Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors

Abstract

Background Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib. Materials, and Methods Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow‐up from initial pexidartinib treatment was 39 months (range, 32–82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. Results In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1–76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low‐grade dose‐dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1–7 months following pexidartinib discontinuation. Five patients from the non‐TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. Conclusion This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long‐term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. Implications for Practice This is the first long‐term pooled analysis to report on the long‐term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.

Results from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT

“…One patient continued to have intermittent liver transaminase elevations more than 1 year after permanent drug withdrawal and was eventually diagnosed with primary biliary cirrhosis considered unrelated to the study drug. Two clinically distinct types of hepatotoxocity have previously been observedaminotransferase elevations and mixed or cholestatic hepatotoxicity (4,18,19). In all cases of drug-related increases in aminotransferase levels in the current study, total bilirubin levels were normal and there were no cases that met criteria for Hy's law.…”

“…The second type of hepatic AR was mixed or cholestatic hepatotoxicity (< 5%), which, in clinically significant cases, presented as an increase in alkaline phosphatase and total bilirubin with aminotransferase elevations. Notably, all cases of serious liver toxicity observed presented in the first 8 weeks of treatment, and all resolved in patients with TGCT (4,18,19).…”

“…Long-term treatment with pexidartinib has been reported to have a predictable effect on hepatic aminotransferases and an unpredictable risk of serious cholestatic or mixed liver injury (19).…”

Drug-Induced Liver Injury: Highlights and Controversies in the Recent Literature

“…Therefore, they recommend routine laboratory monitoring of ALT during treatment with tyrosine kinase inhibitors [128]. Liver test monitoring as part of a Risk Evaluation and Mitigation Strategy has been recommended for pexidartinib, a newly approved colony-stimulating factor-1 receptor inhibitor used in the management of patients with tenosynovial giant cell tumors [129]. While 95% of patients in the clinical trials experienced some hepatic adverse reaction, defined as any elevation of AST/ALT and/or ALP, the majority of abnormalities were low grade, dose dependent, and reversible isolated AST/ALT elevations and felt to be possibly related to colony-stimulating factor-1 receptor inhibition as a pharmacologic rather than a hepatotoxic effect.…”

“…Additionally, in non-tenosynovial giant cell tumors patients with various malignancies, pexidartinib was associated with a form of mixed or cholestatic injury that was irreversible in a few cases and led to a liver transplant in one individual. As the elevations in liver tests in both forms of hepatic abnormalities were seen to occur within the first 8 weeks in nearly all cases, the Risk Evaluation and Mitigation Strategy program requires weekly liver test monitoring for the first 2 months in order to identify patients at risk as early as possible, in which case pexidartinib should be held or discontinued [129].…”