FDA Approves Pexidartinib for Tenosynovial Giant Cell Tumor


The FDA has approved pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor that is associated with severe morbidity or functional limitations and not responsive to improvement with surgery.

The FDA has approved pexidartinib (Turalio) for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) that is associated with severe morbidity or functional limitations and not responsive to improvement with surgery.1

The approval of the small molecule, CSF1R receptor inhibitor was based on findings from the phase III ENLIVEN study, which demonstrated a 38% overall response rate (ORR; 95% CI, 28%-52%) with pexidartinib compared with 0% (95% CI, 0%-6%; P <.0001) with placebo following 25 weeks of treatment based on central review of MRI scans.2

"TGCT can cause debilitating symptoms for patients such as pain, stiffness and limitation of movement. The tumor can significantly affect a patient’s quality of life and cause severe disability," Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, stated in a press release. "Surgery is the primary treatment option, but some patients are not eligible for surgery, and tumors can recur, even after the procedure. Today’s approval is the first FDA-approved therapy to treat this rare disease."

TGCT, which is also known as pigmented villonodular synovitis or giant cell tumor of the tendon sheath, is a nonmalignant tumor of the joint or tendon sheath. The disease can be locally aggressive and debilitating, and is associated with severe morbidity or function limitations.

The multicenter, double-blind, ENLIVEN study had 2 parts, the first of which was a double-blind phase. In this phase, 120 patients with symptomatic advanced TGCT—in whom surgical removal of the tumor would lead to potentially worsening functional limitation or severe morbidity&mdash;were randomized 1:1 to receive either pexidartinib (n = 61) or placebo (n = 59) at 1000 mg daily for 2 weeks followed by 800 mg daily for 22 weeks.

Patients who were eligible for enrollment had histologically confirmed, advanced, symptomatic TGCT with measurable disease ≥2 cm by RECIST v1.1 criteria. Patients were also stratified by US or non-US sites, as well as upper versus lower extremity. Fifty-nine percent of patients were female, and 88% of patients overall were Caucasian. The median age was 45 years (range, 18-79), 8% of patients had upper extremity involvement, and the remaining 92% had lower extremity involvement.

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

Moreover, hierarchical procedure had been specified in the analysis plan in order to adjust for multiplicity in testing the following secondary efficacy outcomes: mean change from baseline in ROM of the affected joint, relative to a reference standard for the same joint at week 25; proportion of responders based on a 50% decrease in TVS at week 25 as measured in centrally evaluated MRI scans; mean change from baseline score in the PROMIS Physical Function Scale at week 25; mean change from baseline score in the Worst Stiffness numeric rating scale (NRS) item at week 25; and proportion of responders from patients who experience ≥30% reduction in the mean Brief Pain Inventory (BPI) Worst Pain NRS item and also did not experience a ≥30% increase in narcotic analgesic use (BPI-30) at 25 weeks.

Findings demonstrated that the ORR was 38% at the end of part 1, with a complete response rate of 15% and a partial response rate of 23%. The median duration of response (DOR) was not reached with pexidartinib (range, 4.6+ to 24.9+) and was not available with placebo. Ninety-six percent of patients had a DOR ≥6 months, and 50% of patients had a DOR ≥12 months.

At a median 6 months of follow-up, none of the responders in the trial progressed. Tumor response was assessed by TVS, which was 56% (95% CI, 43.3%-67.5%) with pexidartinib and 0% (95% CI, 0%-6.1%) with placebo (P <.0001). The responses also correlated with improved patient symptoms and function.

The prescribing information for pexidartinib includes a Boxed Warning to inform the risk of serious and potentially fatal liver injury. Liver tests should be monitored prior to start of treatment and at specified intervals during therapy. Should liver tests become abnormal, pexidartinib may need to be withheld, the dose reduced, or be permanently discontinued, depending on the severity of the liver injury. The agent is only available through the Risk Evaluation and Mitigation Strategy (REMS) Program.

The FDA’s Oncologic Drugs Advisory Committee held a meeting in May 2019 to assess the clinical benefit of pexidartinib in this patient population, as the interpretation of the activity was limited due to a proportion of data missing at 25 weeks for several secondary endpoints, including range of motion (ROM), physical function, and worst stiffness.3 The committee also aimed to characterize the risk of liver injury in patients with TGCT who received therapy with pexidartinib.

Regarding safety, pexidartinib was associated with increases in alanine aminotransferase (ALT; 67%), aspartate aminotransferase (AST; 90%), and total bilirubin (12%); these events reached grade ≥3 severity in one-third of patients. The FDA briefing document for ODAC had also stated the long-term safety profile of pexidartinib was unknown.

There was no statistically significant difference between the 2 arms for worst pain. While these improvements in the secondary endpoints of mean change in ROM, ORR per TVS, mean change in physical function per PROMIS, and mean change in worst stiffness for patients on pexidartinib versus placebo were statistically significant, the FDA stated that the interpretation of the data for these secondary endpoints should be viewed cautiously, due to a high proportion of missing data at 25 weeks for ROM (27%), physical function (43%), and worst stiffness (43%). A similar proportion of patients were missing data across arms.

Some patients on pexidartinib had laboratory abnormalities that indicated drug-induced liver injury (4.9%; upper bound of the 95% CI, 13.7%), which was consistent with data reported in a pooled analysis of all patients with TGCT in a clinical development program of pexidartinib (n = 130). In the majority of those in the TGCT population who had transaminase elevations and total bilirubin increase, there was a return to baseline levels with dose reductions, interruptions, and/or treatment discontinuation.

Further results of the pooled safety population of patients with solid or hematologic cancers treated with pexidartinib (n = 630) showed that there was a total bilirubin of ≥2 x upper limit of normal (ULN) and an AST/ALT ≥3 x ULN.

Two patients in an overall development program of pexidartinib (n = 768) experienced irreversible liver injury which led to death 1 in patient and liver transplant in the second. Eight patients whose liver biopsies were obtained to evaluate these liver abnormalities showed a pattern of hepatocellular injury and ductopenia.

Pexidartinib was also mentioned in ASCO’s January 2019 announcement of selecting progress in treating rare cancers as its Advance of the Year.4


  1. FDA approves first therapy for rare joint tumor. FDA. Published August 2, 2019. https://bit.ly/31bGXqn. Accessed August 2, 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. ODAC Briefing Document. FDA. Published May 14, 2019. https://bit.ly/2Q4VT5p. Accessed May 14, 2019.
  4. 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. J Clin Oncol. 2019;37(10):834-849. doi: 10.1200/JCO.18.02037.
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