Pimicotinib versus placebo for tenosynovial giant cell tumour (MANEUVER): an international, randomised, placebo-controlled, phase 3 trial.

There are few systemic treatment options, highlighting an unmet need.

目前系统性治疗方案有限，突显出未满足的治疗需求。

We report the results of part 1 of the MANEUVER trial, which aimed to evaluate the efficacy and safety of pimicotinib, a highly selective, potent, colony-stimulating factor-1 receptor inhibitor, in patients with TGCT.

我们报告了MANEUVER试验第一部分的结果，该试验旨在评估高度选择性、强效的集落刺激因子-1受体抑制剂pimicotinib在睾丸生殖细胞肿瘤（TGCT）患者中的疗效和安全性。

Methods

MANEUVER is a randomised, placebo-controlled, phase 3 study done in 40 specialised hospitals in Asia, Europe, and North America.

MANEUVER是一项在亚洲、欧洲和北美40家专业医院进行的随机、安慰剂对照、III期研究。

Patients aged 18 years and older with unresectable, symptomatic TGCT (patient-reported worse stiffness or worst pain of at least 4 on a scale of 0-10) were randomly assigned (2:1, double-blind) to oral, once-daily pimicotinib 50 mg or placebo for 24 weeks (part 1).

年龄在18岁及以上的不可切除、有症状的TGCT（患者自报僵硬程度或最严重疼痛至少为4分，满分10分）患者被随机分配（2:1，双盲）口服每日一次的50 mg pimicotinib或安慰剂，为期24周（第1部分）。

An independent statistician used a central interactive web response system to generate the randomisation schedule; stratification was by region (China vs non-China).

一位独立的统计学家使用中央交互式网络响应系统生成随机分配计划；按地区（中国与非中国）进行分层。

Masking was achieved by using placebo identical in appearance to pimicotinib.

通过使用与匹米替尼外观相同的安慰剂来实现盲法。

In part 1, patients, all investigators, and study funders were masked to treatment assignments.

在第一部分中，所有患者、研究者和研究资助者对治疗分配均不知情。

All patients who completed part 1 were allowed to continue to open-label part 2: pimicotinib-treated patients could continue the same dosage and placebo-treated patients could cross over to receive pimicotinib for 24 weeks.

所有完成第一部分的患者均允许继续进入开放标签的第二部分：接受皮米考替尼治疗的患者可以继续使用相同的剂量，接受安慰剂治疗的患者可以交叉使用皮米考替尼治疗24周。

Eligible patients who completed part 2 were allowed to continue once-daily pimicotinib long-term in part 3.

完成第二部分的合格患者被允许在第三部分继续每日一次长期使用皮米考替尼。

The primary endpoint was objective response rate(ORR) at week 25 by blinded independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treatpopulation (all randomised patients).

主要终点是第25周时，根据实体瘤疗效评价标准第1.1版，由盲态独立评审委员会评估的意向治疗人群（所有随机患者）中的客观缓解率（ORR）。

Safety was analysed in patients who received at least one dose of study drug.

安全性分析针对接受至少一剂研究药物的患者进行。

Missing data were not imputed and only observed data were analysed.

未对缺失数据进行估算，仅对观察到的数据进行了分析。

Trial enrolment is complete; the study is registered at ClinicalTrials.gov (NCT05804045) and is ongoing.

试验的招募已经完成；该研究已在ClinicalTrials.gov注册（NCT05804045），目前正在进行中。

Results

Between April 27, 2023, and March 29, 2024, 126 patients were screened and 94 patients (China [n=45], non-China [n=49]) were randomly assigned to, and received, pimicotinib (n=63) or placebo (n=31). 30 (32%) patients were male and 64 (68%) were female.

在2023年4月27日至2024年3月29日期间，共有126名患者接受了筛查，其中94名患者（中国[n=45]，非中国[n=49]）被随机分配并接受了皮米可替尼（n=63）或安慰剂（n=31）。30名（32%）患者为男性，64名（68%）为女性。

ORR at week 25 was 54% (34 of 63) in the pimicotinib group and 3% (one of 31) in the placebo group (absolute difference 51% [95% CI 33-63], p<0·0001).

在第25周时，皮米可替尼组的客观缓解率(ORR)为54%（63人中有34人），安慰剂组为3%（31人中1人）（绝对差异51% [95% 置信区间33-63]，p<0.0001）。

Pimicotinib was associated with mainly mild treatment-emergent adverse events, including mostly manageable asymptomatic laboratory abnormalities and clinical events, such as pruritus, facial oedema, rash, periorbital oedema, and fatigue.

Pimicotinib主要与轻度治疗相关不良事件相关，包括大多数可管理的无症状实验室异常和临床事件，如瘙痒、面部水肿、皮疹、眼周水肿和疲劳。

The only grade 3 or 4 treatment-emergent adverse eventoccurring in more than 10% of pimicotinib-treated patients was increase in blood creatine phosphokinase, in eight (13%) of 63 patients.

在使用pimicotinib治疗的患者中，唯一超过10%发生的3级或4级治疗相关不良事件是血清肌酸激酶增加，在63名患者中有8名（13%）出现此情况。

The most common treatment-emergent adverse events in the placebo group were fatigue and arthralgia.

安慰剂组中最常见的治疗后不良事件是疲劳和关节痛。

Dose reductions occurred in five (8%) of 63 pimicotinib-treated patients and treatment discontinuations in one (2%) of 63 pimicotinib-treated patients.

在63名接受pimicotinib治疗的患者中，有5人（8%）发生了剂量减少，1人（2%）发生了治疗中断。

There was no cholestatic hepatotoxicity, drug-induced liver injury, or hypopigmentation of skin or hair.

未观察到胆汁淤积性肝毒性、药物性肝损伤或皮肤或头发的色素减退。

interpretation

Pimicotinib showed robust antitumour activity with clinically meaningful improvements in TGCT-related functional limitations and symptom burden, offering an effective treatment option with a manageable safety profile for this underserved condition.

Pimicotinib展现了显著的抗肿瘤活性，并在与TGCT相关的功能受限和症状负担方面实现了临床意义上的改善，为这一服务不足的病症提供了一种有效且安全性可控的治疗方案。

funding

Abbisko Therapeutics.

Abbisko 疗法公司