Background

Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection.

Methods

This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with , number .

Findings

Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; absolute difference 39% [95% CI 27–53]; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy.

Interpretation

Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery.

Funding

Daiichi Sankyo.

中文翻译：

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Pexidartinib与安慰剂治疗晚期腱鞘巨细胞瘤（ENLIVEN）：一项随机的3期临床试验。

背景

腱鞘巨细胞瘤（TGCT），一种罕见的局部侵袭性肿瘤，过表达集落刺激因子1（CSF1）。手术是标准的，没有经过批准的全身疗法。我们旨在评估TGCT患者的CSF1受体抑制剂pexidartinib，以为他们提供可行的全身治疗选择，尤其是在不适合手术切除的患者中。

方法

这项3期随机试验分为两个部分。第一部分是一项双盲研究，其中不建议手术的有症状，晚期TGCT的患者通过集成的网络响应系统（1：1）随机分配给pexidartinib或安慰剂组。pexidartinib组的患者在头2周内每天口服负荷剂量为1000 mg pexidartinib（早晨400 mg；晚上600 mg），然后连续22周每天接受800 mg（每天两次400 mg）。第二部分是培西达替尼针对所有患者的开放标签研究。在所有意向治疗患者中评估的主要终点是第25周的总体反应，并由RECIST 1.1版进行了集中评估。在接受至少一剂研究药物的所有患者中分析安全性。这项研究的编号是。

发现

在2015年5月11日至2016年9月30日之间，对174例合格的患者进行了评估，其中120例患者被随机分配并接受了pexidartinib（n = 61）或安慰剂（n = 59）。安慰剂组有11例辍学，佩西达替尼组有9例辍学。混合性或胆汁淤积性肝毒性的出现导致数据监测委员会停止招募目标未达标的六名患者。RECIST观察到，第25周，使用pexidartinib达到总体缓解的患者比例高于安慰剂组（61的24 [39％] vs59个都没有；绝对差异39％[95％CI 27-53]；p <0·0001）。pexidartinib组的61名患者中有8名（13％）发生了严重的不良事件，安慰剂组的59名患者中有1名（2％）发生了严重的不良事件。与pexidartinib相关的不良反应最常见，是头发变色（67％），疲劳（54％），天冬氨酸转氨酶升高（39％），恶心（38％），丙氨酸转氨酶升高（28％）和消化不良（25％）。事件。接受培西达替尼治疗的三例患者的转氨酶升高是正常上限的三倍或更多倍，总胆红素和碱性磷酸酶升高是正常上限的两倍或更多倍，表明混合或胆汁淤积性肝毒性，持续7个月，经活检证实。

解释

Pexidartinib是第一种在TGCT中显示出强大的肿瘤反应，改善的患者症状和功能结局的全身疗法；混合或胆汁淤积性肝毒性是确定的风险。在不能通过手术改善的情况下，佩西达替尼可能被认为是与严重发病或功能受限相关的TGCT的潜在治疗方法。

资金

第一三共。