European Panel Recommends Against Pexidartinib for Tenosynovial Giant Cell Tumor


The European Medicines Agency’s advisory group, the Committee for Medicinal Products for Human Use, has recommended against the acceptance of the marketing authorization for pexidartinib (Turalio) for the treatment of patients with tenosynovial giant cell tumor.

The European Medicines Agency’s advisory group, the Committee for Medicinal Products for Human Use, has recommended against the acceptance of the marketing authorization for pexidartinib (Turalio) for the treatment of patients with tenosynovial giant cell tumor (TGCT).1

The agency cited an unfavorable risk to benefit ratio as the reason for their decision. The committee agreed that although the CSF1R inhibitor was capable of reducing tumors as was demonstrated in the phase 3 ENLIVEN trial, only small improvements were observed in symptoms such as pain and ability to use the joint. They also cited safety concerns, particularly with regard to the impact of the treatment on the liver.

Pexidartinib was designed to block a receptor referred to as CSF1R, which the CSF-1 protein binds to. TGCTs create copious amounts of CSF-1 protein, which results in the buildup of macrophages within the joints and incites outgrowths. Pexidartinib reduces the activity of CSF-1 through blocking CSF1R, which is hypothesized to stop tumor growth and diminish symptoms associated with the disease.

The multicenter, double-blind, ENLIVEN trial was comprised of 2 parts. In the first part, a double-blind phase, 120 patients with symptomatic advanced TGCT were randomized 1:1 to receive either pexidartinib (n = 61) or placebo (n = 59) at 1000 mg daily for the duration of 2 weeks followed by 800 mg daily for the duration of 22 weeks.

To be eligible to participate, patients had to have histologically confirmed, advanced, symptomatic TGCT with measurable disease ≥2 cm per RECIST v1.1 criteria. Patients were stratified by United States or non-US sites in addition to upper versus lower extremity. Over half of patients included (59%) were female and 88% were Caucasian. The median age of the participants was 45 years; 92% had lower extremity involvement and 8% had upper extremity involvement.

The primary end point of the trial was the percentage of patients achieving a complete response (CR) or partial response (PR) as assessed with centrally read MRI scans per RECIST v1.1 criteria, post 24 weeks of treatment.

Secondary endpoints of the trial included range of motion (ROM), response by tumor volume score (TVS), Patient-Reported Outcomes Measurement Information System (PROMIS) physical function, stiffness, and measures of pain reduction.

Results showed that treatment with the agent led to an ORR of 38% at the end of part 1; this was comprised of a CR rate of 15% and a PR rate of 23%.2 The median duration of response (DOR) had not yet been reached with pexidartinib and was not available with placebo. The majority of patients, or 96%, had a DOR of ≥6 months, while half of patients had a DOR of ≥12 months.

None of the participants who responded to treatment on the trial experienced disease progression at a median 6 months of follow-up. Investigators evaluated tumor response by looking at TVS, which was 56% (95% CI, 43.3%-67.5%) with the CSF1R inhibitor versus 0% with placebo (95% CI, 0%-6.1%; P <.0001). Notably, responses were associated with improved patient symptoms and function.

In August 2019, the FDA approved pexidartinib for the treatment of adult patients with symptomatic TGCT that is associated with severe morbidity or functional limitations and not responsive to improvement with surgery.

The prescribing information for the agent included a Boxed Warning to relay the risk of serious, and potentially life-threatening, liver injury. To this end, liver tests should be assessed prior to treatment with pexidartinib as well as at specified intervals during therapy. If liver test results show abnormalities, the agent might need to be held, the dose may need to be reduced, or it might need to be permanently discontinued. The drug is only accessible through the Risk Evaluation and Mitigation Strategy Program.

In May 2019, the FDA’s Oncologic Drugs Advisory Committee held a meeting to assess the clinical benefit of the agent 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 end points, including range of motion (ROM), physical function, and worst stiffness.3 The committee also set out to characterize the risk of liver injury in patients with TGCT who received the agent.

With regard to safety, increases in alanine aminotransferase (ALT; 67%), aspartate aminotransferase (AST; 90%), and total bilirubin (12%) were reported with the agent; these events were grade ≥3 in severity in one-third of patients.

No statistically significant difference was reported between the 2 treatment arms with regard to worse pain. While these improvements in the secondary end points of mean change in ROM, ORR via TVS, mean change in physical function per PROMIS, and mean change in worst stiffness for patients who received pexidartinib compared with placebo were found to be statistically significant, there was 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 who received pexidartinib experienced laboratory abnormalities that signified drug-induced liver injury (4.9%; upper bound of the 95% CI, 13.7%), which proved to be consistent with data reported in a pooled analysis of all patients with TGCT in a clinical development program of the agent. Most of the patients who experienced transaminase elevations and total bilirubin increase experienced a return to baseline levels through the use of dose reductions, interruptions, and/or treatment discontinuation.

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

Moreover, 2 patients in an overall development program of pexidartinib (n = 768) were found to have irreversible liver injury; this resulted in death for first patient and liver transplant in the second. Eight patients whose liver biopsies were collected to evaluate liver abnormalities demonstrated a pattern of hepatocellular injury and ductopenia.

The European Medicines Agency issued their decision on June 25, 2020. Daiichi Sankyo, the company that submitted the authorization application, can ask for re-examination of the opinion within 15 days of receiving the opinion.


  1. Turalio. European Medicines Agency. June 25, 2020. Accessed June 26, 2020.
  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. Accessed May 14, 2019.
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