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《柳叶刀》(The Lancet发表一项3期临床试验,由首都医科大学附属北京积水潭医院牛晓辉教授团队牵头,联合全球40家医疗中心共同开展,旨在评估匹米替尼治疗腱鞘巨细胞瘤患者的有效性与安全性。研究发现,到第25周时,匹米替尼组的客观缓解率为54%,而安慰剂组为3%,且匹米替尼相关治疗后出现的不良事件以轻度为主。结果表明,匹米替尼展现出显著的抗肿瘤活性,可使腱鞘巨细胞瘤相关功能受限与症状负担获得具有临床意义的改善,为该疾病提供了一种有效性明确、安全性可控的治疗方案选择。识别文中二维码或点击文末阅读原文,查阅原文。

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文章摘要

匹米替尼对比安慰剂治疗腱鞘巨细胞瘤(MANEUVER):一项国际、随机、安慰剂对照3期临床试验

背景

腱鞘巨细胞瘤(tenosynovial giant cell tumour, TGCT)是一种罕见的局部侵袭性肿瘤,目前系统治疗方案有限,存在尚未满足的临床需求。本文报告了MANEUVER试验第一部分的结果,旨在评估高选择性强效集落刺激因子‑1受体抑制剂匹米替尼(Pimicotinib)治疗腱鞘巨细胞瘤患者的有效性与安全性。

方法

MANEUVER是一项PP随机、安慰剂对照3期临床试验,在亚洲、欧洲及北美洲共40家专科医学中心开展。入组标准为年龄≥18岁、不可切除且有症状的腱鞘巨细胞瘤患者(患者自评最严重僵硬或最剧烈疼痛评分≥4分,0~10分量表)。按2:1比例双盲随机分配,接受匹米替尼50mg每日1次口服或安慰剂治疗,为期24周(研究第一部分)。由独立统计专家采用中央交互式网络应答系统生成随机序列,按地区(中国vs非中国)分层。采用与匹米替尼外观一致的安慰剂实现盲法。在第一部分中,患者、所有研究者及研究资助方均对治疗分组设盲。完成第一部分的所有患者均可进入开放标签的第二部分研究:原匹米替尼组维持原剂量继续治疗,原安慰剂组交叉接受匹米替尼治疗,均为期24周。完成第二部分且符合条件的患者,可进入第三部分研究,接受匹米替尼每日1次长期治疗。主要终点为,第25周时,由盲态独立评审委员会依据实体瘤疗效评价标准1.1版在意向治疗人群(所有随机患者)中评估的客观缓解率(objective response rate, ORR)。安全性分析纳入至少接受过一次研究药物治疗的患者。缺失数据不进行填补,仅分析实际观察到的数据。试验入组已完成;该研究已在ClinicalTrials.gov注册(NCT05804045),目前仍在进行中。

结果

2023年4月27日至2024年3月29日期间,共筛选126例患者,94例患者(中国45例,非中国49例)被随机分配并接受治疗:匹米替尼组63例,安慰剂组31例。男性30例(32%),女性64例(68%)。第25周客观缓解率(ORR):匹米替尼组为54%(63例中34例),安慰剂组为3%(31例中1例);组间绝对差异51%(95% CI 33~63,P<0.0001)。匹米替尼相关治疗后出现的不良事件以轻度为主,多为可控的无症状实验室指标异常及临床事件,包括瘙痒、面部水肿、皮疹、眶周水肿、乏力等。在匹米替尼组,发生率超过10%的3级别或4级治疗后不良事件仅为血肌酸磷酸激酶升高,见于8例(13%)患者。安慰剂组最常见治疗后不良事件为乏力和关节痛。在匹米替尼组,5例(8%)患者出现剂量下调,1例(2%)患者终止治疗。研究中未观察到胆汁淤积性肝毒性、药物性肝损伤以及皮肤或毛发色素减退。

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解释

匹米替尼展现出显著的抗肿瘤活性,可使腱鞘巨细胞瘤相关功能受限与症状负担获得具有临床意义的改善,为这种治疗需求未被充分满足的疾病提供了一种有效性明确、安全性可控的治疗方案选择。END

团队介绍

本研究由首都医科大学附属北京积水潭医院联合全球共40家医疗中心共同开展,牛晓辉教授为通讯作者,徐海荣教授为第一作者。


Funding
Abbisko Therapeutics.

Declaration of interests

VR received consulting fees and honoraria from EMD Serono. JM-B received grants (paid to his institution) from Abbisko Therapeutics, Biosplice, Boehringer Ingelheim, Bristol-Myers Squibb, Cebiotex, Deciphera, Eli Lilly, Immunome, Inhibrx, Karyopharm, Lixte, Pfizer, PharmaMar, Philogen, PTC Therapeutics, Rain Therapeutics, Springworks Therapy, and Synox; consulting fees from Deciphera and PharmaMar; honoraria from Abbisko Therapeutics, Adium, Bayer, Boehringer Ingelheim, Cogent Bioscience, Deciphera, GSK, PharmaMar, and Roche; travel support from PharmaMar; and is the CEO of Sarcoma Research Solutions. AAR received institutional support from 23andMe, Abbisko Therapeutics, AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BioNTech, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cogent Biosciences, Daiichi Sankyo, Deciphera, Frontier Biopharma, Gilead, GSK, Intensity Therapeutics, Iterion Therapeutics, Karyopharm, Kelun-Biotech, MedImmune, Medison, Merck, Neoleukin Therapeutics, Novartis, Pfizer, Polaris, Roche/Genentech, Rain Therapeutics, and Symphogen; honoraria from Boehringer Ingelheim and Medison; and participated on a data safety monitoring or advisory board for CD40Life and Inhibrx. CS received honoraria from Deciphera, PharmaMar, and Roche; travel support from Bayer, Gilead, and PharmaMar; was a steering committee member for NewBay; and participated in advisory boards for Deciphera and IDRX. SS received grants (paid to her institution) from Abbisko Therapeutics, Daiichi Sankyo, Deciphera, and SynOx Therapeutics; and participated in advisory boards for Daiichi Sankyo, Deciphera, and Merck Serono. GGB received consulting fees from Eli Lilly and PharmaMar; honoraria from Eli Lilly, GSK, Istituto Gentili, MSD, and PharmaMar; travel support from Eli Lilly, Istituto Gentili, and PharmMar; and participated in advisory boards for Deciphera, GSK, and MSD. PR received research funding (paid to his institution) from Bristol-Myers Squibb, Novartis, Pfizer, Roche; consulting fees from Bristol-Myers Squibb, Genesis, Medison Pharma, MSD, Novartis, Pierre Fabre, and Philogen; honoraria from Bristol-Myers Squibb, Genesis, Medison Pharma, MSD, Novartis, and Pierre Fabre; participated in speakers bureaus for Bristol-Myers Squibb, Genesis, MSD, Novartis, and Pierre Fabre; and travel support from Pierre Fabre. GT participated in advisory boards for Deciphera and SynOx. All other authors declare no competing interests.



中文翻译仅供参考,所有内容以英文原文为准。

DOI: 10.1016/S0140-6736(25)02602-9
题图Copyright: PR J L Kemeny via Science Photo Library

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