2018 ASCO: Pexidartinib in Tenosynovial Giant Cell Tumor

Key Points

  • The phase III ENLIVEN study showed a statistically significant 39% overall response rate at week 25.
  • Pexidartinib had a 56% overall response rate by tumor volume score compared to no response in patients who received placebo.
  • Clinically meaningful improvement vs placebo was observed in range of motion, PROMIS physical function, and worst stiffness. There was also a nonsignificant improvement in pain response.
  • Hepatic toxicities were more frequent with pexidartinib vs placebo.

The phase III ENLIVEN study showed a statistically significant 39% overall response rate at week 25 based on central review of magnetic resonance imaging (MRI) scans using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (the primary endpoint) for patients treated with oral pexidartinib compared to no tumor response among patients who received placebo (P < .0001). Patients enrolled in the trial were those with tenosynovial giant cell tumor (TGCT) for whom surgery would be associated with potentially worse function or severe morbidity. After a median 6-month follow-up (longest = 17 months), no responders in the ENLIVEN study had shown disease progression. These findings were presented by Tap et al at the 2018 ASCO Annual Meeting (Abstract 11502).

“Current treatment options for TGCT are largely limited to surgery in order to remove as much of the tumor as possible. Despite the best surgical intervention, the recurrence rate of diffuse TGCT is high, and the disease may advance to the point where surgery is no longer an option,” said William D. Tap, MD, lead investigator of the study and Chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center. “Pexidartinib may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended.”

Pexidartinib is an investigational, oral small molecule that potently inhibits colony-stimulating factor 1 receptor, a primary growth driver of abnormal cells in the synovium that cause TGCT.

Further Findings

In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib vs placebo (aspartate transaminase or alanine transaminase levels ≥ 3× the upper limit of normal: 33%, total bilirubin levels ≥ 2× the upper limit of normal: 5%; n = 61). Eight patients discontinued pexidartinib due to hepatic adverse events; 4 were serious nonfatal adverse events with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, 2 severe liver toxicity cases were observed (1 required liver transplant, 1 was associated with death).

Other adverse events with a frequency > 10% noted in ENLIVEN and more common with pexidartinib included hair color changes, pruritus, rash, vomiting, abdominal pain, constipation, fatigue, dysgeusia, facial edema, peripheral edema, periorbital edema, decreased appetite, and hypertension.

Secondary efficacy endpoints demonstrated that patients treated with pexidartinib had a 56% overall response rate by tumor volume score, compared to no response in patients who received placebo (P < .0001). Clinically meaningful improvement vs placebo was observed in other secondary efficacy endpoints, including range of motion (+15% vs +6%, P = .0043), PROMIS physical function (+4.1 vs –0.9, P = .0019), and worst stiffness (–2.5 vs –0.3, P < .0001). There was also a nonsignificant improvement in pain response (31% vs 15%).

About the ENLIVEN Study

ENLIVEN, a double-blind, randomized, global, multicenter, phase III study, evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomly assigned (1:1) to receive either pexidartinib or placebo at 1,000 mg/d for 2 weeks followed by 800 mg/d for 22 weeks in order to evaluate the efficacy and safety of pexidartinib vs placebo.

The primary endpoint of the study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (week 25), as assessed with centrally read MRI scans using RECIST 1.1 criteria. Key secondary endpoints included range of motion, response by tumor volume score, PROMIS physical function, stiffness, and measures of pain reduction.

After completing the first part of the study, patients randomized to either pexidartinib or placebo were eligible to take part in the second part of ENLIVEN, a long-term, open-label part where patients could continue to receive or start to receive pexidartinib. In October 2016, following 2 reported cases of serious, nonfatal liver toxicity in the ENLIVEN study, the data monitoring committee (DMC) recommended that patients receiving placebo in the first part of the study should no longer be eligible to start pexidartinib in the second part of the study. A total of 120 patients who were enrolled prior to the DMC recommendation continued with the study according to the revised protocol. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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