NCCN Grants Category 1 Recommendation to Pexidartinib for TGCT

The National Comprehensive Cancer Network has updated its Clinical Practice Guidelines in Oncology for Soft Tissue Sarcoma to include a category 1 recommendation for pexidartinib (Turalio) for the treatment of patients with tenosynovial giant cell tumor.

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology for Soft Tissue Sarcoma to include a category 1 recommendation for pexidartinib (Turalio) for the treatment of patients with tenosynovial giant cell tumor (TGCT).1

The recommendation is based on findings from the placebo-controlled phase III ENLIVEN trial, which was also the basis for pexidartinib’s August 2019 FDA approval 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. Results of ENLIVEN demonstrated that pexidartinib elicited a 39% overall response rate (ORR; 95% CI, 27%-53%) 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.2,3

The NCCN Clinical Practice Guidelines are developed through review of evidence and recommendations from oncology physicians and researchers, and are designed to help set the standard for clinical policy in cancer care. A category 1 recommendation means that based upon high level of evidence, there is uniform consensus that the intervention is appropriate.

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—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 complete response rate of 15% and a PR 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.

Regarding safety, serious adverse events (AEs) occurred in 13% of 61 patients in the pexidartinib group and one (2%) of 59 patients who received placebo. The most frequent pexidartinib-associated AEs were hair color changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%). Three patients given pexidartinib had aminotransferase elevations 3 or more times the upper limit of normal (ULN), with total bilirubin and alkaline phosphatase 2 or more times ULN indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy.

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 Program.


  1. NCCN Recognizes Pexidartinib (TURALIO) as Category 1 Treatment Option for TGCT, a Rare and Debilitating Tumor. Daiichi Sankyo. Published September 26, 2019. Accessed September 26, 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. Tap WD, Gelderblom H, Palmerini E, et al. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet Oncol. 2019;394(10197):478-487. doi: 10.1016/S0140-6736(19)30764-0.