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FDA advisory committee supports approval of pexidartinib for tenosynovial giant cell tumor
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The FDA’s Oncologic Drugs Advisory Committee, or ODAC, today voted 12-3 that the benefits of pexidartinib outweigh the risks for the treatment of adults with tenosynovial giant cell tumor not amenable to surgical resection.
If approved, pexidartinib (Daiichi Sankyo) — a novel, oral small molecule inhibitor of colony stimulating factor-1 receptor, the primary growth driver of abnormal cells in the synovium that cause tenosynovial giant cell tumor (TGCT) — would be the first FDA-approved therapy for the disease.
TGCT — also called pigmented villonodular synovitis or giant cell tumor of the tendon sheath — can be locally aggressive and debilitating. Surgical resection is the primary treatment; however, treatment options are limited for patients whose disease is not amenable to surgery.
The randomized double-blind, placebo-controlled phase 3 ENLIVEN study trial evaluated pexidartinib compared with placebo in patients with TGCT unable to undergo surgical resection.
Overall response rate at week 25 served as the study’s primary endpoint.
As HemOnc Today previously reported, results presented at last year’s ASCO Annual Meeting showed 39% of patients assigned pexidartinib responded to treatment compared with 0% of patients assigned placebo (P < .0001).
Further, researchers reported statistically significant improvements with pexidartinib in range of motion; ORR per tumor volume score; mean change in physical function in the Patient-Reported Outcomes Measurement Information System, or PROMIS, score; and mean change in worse stiffness.
The most common adverse events associated with pexidartinib included changes in hair color, fatigue, increased aspartate aminotransferase, eye/facial edema, increased alanine aminotransferase, rash, dysgeusia and vomiting. Serious adverse events occurred in 13% of patients, and 13% of patients discontinued treatment due to an adverse event.
Importantly, more patients assigned pexidartinib experienced hepatic toxicities, with 67% of patients experiencing alanine aminotransferase elevation, 90% with aspartate aminotransferase and 12% with total bilirubin elevations. Thirty-three percent of patients treated with pexidartinib had aspartate aminotransferase or alanine aminotransferase levels at least three times the upper limit of normal compared with 5 percent of placebo-treated patients.
Among all commercial-sponsored and investigator-initiated trials, two of 768 pexidartinib-treated patients (observed rate, 0.3%) experienced irreversible liver injury, resulting in liver transplantation and death.
Based on these data, the ODAC panel considered whether pexidartinib causes subacute or chronic injury that could lead to cirrhosis, and potential long-term exposures risks.
Further, despite the improvements observed in range of motion, physical function and worst stiffness, these outcomes were limited by several factors, including the high proportion of patients with missing data, changes in the statistical analysis plan for these endpoints, potential unblinding due to hair color changes in patients who received pexidartinib, and limitations in establishing a clinically meaningful threshold of benefit for range of motion.
Ultimately, however, the committee voted that the benefits of pexidartinib outweigh these risks.
“Today's vote in favor of pexidartinib marks a significant step toward delivering the first approved systemic therapy for select TGCT patients whose disease is not amenable to improvement with surgery,” Antoine Yver, MD, MSc, executive vice president and global head of oncology research and development at Daiichi Sankyo, said in a press release. “Some people living with TGCT experience debilitating symptoms and need innovative treatment options. We believe that pexidartinib has the potential to help address this need by offering carefully selected TGCT patients an important treatment advancement, and we look forward to working with the FDA as it completes its review of our application.”
Pexidartinib previously received FDA priority review, with a PDUFA date of Aug. 3.