Pexidartinib in the Management of Advanced Tenosynovial Giant Cell Tumor: Focus on Patient Selection and Special Considerations

Figures & data

Table 1 Overview of Key Reviewed Studies

Study	Type	Patient Population	Results
Giustini N et al^Citation1	Case report	1 TGCT patient who was not considered for surgery due to excessive morbidity; treated with pexidartinib for 4 months	● Tumor volume on MRI had decreased by 48% at 4 months according to RECIST criteria ● Disease was stable at 55 months
Gelderblom H et al^Citation8	Retrospective pooled analysis of 3 pexidartinib studies: 1. Phase 1 extension study (1000 mg/d) 2. ENLIVEN patients given pexidartinib (1000 mg/d for 2 weeks and 800 mg/d for 22 weeks) 3. ENLIVEN crossover patients (800 mg/d)	130 patients with symptomatic, unresectable TGCT confirmed on histology (39, 61, and 30 patients)	By RECIST criteria: ● Overall response rate: 60% ● Median time to response: 3.4 months ● Among responders, 62% had partial response by 6 months and 92% by 18 months By tumor volume score: ● Overall response rate: 65% ● Median time to response: 2.8 months ● Median duration of response: 47 months Treatment-emergent adverse events ● Hair color changes: 75% ● Aminotransferase elevations: 92% ● Mixed/cholestatic hepatotoxicity: 3% (all cases were in first 2 months of treatment and were reversible)
Tap WD et al^Citation12	Phase 3 randomized trial. ● Part 1: Double-blind study of patients assigned to pexidartinib (1000 mg/d for 2 weeks, then 800 mg/d for 22 weeks) or placebo. ● Part 2: Open-label treatment with pexidartinib for all patients.	120 patients with symptomatic, advanced TGCT for whom surgery was not recommended	Overall response by RECIST at 25 weeks ● Pexidartinib: 39% ● Placebo: 0% ● Absolute difference: 39% (95% CI, 27−53%; p<0.0001) Serious adverse events ● Pexidartinib: 13% ● Placebo: 2% ● Three pexidartinib recipients had liver enzyme elevations suggesting cholestatic hepatotoxicity, including one case confirmed by biopsy Pexidartinib-associated adverse events: ● Hair color changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), dysgeusia (25%)
Mastboom MJL et al^Citation13	International multicenter retrospective cohort study	966 patients with histologically proven diffuse-type TGCT of large joint who were treated with surgery in 31 sarcoma reference centers between 1990 and 2017	● Tumor recurred in 44% of patients by follow up (median, 54 months; IQR, 27−97 months) ● Prevalence of recurrence-free survival was 62% at 3 years, 55% at 5 years, and 40% at 10 years ● 12% of patients with complete data had surgical complications
Griffin AM et al^Citation14	Retrospective review	50 patients treated with radiotherapy and surgery between 1972 and 2006. 49 had diffuse TGCT with both intra-articular and extra-articular disease; 1 had malignant TGCT	● 30 patients (60%) underwent at least 2 operations before radiotherapy At follow up (mean, 94 months): ● 47 patients (94%) had stable disease or no recurrence on serial cross-sectional imaging ● 2 patients had had total hip arthroplasty due to progressive osteoarthritis ● 4 patients had had avascular necrosis, one of which occurred posttreatment
Mollon B et al^Citation15	Systematic review/meta-analysis	630 patients in 35 observational studies of surgical synovectomy to treat PVNS of the knee	● 137 patients (22%) had recurrence after synovectomy ● Analysis found “low-quality” evidence that recurrence risk was lower for open synovectomy (OR, 0.47; 95% CI, 0.25−0.90) and for combined open and arthroscopic synovectomy (OR, 0.19; 95% CI, 0.06−0.58) than for arthroscopic surgery ● Analysis found “very low-quality evidence” that perioperative radiotherapy reduces recurrence risk (OR, 0.31; 95% CI, 0.14−0.70)
Xiang X et al^Citation17	Case study report	Two males with knee swelling who underwent image-guided, intensity-modulated radiotherapy after incomplete synovectomy. Diffuse TGCT was confirmed by postoperative pathology.	● At one year, no disease progression was evident on MRI ● No adverse events were attributed to radiotherapy during follow up
Berger B et al^Citation18	Retrospective review	7 patients with diffuse PVNS, mostly at the knee, who were treated with 6-millivolt photo radiotherapy after radical surgery	● No persistent or recurrent disease or acute or late adverse effects were observed at follow-up (mean, 29 months; range, 3−112 months) ● 6 patients reported excellent quality of life and “asymptomatic limb function” ● 1 patient reported persistent restriction of joint movement following multiple surgeries
Horoschak M et al^Citation20	Retrospective review	17 PVNS patients with 18 sites of disease who were treated with radiation between 1993 and 2007	● During follow-up (mean, 46 months), 12 of 16 sites (75%) with previous cytoreductive surgery displayed initial local control (mean time to recurrence, 38 months) ● Ultimate local control after repeat resection was 100% (mean follow-up, 61 months) ● Growth occurred in 2 sites without prior cytoreductive surgery after radiotherapy (mean time to documented growth, 10.5 months) ● 17/18 involved joints (94%) had excellent or good PVNS-related function; one site (6%) had fair function ● No patients underwent amputation or had grade 3/4 adverse events
Dürr HR et al^Citation22	Retrospective review	32 patients with diffuse PVNS who underwent a total of 37 open synovectomies from 1996 to 2014; adjuvant radiosynoviorthesis was administered following 26 of the resections	● 9 lesions (24%) had recurred by follow-up (median, 19 months postsurgery)—3 in cases of primary disease and 6 in already recurring cases ● Recurrence occurred in 6/26 (23%) cases in which radiosynoviorthesis was performed and 3/11 (27%) cases without radiosynoviorthesis
Ottaviani S et al^Citation23	Retrospective review	122 patients with PVNS confirmed on histology; 98% underwent synovectomy	● During follow up (mean, 5.8 years), the relapse rate was 30% (knee) and 9% (other sites) for patients with diffuse disease treated with surgery and then isotopic synoviorthesis ● Mean time to relapse was 2.6 years (knee) and 2.4 years (other sites)
Park G et al^Citation24	Retrospective study	23 patients who received radiotherapy after synovectomy between 1998 and 2007	● During follow-up (median, 9 years; range, 0.8−12 years), 4 patients had disease recurrence (median time to recurrence, 5 years); local control was achieved for three of them though salvage synovectomy ● 22 patients reported excellent or good joint function, while 1 who did not receive salvage synovectomy reported poor joint function ● No grade 3 toxicities or radiation-related malignancies were documented
Lewis JH et al^Citation32	Pooled analysis of safety data from 4 clinical trials of pexidartinib	140 TGCT patients and 658 patients with various malignancies	● Median follow up: 39 months ● Hepatic adverse reactions were seen in 5% of TGCT patients (median duration of exposure, 19 months) ● 128 TGCT patients (91%) had reversible dose-dependent AST/ALT elevations without ALP elevation ● 5 TGCT patients (4%) experienced mixed or cholestatic hepatotoxicity; all recovered within 7 months of pexidartinib discontinuation ● 5 non-TGCT patients (1%) had severe hepatic adverse reactions, two of which were irreversible
Tap WD et al^Citation33	Multicenter phase 1 trial: ● Part 1: Dose-escalation study of pexidartinib administered orally to patients with solid tumors. ● Part 2: Extension study investigating pexidartinib (100 mg/d) in TGCT patients.	● Part 1: 41 solid tumor patients ● Part 2: 23 TGCT patients	● Median duration of response: >8 months ● Responses generally seen within 4 months of treatment initiation ● Most frequent adverse events: fatigue, change in hair color, nausea, dysgeusia, periorbital edema ● Decrease in tumor volume was sustained in most patients who responded to treatment
Van De Sande M et al^Citation34	Analysis of patient-reported outcome data from ENLIVEN (double-blinded, randomized phase 3 trial)	Adults with symptomatic, advanced TGCT	Change in physical function at 25 weeks (assessed using Patient-Reported Outcomes Measurement Information System-Physical Function) ● Pexidartinib: 4.1 (95% CI, 1.8−6.3) ● Placebo: −0.9 (95% CI, −3.0 to 1.2) Change in worst stiffness (assessed using a numerical rating scale) ● Pexidartinib: −2.5 (95% CI, −3.0 to −1.9) ● Placebo: −0.3 (95% CI, −0.9 to 0.3) ● Improvements were maintained after 50 weeks of pexidartinib treatment
Smith CC et al^Citation38	Phase 1/2 study ● Part 1: Dose escalation ● Part 2: Dose expansion	90 patients (34 part 1, 56 part 2) with relapsed or refractory FLT3-ITD-mutant acute myeloid leukemia	● Most common adverse events were diarrhea (50%), fatigue (47%), nausea (46%) ● Overall response rate: 21% ● Median overall survival in dose expansion cohort: 112 days (90% CI, 77−150 days) ● Median overall survival of those in complete remission: 265 days (90% CI, 170−422 days)

Abbreviations: TGCT, tenosynovial giant cell tumor; MRI, magnetic resonance imaging; RECIST, response evaluation criteria in solid tumors; CI, confidence interval; IQR, interquartile range; PVNS, pigmented villonodular synovitis; OR, odds ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.

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