(P 199) PEXIDARTINIB RISK EVALUATION AND MITIGATION STRATEGY PROGRAM: 3-YEAR SAFETY DATA ASSESSMENT

Objective: Pexidartinib is a first-in-class colony-stimulating factor-1 receptor blocker indicated for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations that are not amenable to improvement with surgery. Due to the potential risk of hepatotoxicity, pexidartinib (400 mg orally twice daily) was granted approval by the US Food and Drug Administration (FDA) on the condition of establishing a Risk Evaluation and Mitigation Strategy (REMS) program. The 3-year (August 2019-June 2022) cumulative safety data collected from patients enrolled in the pexidartinib REMS (pREMS) program are described here.

Methods: The pREMS program consists of elements to ensure safe use, a communication plan, an implementation system, and a timetable for REMS assessments. Healthcare providers prescribing pexidartinib must be both educated and certified in the pREMS program and educate their patients with TGCT who are receiving the drug. Dispensing pharmacies and distributors of pexidartinib must also be certified in the program. Scheduled safety assessments were collected on Patient Access Forms (PAFs).

Results: During the 3-year period, 451 TGCT patients, 369 prescribers, 2 wholesalers/distributors, and 2 pharmacies were certified or enrolled in the pREMS program. Of the adverse events (AEs), the majority (94.2%) were nonserious. Hair color changes were the most frequently reported nonserious AE (4.4%), and increased aspartate aminotransferase (AST; 0.5%) was the most frequently reported serious AE.

Of the 451 TGCT patients, only 51 (2.4%) lab tests had ALT or AST liver enzymes >3× ULN and TBIL >2× ULN, 17 (0.8%) had ALT or AST >10× ULN with/without TBIL elevation, and 12 (0.6%) had TBIL ≥2× ULN without changes in ALT or AST. Twenty-one cases (4.7%) that met the criteria for a liver AE indicated that the pattern of reported hepatic injury was consistent with the ENLIVEN trial results. There were no events of irreversible liver injury. Following initiation of pexidartinib, treatment interruption was seen in 98 (21.7%) patients, which was (n=106) primarily due to hepatic AEs (n=24; 22.6%), nonhepatic AEs (n=15; 14.2%), disease progression (n=2; 1.9%), and death (n=1; 0.9%). In patients resuming treatment, all were at a lower dose. Treatment discontinuation was reported in 132 patients (29.3%; 137 events), primarily due to hepatic AEs (n=26; 19%), nonhepatic AEs (n=23; 16.8%), disease progression (n=13; 9.5%), confirmed pregnancy (n=2; 1.5%), and death (n=1; 0.7%; not related to hepatotoxicity).

Based on Liver AE Report Forms (LAERFs; 65 patients, 95 LAERFs), 12 (12.6%) cases required hepatology referral, 14 (14.7%) liver ultrasound, 12 (12.6%) other liver imaging, and 5 (5.3%) endoscopic retrograde cholangiopancreatography. Of these, 14 (14.7%) cases required hospitalization, 1 (1.1%) liver dialysis, 6 (6.3%) medication prescribed to treat liver injury, and 7 (7.4%) “other.” Liver AEs resolved in 33 (34.7%) cases, 51 (53.7%) cases were ongoing, and 1 (1.1%) case resolved with sequelae. No liver transplant or hepatotoxicity-related death was reported.

Conclusion: The safety profile of pexidartinib remains consistent with the data from the ENLIVEN trial. Furthermore, no new hepatic safety signals were identified. Based on data collected from the pREMS program, careful monitoring of liver enzyme levels combined with early intervention using dose modifications and permanent discontinuation are being actively conducted to mitigate the risk of potential hepatotoxicity. Overall, the results of this cumulative safety data assessment suggest that the pREMS program is ensuring the safe use of pexidartinib in patients with TGCT.