On August 2, the oral colony-stimulating factor 1 receptor inhibitor pexidartinib was approved for treatment of adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery.^1,2 It is the first drug specifically approved to treat this rare tumor of the joints.

Pexidartinib has a boxed warning for hepatotoxicity. It is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).

Supporting Efficacy Data

Approval was based on findings from the double-blind phase III ENLIVEN trial (ClinicalTrials.gov identifier NCT02371369).^2,3 In the trial, 120 patients were randomly assigned to receive pexidartinib at 400 mg in the morning and 600 mg in the evening for 2 weeks followed by 400 mg twice daily (n = 61) or placebo (n = 59), with treatment continuing until disease progression or unacceptable toxicity. Patients were required to have measurable disease on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The trial excluded patients with alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin > 1.5 × the upper limit of normal (ULN) and those with known active or chronic infection with hepatitis B or C virus or HIV infection.

The major efficacy outcome measure was overall response rate on blinded independent central review at week 25 using RECIST v1.1. Additional efficacy measures were mean change from baseline in range of motion of the affected joint at week 25 and overall response rate on blinded independent central review at week 25 according to tumor volume score.

The median age of patients was 44 years, 59% were female, 88% were white, 53% had prior surgery, 88% were diagnosed with diffuse tenosynovial giant cell tumor, and 9% had previously been treated with systemic therapy. Disease locations were the knee (61%), ankle (18%), hip (11%), wrist (3%), foot (3%), and other (5%).

The overall response rate at week 25 was 38% in the pexidartinib group vs 0% in the placebo group (P < .0001), with a complete response observed in 15% of patients treated with pexidartinib. The duration of response ranged from 6.9+ to 24.9+ months. Pexidartinib was associated with significant improvements in mean change in range of motion of the affected joint and overall response rate on tumor volume score (56% vs 0%, P < .0001).

How It Works

Pexidartinib is a small molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS3 harboring an ITD mutation. Overexpression of the CSF1R ligand promotes cell proliferation and accumulation in the synovium. In vitro, pexidartinib inhibited proliferation of cell lines dependent on CSF1R and ligand-induced autophosphorylation of CSF1R. Pexidartinib also inhibited the proliferation of a CSF1R-dependent cell line in vivo.

How It Is Used

The recommended dosage of pexidartinib is 400 mg taken orally twice daily (total daily dose of 800 mg) on an empty stomach (at least 1 hour before or 2 hours after a meal or snack) until disease progression or unacceptable toxicity. The recommended dosage in patients with mild to severe renal impairment is 200 mg in the morning and 400 mg in the evening.

Recommended dose reductions for adverse reactions are to 200 mg in the morning and 400 mg in the evening for the first reduction and to 200 mg in the morning and evening for the second reduction. Treatment should be discontinued in patients who cannot tolerate 200 mg twice daily.

Product labeling provides recommended dosage modifications, including withholding of treatment, dose reduction, and permanent treatment discontinuation, for hepatotoxicity according to increased ALT or AST, increased alkaline phosphatase (ALP) or gammaglutamyl transferase, and increased direct or total bilirubin and for any severe or intolerable adverse reactions.

Coadministration of pexidartinib with other products known to cause hepatotoxicity, strong CYP3A inhibitors, strong CYP3A inducers, uridine glucuronyl transferase (UGT) inhibitors, and proton pump inhibitors should be avoided. If concomitant use with a strong CYP3A inhibitor or UGT inhibitor cannot be avoided, the daily dose of pexidartinib should be reduced from the planned total daily doses of 800 or 600 mg to 200 mg twice daily and from the planned total daily dose of 400 mg to 200 mg once daily. Histamine-2 receptor antagonists or antacids should be used if an acid-reducing agent is required.

Safety Profile

As noted, the ENLIVEN trial excluded patients with ALT, AST, or total bilirubin > 1.5 × ULN as well as patients with known active or chronic infection with hepatitis B or C virus or HIV infection.

In the ENLIVEN trial, 79% of patients received pexidartinib for at least 6 months and 66% for more than 1 year. The most common (> 20%) adverse events of any grade, including laboratory abnormalities, in the pexidartinib group were increased lactate dehydrogenase (LDH; 92% vs 5% in placebo group), increased AST (88% vs 15%), hair color changes (67% vs 3%), fatigue (64% vs 41%), increased ALT (64% vs 22%), decreased neutrophils (47% vs 9%), increased cholesterol (44% vs 25%), increased ALP (39% vs 2%), decreased lymphocytes (38% vs 3%), eye edema (30% vs 5%), decreased hemoglobin (30% vs 14%), rash (28% vs 7%), dysgeusia (26% vs 2%), and decreased phosphate (25% vs 5%). The most common nonlaboratory grade ≥ 3 adverse event was hypertension. The most common grade ≥ 3 hepatic or other laboratory abnormalities were increased ALT and increased AST.

Serious adverse events occurred in 13% of the pexidartinib group. Adverse events led to dose reduction or interruption in 38% of patients. Adverse events led to permanent discontinuation in 13%.

Pexidartinib has a boxed warning for hepatotoxicity. It can cause serious and potentially fatal liver injury. Liver tests must be monitored prior to initiation of pexidartinib, weekly for the first 8 weeks of treatment, every 2 weeks for the next month, and every 3 months thereafter. Pexidartinib is available only through a restricted program. Further information is available at turalioREMS.com. Pexidartinib also has warnings/precautions for embryofetal toxicity. Patients should be advised not to breastfeed while receiving pexidartinib. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves pexidartinib for tenosynovial giant cell tumor. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pexidartinib-tenosynovial-giant-cell-tumor. Accessed on August 12, 2019.

2. Pexidartinib (Turalio) capsules prescribing information, Daiichi Sankyo, Inc, August 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211810s000lbl.pdf. Accessed on August 12, 2019.

3. Tap WD, Gelderblom H, Palmerini E, et al: Pexidartinib vs placebo for advanced tenosynovial giant cell tumour (ENLIVEN): A randomised phase III trial. Lancet 394:478-487, 2019.