The FDA granted approval to pexidartinib (Turalio, Daiichi Sankyo) capsules for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not responsive to improvement with surgery.

A rare tumor, TGCT affects the synovium and tendon sheaths. The tumor is rarely malignant but causes the synovium and tendon sheaths to thicken and overgrow, damaging the surrounding tissue.

The FDA approval of pexidartinib is based on the results of the pivotal phase 3 ENLIVEN trial, the first placebo-controlled study of a systemic therapy in patients with TGCT for whom surgical removal of the tumor was associated with a potentially worsening functional limitation or severe morbidity. 

The first part of the multicenter, international study, the double-blind phase, enrolled 120 patients who were randomly assigned to receive either pexidartinib at 1,000 mg per day for two weeks followed by 800 mg per day for 22 weeks or matching placebo, to evaluate the efficacy and safety of pexidartinib versus placebo. The major efficacy outcome measure was overall response rate (ORR) at week 25, which was the percentage of patients achieving a complete or partial response after 24 weeks of treatment. Additional efficacy outcome measures included range of motion and response by the tumor volume score. 

After completing the first part of the study, patients randomly assigned to either pexidartinib or placebo were eligible to enter the second part of ENLIVEN, a long-term, open-label portion of the study in which patients could continue to receive or start to receive pexidartinib.

Results showed the primary end point of tumor response rate by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) was 38% (95% CI, 27%-50%) in 61 pexidartinib-treated patients and 0% (95% CI, 0%-6%) in 59 placebo-treated patients at week 25 (P<0.0001). In addition, ORR by the tumor volume score was 56% (95% CI, 43%-67%) in patients receiving pexidartinib and 0% in patients in the placebo arm at week 25 (P<0.0001). 

Furthermore, analysis of mean change from baseline in range of motion at week 25 demonstrated a statistically significant improvement in 45 patients treated with pexidartinib compared with 43 placebo patients.

The prescribing information for pexidartinib includes a boxed warning to advise about a risk for serious and potentially fatal liver injury. Health care professionals should monitor liver tests prior to beginning treatment and at specified intervals during treatment, according to the FDA. If liver tests become abnormal, pexidartinib may need to be withheld, the dose reduced or permanently discontinued depending on the severity of the liver injury. 

Pexidartinib is available only through the Pexidartinib Risk Evaluation and Mitigation Strategy (REMS) program.

Common side effects in patients taking pexidartinib were increased lactate dehydrogenase, increased aspartate aminotransferase, loss of hair color, increased alanine aminotransferase and increased cholesterol. Additional side effects included neutropenia, increased alkaline phosphatase, decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia and decreased phosphate. For full prescribing information, click here.

The FDA advises health care professionals to tell females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with pexidartinib. Women who are pregnant or breastfeeding should not use pexidartinib because it may cause harm to a developing fetus or newborn. 

Although the exact incidence of TGCT is not known, it is estimated that it is 11 to 50 cases per million person-years, based on studies from three countries. TGCT is subcategorized into two types: localized, which is more common and accounts for 80% to 90% of cases, and diffuse, which accounts for 10% to 20% of cases.

The current standard of care for TGCT is surgical resection. However, in patients with a recurrent, difficult-to-treat or diffuse form of TGCT, the tumor may wrap around bone, tendons, ligaments and other parts of the joint. In these cases, the tumor may be difficult to remove and/or may not be amenable to improvement with surgery. Multiple surgeries for more severe cases can lead to significant joint damage, debilitating functional impairments and reduced quality of life, and amputation may be considered.

Recurrence rates for localized TGCT are estimated to be up to 15% following complete resection. Diffuse TGCT recurrence rates are estimated to be about 20% to 50% following complete resection. TGCT affects all age groups; the diffuse type on average occurs most often in people younger than 40 years, and the localized type typically occurs in people between 30 and 50 years old.

 “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,” said Richard Pazdur, MD, the 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. “Surgery is the primary treatment option, but some patients are not eligible for surgery, and tumors can recur, even after the procedure.”

The FDA granted this application breakthrough therapy designation and priority review designation. Pexidartinib also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. 

—Clinical Oncology News Staff