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

James H Lewis, Hans Gelderblom, Michiel van de Sande, Silvia Stacchiotti, John H Healey, William D Tap, Andrew J Wagner, Antonio Lopez Pousa, Mihaela Druta, Chia-Chi Lin, Hideo A Baba, Youngsook Choi, Qiang Wang, Dale E Shuster, Sebastian Bauer, James H Lewis, Hans Gelderblom, Michiel van de Sande, Silvia Stacchiotti, John H Healey, William D Tap, Andrew J Wagner, Antonio Lopez Pousa, Mihaela Druta, Chia-Chi Lin, Hideo A Baba, Youngsook Choi, Qiang Wang, Dale E Shuster, Sebastian Bauer

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.

Keywords: Adverse reactions; Hepatic safety; Long-term; Pexidartinib; Tenosynovial giant cell tumor.

Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.

Figures

Figure 1
Figure 1
Kaplan‐Meier curve of time to first occurrence of hepatic adverse reactions. Hepatic Laboratory Criteria: alanine aminotransferase >3× upper limit of normal (ULN), or aspartate aminotransferase >3× ULN, or alkaline phosphatase (ALP) >2× ULN, or total bilirubin > ULN, or direct bilirubin > ULN. If ALP >2× ULN and gamma‐glutamyl transferase (GGT) is measured on the same date, GGT must also be >2× ULN.Abbreviation: TGCT, tenosynovial giant cell tumor.
Figure 2
Figure 2
Clinical laboratory results of patients with tenosynovial giant cell tumors (TGCTs) experiencing serious hepatic adverse reactions. (A): Case no. 1. (B): Case no. 1: H&E: portal tract (black circle) without a bile duct or ductular proliferation but with few inflammatory cells. 400× magnification. (C): Case no. 1: immunohistochemical staining against CK7. Portal tract shows loss of bile duct but CK7‐positive adjacent hepatocytes indicating chronic cholestasis (arrows). 400× magnification. (D): Case no. 2. (E): Case no. 3. (F): Case no. 4. (G): Case no. 5.Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BL, baseline; CK7, cytokeratin 7; d, day; H&E, hematoxylin and eosin; LFT, liver function test; ULN, upper limit of normal.

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