美国纪念斯隆凯特琳癌症中心和威尔康奈尔医学院的Emanuela Palmerini研究小组宣布，他们发现pexidartinib可有效治疗晚期腱鞘巨细胞瘤。 这一研究成果发表在2019年8月10日出版的国际学术期刊《柳叶刀》上。

研究团队旨在评估pexidartinib作为一类CSF1受体抑制剂，为不宜手术的TGCT患者提供一个系统治疗方案的可行性。

该三期随机试验中，120例不宜手术的晚期TGCT患者被随机（1:1）分配到pexidartinib组(n=61)或安慰剂组(n=59)。治疗的第25周，pexidartinib组的总有效率为39%，显著高于安慰剂组；pexidartinib组中有8例发生严重不良反应，安慰剂组有1例发生严重不良反应。

pexidartinib常见的不良反应包括毛发颜色变化(67%)、疲劳(54%)、天门冬氨酸转氨酶升高(39%)、脑水肿(38%)、丙氨酸转氨酶升高(28%)和运动障碍(25%)。pexidartinib组中有3例患者转氨酶升高3倍以上，总胆红素和碱性磷酸酶升高2倍以上，提示混合或胆汁淤积性肝中毒，其中1例患者的不良反应持续达7个月，并经活检证实。

Pexidartinib治疗TGCT显示出较强的抗瘤反应，并可有效改善患者症状，可作为一种潜在的TGCT治疗方案，尤其针对那些无法手术的晚期患者，但需注意混合或胆汁淤积性肝中毒的风险较高。

据悉，腱鞘巨细胞瘤(TGCT)是一种罕见的局部侵袭性肿瘤，常过度表达集落刺激因子1 (CSF1)。除了手术目前没有公认的系统性疗法。

附：英文原文

Title: Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial

Author: William D Tap, MD, Prof Hans Gelderblom, MD, Emanuela Palmerini, MD, Jayesh Desai, MBBS, Prof Sebastian Bauer, MD, Prof Jean-Yves Blay, MD, Thierry Alcindor, MD, Kristen Ganjoo, MD, Javier Martín-Broto, MD, Prof Christopher W Ryan, MD, Prof David M Thomas, FRACP, Charles Peterfy, MD, John H Healey, MD, Michiel van de Sande, MD, Heather L Gelhorn, PhD, Dale E Shuster, PhD, Qiang Wang, PhD, Antoine Yver, MD, Henry H Hsu, MD, Paul S Lin, MD, Sandra Tong-Starksen, MD, Silvia Stacchiotti, MD, Andrew J Wagner, MD, on behalf of the ENLIVEN investigators

Issue&Volume: VOLUME 394, ISSUE 10197, P478-487, AUGUST 10, 2019

Summary:

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 ClinicalTrials.gov, number NCT02371369.

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.

DOI: https://doi.org/10.1016/S0140-6736(19)30764-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30764-0/fulltext