The US Food and Drug Administration (FDA) today approved the novel oral therapy pexidartinib (Turalio, Daiichi Sankyo) for the treatment of tenosynovial giant cell tumor (TGCT), a rare, nonmalignant growth that can be locally aggressive and debilitating.
Pexidartinib is the first-ever systemic therapy for the disease, and acts as an inhibitor of colony stimulating factor-1 receptor, which is a primary growth driver of abnormal cells in the synovium that cause the disease.
"Today's approval is the first FDA-approved therapy to treat this rare disease," said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.
However, the drug's prescribing information includes a Boxed Warning to advise healthcare professionals and patients about the risk of serious and potentially fatal liver injury with the drug.
TGCT affects the synovium-lined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness, and reduced mobility in the affected joint or limb. The condition tends to develop in younger, working-age adults, and can be debilitating.
Surgery is primary treatment for TGCT and may involve multiple synovectomies, joint replacement, and even amputation in the most severe cases.
"TGCT can be a very difficult disease to manage, with treatment options largely limited to surgery to remove as much of the tumor as possible. Despite the best surgical intervention, recurrence of diffuse TGCT is high and the disease may advance to the point where surgery is no longer an option," commented William Tap, MD, in 2015. Tap is chief of the sarcoma medical oncology service at Memorial Sloan Kettering Cancer Center in New York City and led an early trial of the product.
First Placebo-Controlled Trial
The new approval is based on the efficacy and safety results of the pivotal phase 3 ENLIVEN study, the first placebo-controlled study of a systemic therapy in this setting.
This study was discussed at an FDA Oncologic Drugs Advisory Committee (ODAC) meeting in May, which included a briefing document.
All of the patients in the trial were noncandidates for surgery.
The study population was 59% female and 88% white, with a median age of 45 years. A minority of patients had upper extremity involvement (8%) and a majority (92%) had lower extremity involvement
The primary endpoint was overall response rate (ORR), and this was significantly improved. At week 25, patients treated with pexidartinib (n = 61) had an ORR of 38% vs 0% for placebo-treated patients (n = 59) (P < .0001). The complete response rate was 15% and the partial response rate was 23%.
A total of 22 out of 23 responders who had been followed for a minimum of 6 months following the initial response maintained their response for 6 or more months, and all 13 responders who had been followed for a minimum of 12 months following the initial response maintained their response for 12 or more months.
There were also statistically significant improvements in secondary endpoints such as mean changes in range of motion, physical function, and worst stiffness.
However, a "high proportion" of patients had missing data for these three measures (ranging from 27% to 43%), the ODAC briefing document noted. These assessments "may not be missing at random," reads the document, and "may lead to a biased interpretation of the benefit of pexidartinib."
Also, there was no improvement seen for worst pain.
Nevertheless, ODAC recommended approval of the new drug, voting 12 to 3 (zero abstained) to agree that the demonstrated benefit of pexidartinib outweighs the risks as a treatment for TGCT.
"I voted 'yes.' While I am quite concerned about the ramifications of the drug on the liver, this drug really does have the potential to be life changing," said ODAC member Valerae Lewis, MD in an online news story. She is chair of the Department of Orthopaedic Oncology at the University of Texas MD Anderson Cancer Center in Houston.
The most common adverse events (≥20%) were changes in hair color, fatigue, increased aspartate aminotransferase (AST), eye/facial edema, increased alanine aminotransferase (ALT), rash, dysgeusia (distorted sense of taste), and vomiting, according to company data. Serious adverse events were reported by 13% of treated patients, and 13% of patients permanently discontinued the drug because of adverse events.
The liver toxicities seen with pexidartinib in some patients are a concern of investigators, and a study is underway to examine these safety issues, according to a published report (J Clin Oncol. 2018;36:suppl.11502).
Pexidartinib may need to be withheld, dose reduced, or permanently discontinued, depending on the severity of any liver injury. The new drug is available only through the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program.
Dosage of the drug is 400 mg orally twice daily on an empty stomach until disease progression of unacceptable toxicity.
Follow Medscape's Nick Mulcahy on Twitter. For more from Medscape Oncology, follow us on Twitter
Cite this: FDA Approves First Drug for Tenosynovial Giant Cell Tumor - Medscape - Aug 02, 2019.