Lewis James H, Gelderblom Hans, van de Sande Michiel, Stacchiotti Silvia, Healey John H, Tap William D, Wagner Andrew J, Pousa Antonio Lopez, Druta Mihaela, Lin Chia-Chi, Baba Hideo A, Choi Youngsook, Wang Qiang, Shuster Dale E, Bauer Sebastian
Georgetown University Hospital, Washington, District of Columbia, USA.
Leiden University Medical Center, Leiden, The Netherlands.
Oncologist. 2021 May;26(5):e863-e873. doi: 10.1002/onco.13629. Epub 2020 Dec 24.
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.
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.
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.
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.
培西达替尼在美国被批准用于治疗腱鞘巨细胞瘤（TGCT）。在此，我们评估了接受培西达替尼治疗的TGCT患者的肝脏安全性。
通过肝酶检测异常的类型和程度评估肝脏不良反应（AR），分为（a）单纯转氨酶升高（丙氨酸[ALT]或天冬氨酸[AST]升高，碱性磷酸酶[ALP]或胆红素无显著升高），或（b）混合性或胆汁淤积性肝毒性（根据判定结果，ALP升高，伴或不伴有ALT/AST及胆红素升高）。在临床研究NCT01004861、NCT02371369、NCT02734433和NCT03291288中，140例TGCT患者从首次接受培西达替尼治疗开始的中位随访时间为39个月（范围32 - 82个月）。
总体而言，接受培西达替尼治疗的TGCT患者中，95%（133/140）出现了肝脏AR。共有128例患者（91%）出现可逆的、低级别剂量依赖性单纯AST/ALT升高，ALP无显著升高。5例患者（4%）出现严重的混合性或胆汁淤积性损伤。无病例符合海氏法则标准。肝脏AR主要在开始治疗的前2个月出现。所有5例严重肝脏AR病例在停用培西达替尼后1 - 7个月恢复。非TGCT人群（N = 658）中有5例患者出现严重肝脏AR，其中2例为不可逆病例。
这项汇总分析提供的信息有助于为治疗医生对TCGT患者进行风险评估奠定基础，TCGT是一种局部侵袭性但通常不发生转移的肿瘤。特别是，长期使用培西达替尼对肝脏转氨酶有可预测的影响，但严重胆汁淤积或混合性肝损伤的风险不可预测。
这是第一项长期汇总分析，报告了培西达替尼在伴有严重发病率或功能受限且手术无法改善的腱鞘巨细胞瘤患者中的长期肝脏安全性。这些发现超出了先前发表的内容，描述了在整个临床开发项目中培西达替尼治疗后观察到的肝毒性实例。这些信息对医学肿瘤学家和骨肿瘤学家高度相关，并为在培西达替尼风险评估和缓解安全项目中对合适患者正确使用该药提供了指导。
