director, Global Oncology R&D, Daiichi Sankyo, the manufacturer of pexidartinib.

"Current treatment options for TGCT are largely limited to surgery, but for some patients the disease is debilitating and not amenable to improvement with surgery. We are committed to working with the FDA to potentially bring pexidartinib to carefully selected patients as soon as possible," added Shuster.

TGCT, which is also referred to as pigmented villonodular synovitis or giant cell tumor of the tendon sheath, is a nonmalignant tumor of the joint or tendon sheath. TGCT is said to be locally aggressive and debilitating in some patients, and is associated with severe morbidity or function limitations. Currently, there are no FDA-approved systemic therapies for TGCT, and surgery is the primary treatment.

In the international, multicenter, double-blind, phase III ENLIVEN study, investigators evaluated pexidartinib in patients with symptomatic advanced TGCT in whom surgical removal of the tumor would lead to potentially worsening functional limitation or severe morbidity. In the first part of the study, which was the double-blind phase, 120 patients were randomized 1:1 to receive either pexidartinib or placebo at 1000 mg daily for 2 weeks followed by 800 mg daily for 22 weeks.

The primary endpoint of the study was the percentage of patients achieving a complete or partial response, assessed with centrally read MRI scans using RECIST 1.1 criteria, after 24 weeks of treatment. Secondary endpoints included range of motion, response by tumor volume score, Patient-Reported Outcomes Measurement Information System physical function, stiffness, and measures of pain reduction.

Patients had histologically confirmed, advanced, symptomatic TGCT with measurable disease ≥2 cm by RECIST v1.1 criteria. Stratification factors included US versus non-US sites, and upper versus lower extremity.

Results, which were presented at the 2018 ASCO Annual Meeting, showed that the ORR was 39.3% (95% CI, 28.1-51.9) in the pexidartinib arm versus 0% (95% CI, 0-6.1) in the placebo arm (P<.0001) at the end of part 1. After a median 6 months of follow-up, no responders in the trial progressed. Tumor response was assessed by tumor volume score (TVS), which was 56% (95% CI, 43.3-67.5) with pexidartinib and 0% (95% CI, 0-6.1) with placebo (P<.0001). Responses correlated with improved patient symptoms and function, as well.

In patients who crossed over to pexidartinib at a starting dose of 800 mg daily (n = 30), the RECIST v.1 ORR and TVS ORR were 30% and 57% at week 25, respectively.

Regarding safety, 98% (n = 60) of patients on pexidartinib and 93% (n = 55) of the placebo arm experienced all-grade adverse events (AEs). Grade 3/4 AEs were higher with pexidartinib (44%; n = 27) than with placebo (12%; n = 7), and serious AEs were reported in 13% (n = 8) of those on the pexidartinib arm compared with 2% (n = 1) of patients on the placebo arm.

Hepatic toxicities were more frequent with pexidartinib versus placebo (AST or ALT ≥3 x ULN, 33% vs 0% and total bilirubin ≥2 x ULN, 5% vs 0%). Additionally, 8 patients discontinued pexidartinib due to hepatic AEs; 4 patients had serious nonfatal AEs with increased bilirubin, one lasting approximately 7 months.

In non-TGCT development trials of pexidartinib, there were 2 severe liver toxicity cases observed. One case required liver transplant and the other was associated with death.

For patients who completed part 1, they may continue onto part 2 of the ENLIVEN trial, which will be an open-label extension portion.

Pexidartinib was also mentioned in ASCO’s January 2019 announcement of selecting progress in treating rare cancers as its Advance of the Year.3ASCO made the announcement as part of Clinical Cancer Advances 2019: ASCO’s Annual Report on Progress Against Cancer, an annual update that highlights the most impactful clinical research milestones and policy developments that have been achieved over the past year in oncology.


  1. FDA Grants Priority Review for Daiichi Sankyo's New Drug Application for CSF1R Inhibitor Pexidartinib for Treatment of Patients with TGCT, a Rare, Debilitating Tumor. Daiichi Sankyo. Published February 5, 2019. Accessed February 5, 2019.
  2. Tap WD, Gelderblom H, Stacchiotti S, et al. Final results of ENLIVEN: A global, double-blind, randomized, placebo-controlled, phase 3 study of pexidartinib in advanced tenosynovial giant cell tumor (TGCT).J Clin Oncol. 2018;36 (suppl; abstr 11502). doi: 10.1200/JCO.2018.36.15_suppl.11502.
  3. Pal SK, Miller MJ, Agarwal N, et al. Clinical Cancer Advances 2019: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology [published online ahead of print].J Clin Oncol. doi: 10.1200/JCO.18.02037.