A Phase III, Multicentre, Randomised, Double-Blind Study to Assess the Safety and Efficacy of Emactuzumab vs. Placebo in Subjects With Tenosynovial Giant Cell Tumour

This is a multicenter, Phase 3, randomised, double-blind, placebo-controlled study, which aims to evaluate the efficacy and safety of the investigational drug emactuzumab for the treatment of patients with localized or diffuse TGCT where surgical removal of the tumor is not viewed as an option.
The study consists of two parts. In Part 1, eligible subjects will be assigned in a 2:1 ratio to receive either emactuzumab or matching placebo in a double-blind fashion, that will be administered in total 5 times as an intravenous (i.v.) infusion once every 2 weeks. This will be followed by an observation period of 3 months leading to a total duration of 24 weeks in Part 1. A number of assessments will be carried out during the course of the study, including physical examinations, blood tests, imaging studies, electrocardiograms, and questionnaires. Part 2 is a long-term double-blind follow-up phase of the subjects on emactuzumab or placebo. Subjects assigned to placebo in Part 1 have the option, subject to eligibility, to crossover to receive open-label emactuzumab in Part 2. Subjects assigned to active drug in Part 1 have the option to receive open-label retreatment under certain circumstances.

开始日期2024-10-09

申办/合作机构

Synox Therapeutics Ltd.

NCT03768063

/ Active, not recruiting临床3期

An Open Label, Multicenter Extension Study in Patients Previously Enrolled in a Genentech and/or F. Hoffmann-La Roche Ltd Sponsored Atezolizumab Study (IMbrella B)

This is an open-label, multicenter, extension study. Patients who are receiving clinical benefit from atezolizumab monotherapy or atezolizumab in combination with other agent(s) or combination/comparator agent(s) during participation in a Genentech or Roche-sponsored study (the parent study), who are eligible to continue treatment and who do not have access to the study treatment locally, may continue to receive study treatment in this extension study following roll-over from the parent study.

开始日期2019-02-28

申办/合作机构

Hoffmann-La Roche, Inc.

NCT03369964

/ Withdrawn临床1期

A Phase Ib Study of The Safety and Pharmacology of Atezolizumab in Combination With an Immunotherapy Agent Investigated With or Without Anti-Cd20 Therapy in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

This study will investigate the safety, pharmacology, and activity of atezolizumab in combination with immunotherapy agents with or without an anti-CD20 agent (i.e., obinutuzumab) in patients with relapsed or refractory (R/R) follicular lymphoma (FL). The first immunotherapy molecule investigated will be emactuzumab (Arm A) in two combinations.

开始日期2018-03-14

申办/合作机构

Hoffmann-La Roche, Inc.

100 项与 Emactuzumab 相关的临床结果

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100 项与 Emactuzumab 相关的转化医学

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100 项与 Emactuzumab 相关的专利（医药）

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项与 Emactuzumab 相关的文献（医药）

2023-10-01·Hematology/oncology and stem cell therapy

Updates on the Treatment of Tenosynovial Giant Cell Tumor

Review

作者: Chan, Abigail S. ; Singh, Vikas ; Katiyar, Vatsala ; Dy, Paul

Tenosynovial giant cell tumor (TGCT) is a rare inflammatory disorder affecting the joint synovium, bursae, and tendon sheaths that causes non-specific and often insidious joint discomfort. The application of systemic chemotherapy has been limited due to poor and unsustained disease responses. Surgery with or without adjuvant radiation is the primary treatment modality for TGCT. With its locally destructive nature and increased recurrence, multiple surgical interventions become necessary throughout the course of the disease, leading to disfigurement, decreased quality of life, and increased mortality. However, owing to recent evidence demonstrating the overexpression of colony-stimulating factor 1 (CSF-1) in TGCT, selective tyrosine kinase inhibitors targeting CSF-1 receptors are being developed. Pex- idartinib is the first CSF-1 receptor inhibitor approved for the treatment of TGCT. Here, we discuss various available treatment strategies and ongoing investigations and trials targeting diffuse TGCT, which include nilotinib, lacnotuzu- mab, cabiralizumab, vimseltinib, and emactuzumab.

2022-05-01·Journal for immunotherapy of cancer2区 · 医学

Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade

2区 · 医学

ArticleOA

作者: Jean-Pascal Machiels ; Philippe Cassier ; Stephane Champiat ; Dominik Rüttinger ; Catherine Terret ; Dmitriy Zamarin ; Carl Watson ; Michael A Cannarile ; F Stephen Hodi ; Carola Ries ; Wolfgang Jacob ; Carlos Gomez-Roca ; Jose Luis Perez Gracia ; Alvaro Taus ; Francesca Michielin ; Joseph P Eder ; Randolph Christen ; Valentina Boni ; Aurelien Marabelle ; David Mcdermott ; Maria Martinez Garcia ; Ryan Sullivan ; Galina Babitzki ; Sandrine Aspeslagh ; Martin Weisser ; Konstanty Korski ; Navid Hafez ; Anna-Maria Jegg ; Georgina Meneses-Lorente ; Jean-Pierre Delord

Background:

This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).

Methods:

Emactuzumab (500–1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.

Results:

Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.

Conclusion:

Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

2020-12-01·European journal of cancer (Oxford, England : 1990)1区 · 医学

Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour

1区 · 医学

Article

作者: Dominik Rüttinger ; Wolfgang Jacob ; Michael Cannarile ; Carlos Gomez-Roca ; Keelara Abiraj ; Christophe Le Tourneau ; Jean-Yves Blay ; Philippe A. Cassier ; Randolph Christen ; Carl Watson ; Irina Klaman ; Anna-Maria Jegg ; Antoine Italiano ; Maud Toulmonde ; Kristy Weber ; Delphine Loirat ; Sandra P. D'Angelo ; Jean-Pierre Delord ; Martin Weisser ; Carola H. Ries ; Francesca Michielin

OBJECTIVES:

This study investigated the safety, clinical activity and patient-reported outcomes of patients with diffuse-type tenosynovial giant-cell tumour (dTGCT) of the soft tissue who were treated with emactuzumab, a humanised anti-colony stimulating factor 1 receptor (CSF1R) monoclonal antibody and were followed up for up to 2 years after the start of treatment.

METHODS:

In this open-label phase 1 study (ClinicalTrials.govNCT01494688), patients received intravenous (IV) emactuzumab from 900 to 2000 mg every two weeks in the dose-escalation phase and at the optimal biological dose of 1000 mg with different schedules in the dose-expansion phase. Adverse event (AE) rates and biomarker assessments from tumour biopsies were analysed. Quality of life was assessed using a standard questionnaire (EuroQol-5D-3L) and the WOMAC® 3.1 Osteoarthritis Index. Tumour responses were determined with magnetic resonance imaging.

RESULTS:

Altogether, 63 patients were enrolled into the study. The most frequently reported AEs were pruritus, asthenia and oedema. In 36 patients for whom biopsy tissue was available a substantial decrease of CSF1R-positive and CD68/CD163-positive macrophages was detected. The independently reviewed best overall objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors version 1.1) was 71%. Responses were durable, and an ORR of 70% and 64% was determined after one or two years after enrolment into the study. Clinical activity was accompanied by an improvement in EuroQol-5D-3L and particularly the joint disorder-specific WOMAC score.

CONCLUSIONS:

Systemic therapy of dTGCT patients with emactuzumab resulted in pronounced and durable responses associated with symptomatic improvement and a manageable safety profile.

项与 Emactuzumab 相关的新闻（医药）

2026-05-18

·盛京骨与软组织肿瘤

盛京骨肿瘤文献荟萃（128）培西达替尼为腱鞘巨细胞瘤患者提供适度的疼痛缓解：ENLIVEN 研究结果

培西达替尼为腱鞘巨细胞瘤患者提供适度的疼痛缓解： ENLIVEN 研究结果作者：John H Healey 期刊：Clin Orthop Relat Res 期刊年限：2023 Jan 1 摘要背景：口服PLX3397（培西达替尼）治疗色素沉着绒毛结节性滑膜炎或腱鞘巨细胞瘤患者的双盲、随机、安慰剂对照III期研究（ENLIVEN）显示培西达替尼能够为不适合手术改善的腱鞘巨细胞瘤（TGCT）成人患者带来产生显著的客观肿瘤缓解效果。基于这些结果，2019年培西达替尼在美国作为突破性疗法获得孤儿药资格认定并在该人群中获得了加速审批。然而ENLIVEN研究中培西达替尼缓解疼痛的能力未得到充分阐述且疼痛缓解与客观肿瘤缓解之间的关系亦未得到阐述。目的：（1）在ENLIVEN研究中培西达替尼治疗达到了何种程度的疼痛缓解？（2）疼痛缓解与客观肿瘤缓解之间有何关联？（3）疼痛缓解效果的持续时间如何？方法：本研究包含了ENLIVEN试验中预设的主要评估和探索性评估即患者对肿瘤部位最严重疼痛的自我评估。ENLIVEN是一项III期随机、安慰剂对照临床试验在该试验中患有腱鞘巨细胞瘤且无法通过手术获得改善的成人患者接受了为期24周的培西达替尼或安慰剂治疗，之后符合条件的患者可转为接受开放标签的培西达替尼治疗。在174例接受资格评估的患者中121例被随机分配（50%[60例]至安慰剂组，50%[61例]至培西达替尼组），120例接受了安慰剂或培西达替尼给药（59例接受安慰剂，61例接受培西达替尼）并纳入意向性治疗分析。总治疗人群中59%（120例中的71例）为女性，88%（120例中的106例）为白人。平均年龄为45±13岁。肿瘤多位于下肢（92%[120例中的110例]），最常见于膝关节（61%[120例中的73例]）和踝关节（18%[120例中的21例]）。作为次要结局指标，患者采用11点数字评定量表（NRS）对过去24小时内肿瘤部位的最严重疼痛程度进行评分。疼痛缓解的主要定义为：从基线至第25周，每周平均最严重疼痛NRS评分下降≥30%且麻醉性镇痛药使用增加<30%。计划中的疼痛探索性评估包括：采用其他阈值定义的疼痛缓解频率，例如最严重疼痛NRS评分下降≥50%或下降至少2分（最小临床重要性差值，MCID）；基线至第25周疼痛减轻的幅度；最严重疼痛NRS评分与RECIST1.1标准评估的肿瘤缩小之间的相关性；以及在开放标签扩展期疼痛缓解的持续性。在试验的随机分配阶段根据意向性治疗分析对疼痛反应进行了比较，单侧检验阈值p<0.025以降低假阳性结果的风险。疼痛评估完成情况：安慰剂组59例患者中有35例（59%）完成，培西达替尼组61例患者中有33例（54%）完成。两组治疗人群的人口统计学特征和疾病特征均无显著差异。结果：在疼痛缓解的主要评估指标上培西达替尼组与安慰剂组之间未检测到统计学差异（缓解率：31%[19/61][95%CI21%至44%]vs.15%[9/59][95%CI8%至27%]；单侧p=0.03）。在探索性评估中培西达替尼提供了适度的疼痛改善（采用50%阈值时，缓解率：26%[16/61][95%CI17%至38%]vs.10%[6/59][95%CI5%至20%]，单侧p=0.02；采用MCID阈值时，缓解率：31%[19/61][95%CI21%至44%]vs.14%[8/59][95%CI7%至25%]，单侧p=0.02）。从基线至第25周，每周平均最严重疼痛NRS评分的最小二乘均值变化在培西达替尼治疗组中大于安慰剂组（-2.5[95%CI-3.0 至-1.9]vs.-0.3[95%CI-0.9 至0.3]；p<0.001），尽管两组之间的均值差异（-2.2[95%CI-3.0至-1.4]）仅略高于MCID。每周平均最严重疼痛NRS评分的改善与肿瘤大小的缩小（r=0.44；p<0.001）及肿瘤体积评分的缩小（r=0.61；p<0.001）均存在相关性。对于进入开放标签扩展期研究的患者，最严重疼痛NRS评分较基线的变化与随机化部分结束时的变化相似且略高于MCID（接受培西达替尼治疗25周后平均变化为-2.7±2.2，治疗50周后为-3.3±1.7）。结论：基于本项研究培西达替尼可为这些患者带来适度的疼痛减轻（其程度仅略大于最小临床重要性差值）这可能是该药物的额外获益。然而目前的研究结果尚不足以支持将培西达替尼作为缓解疼痛的常规用药。证据级别：II级，治疗性研究引言腱鞘巨细胞瘤（TGCT）是一种罕见的肿瘤疾病最常诊断于青中年成人。TGCT累及关节、滑囊和腱鞘，很少发生转移。TGCT会通过多种方式损害患者的功能和生活质量，但患者普遍认为疼痛是最主要的症状。手术是治疗TGCT的常用方法，但并非总能根除肿瘤或减轻疼痛还可能导致术后并发症。一项针对接受弥漫型TGCT手术切除患者的回顾性研究发现，在中位随访54个月时疼痛减轻了59%，但44%的患者出现了复发。培西达替尼是一种口服活性的集落刺激因子-1受体抑制剂于2019年作为突破性疗法获得美国加速批准并授予孤儿药资格，适用于患有症状性TGCT、伴有严重并发症或功能受限且手术无法改善病情的成年患者。该适应症的批准主要基于一项口服PLX3397治疗色素沉着绒毛结节性滑膜炎或腱鞘巨细胞瘤患者的双盲、随机、安慰剂对照III期研究（ENLIVEN）的结果。在该研究中有症状的晚期TGCT患者被随机分配，接受培西达替尼（n=61）或安慰剂（n=59）治疗24周至第25周时根据RECIST1.1版标准评估，培西达替尼组达到肿瘤缓解的患者比例高于安慰剂组（39%vs.0%）；根据肿瘤体积评分评估，亦得出相同结论（56%vs.0%）。此外培西达替尼治疗组患者在患者报告的僵硬感和身体功能方面的改善也优于安慰剂组。疼痛是TGCT最突出的症状之一。这一事实加上有证据表明疼痛与肿瘤治疗反应之间存在关联，使我们思考培西达替尼是否有助于减轻TGCT患者的疼痛。在ENLIVEN研究中疼痛作为次要终点，采用最严重疼痛数字评定量表（NRS）进行评估，但初始报告中并未充分详细描述培西达替尼缓解疼痛的能力并且疼痛缓解与客观肿瘤缓解之间的关系亦未被阐述。因此我们根据ENLIVEN试验数据的预设分析结果，回答以下三个问题：（1）培西达替尼治疗达到了何种程度的疼痛缓解？（2）疼痛缓解与客观肿瘤缓解之间有何关联？（3）疼痛缓解的持续性如何？患者与方法研究设计这是对ENLIVEN试验（NCT02371369）中最严重疼痛NRS评分数据的一项方案预设分析。简言之ENLIVEN是一项分为两部分的双盲、随机、安慰剂对照、多中心III期研究（第1部分）随后为开放标签扩展期（第2部分）旨在比较培西达替尼与安慰剂对不适合手术治疗的症状性TGCT成年患者的安全性和有效性。在患者通过集成的网络应答系统按1:1比例随机分配，分别接受培西达替尼（每日1000毫克，持续2周；随后每日800毫克，持续22周）或相同的安慰剂（持续24周）。治疗医师及进行评估的研究人员均对治疗分组设盲。完成第1部分的患者有资格进入第2部分接受开放标签的培西达替尼治疗。关于ENLIVEN研究方案的更多详细信息请访问https://clinicaltrials.gov /ct2 /show /results /NCT02371369。该试验在澳大利亚、北美（加拿大和美国）及欧洲（丹麦、法国、德国、匈牙利、意大利、荷兰、波兰、西班牙和英国）的39家医院和癌症中心进行。研究对象为年龄≥18岁、经组织学确诊患有TGCT且处于晚期的成年患者，此类患者的手术切除可能加剧功能受限或导致严重并发症。患者还必须满足最严重疼痛或最严重僵硬NRS评分≥4分（采用0[无]至11[可能达到最严重僵硬]的11分量表）且肿瘤大小至少为2cm。排除既往接受过培西达替尼或任何靶向集落刺激因子-1或集落刺激因子-1受体的生物制剂治疗、存在转移性TGCT、或患有需要治疗的活动性癌症患者。 ENLIVEN试验的主要终点是第25周时的肿瘤缓解比例，该评估基于对MRI影像进行的设盲、独立中心审查其中肿瘤大小以肿瘤直径之和进行测量。我们将肿瘤体积评分作为次要终点指标，该评分对应于最大扩张的滑膜腔或腱鞘所累及体积的百分比。我们采用最严重疼痛NRS作为次要终点评估疼痛，该量表改编自简明疼痛量表（BPI）简版。患者使用11点NRS对过去24小时内“肿瘤部位”的最严重疼痛进行评分，评分范围从“0——无痛”到“10——你能想象的最严重的疼痛”。最严重疼痛NRS数据通过电子手持设备每日收集。每日疼痛评分由患者对疼痛强度的11点评分确定。每周平均疼痛评分基于完整记录按照预设评估进行计算。计算每周平均值需提供7天中至少4天的数据。最严重疼痛NRS下降至少2分被定义为ENLIVEN研究中的最小临床重要性差值（MCID）因为这对应于简明疼痛量表中最严重疼痛NRS条目出现具有临床意义的变化。我们对麻醉性镇痛药的使用进行了量化因为其被纳入疼痛缓解的定义中以考虑使用这些止痛药物可能带来的混杂效应。麻醉性镇痛药的使用量通过将每日剂量单位乘以服用单位数再除以数据可获得的天数来计算平均值。对于因合并使用不同种类麻醉药物而导致麻醉药物类型或剂量发生变化的患者，麻醉性镇痛药的使用量在等效镇痛转换至吗啡等效剂量后进行计算。计算算术平均值需要至少7天中有4天有效的记录数据，其中包含某一天未使用麻醉性镇痛药的记录。纳入所有患者在2015年5月11日至2016年9月30日期间共174例患者接受了资格评估其中121例被随机分配（50%[60例]至安慰剂组，50%[61例]至培西达替尼组）（图1）。安慰剂组中有1例随机分组的患者未接受给药。研究第1部分（随机分配阶段）中安慰剂组59例患者中有48例（81%）完成，培西达替尼组61例患者中有52例（85%）完成。第1部分的数据截止日期为2017年3月27日即所有患者均已完成第1部分最终评估时间。由于停药、依从性差及数据收集问题，可获得基线和第25周最严重疼痛NRS数据的患者比例为：安慰剂组59例中有35例（59%），培西达替尼组61例中有33例（54%）。停药的具体原因已在其他文献中报道。第2部分（开放标签部分）纳入了78例患者，入组时间为2016年9月29日至2017年3月27日。其中30例在第1部分接受安慰剂的患者在第2部分转为接受培西达替尼；其余48例在第1部分接受培西达替尼的患者在第2部分继续接受该药治疗。本文报告的数据收集截至2018年1月31日。图1 本研究纳入患者的流程图。在ENLIVEN试验的第1部分，患者被随机分配接受安慰剂或培西达替尼治疗24周。第1部分结束时（第25周），患者可进入第2部分，所有患者在此部分均接受开放标签的培西达替尼治疗。a导致研究中止的8例不良事件中有7例与肝脏相关。人口统计学特征接受治疗的总体人群中女性占59%（120例中的71例）白人占88%（120例中的106例）（补充表1；http://links.lww.com /CORR /A902）平均年龄为45±13岁。肿瘤多位于下肢（92%[120例中的110例]）最常见于膝关节（61%[120例中的73例]）和踝关节（18%[120例中的21例]）。如前所述两组患者的基线特征（年龄、种族、地理区域、病变部位、既往TGCT手术次数、既往全身治疗史、肿瘤大小、关节活动度及止痛药使用情况）相似。样本量估算如前所述该研究的样本量设计足以检测出从基线到第25周期间客观肿瘤缓解（即非基于疼痛缓解的评估）方面具有临床意义的差异。简而言之计划纳入126例患者作为样本量以提供90%的统计检验效能用于检测缓解率方面25%的差异（基于客观肿瘤缓解：安慰剂组为10%，培西达替尼组为35%）采用双侧、两样本比较，检验水准α=0.05。基于疼痛缓解的主要定义和单侧α=0.025进行的事后检验效能计算表明ENLIVEN研究（把握度为52%）在疼痛主要评估方面的检验效能不足（补充表2； http://links.lww.com /CORR /A903）。伦理批准 ENLIVEN试验获得了各参与中心机构审查委员会的批准并遵循《赫尔辛基宣言》、国际协调理事会药物临床试验质量管理规范指南以及美国健康保险携带和责任法案进行。所有患者均签署了书面知情同意书参与本试验。本试验已在ClinicalTrials.gov注册（注册号：NCT02371369）主要终点及其他次要终点的结果已在其他文献中报道。本文报告了试验随机化部分和开放标签部分中患者报告的疼痛缓解的完整分析结果。研究结果与统计学分析统计学分析采用SAS9.4（SASInstitute）软件进行。对于第1部分分析基于随机分组后的意向治疗人群进行；对于第2部分，分析在接受开放标签培西达替尼治疗的所有患者中进行。对缺失数据未进行替换或插补。本研究的主要目标是确定ENLIVEN试验第1部分（随机化部分）中培西达替尼治疗所达到的疼痛缓解水平。根据ENLIVEN研究方案中的规定疼痛缓解的主要定义为：从基线至第25周，每周平均最严重疼痛NRS评分下降≥30%且麻醉性镇痛药使用增加<30%。方案预设的疼痛缓解探索性评估采用相同的麻醉性镇痛药使用阈值，但每周平均最严重疼痛NRS评分的替代阈值分别为下降≥50%以及下降至少达到最小临床重要性差值（MCID即2分）。在基线和第25周均未使用麻醉性镇痛药的患者视为麻醉性镇痛药使用增加<30%。为降低假阳性结果的可能我们采用单侧Fisher精确检验比较治疗组之间的缓解率百分比，统计学显著性阈值为p≤0.025。如果患者的评估结果缺失或可用数据不足则将其归为无应答者。在一项预设的支持性分析中我们采用重复测量混合模型比较了治疗组之间从基线至第25周时每周平均最严重疼痛NRS评分的平均变化。在该模型中基线的评分变化作为因变量，治疗组别、访视次数、治疗组别与访视次数的交互作用、研究中心所在地（美国与非美国）、基线最严重疼痛NRS评分以及基线评分与访视次数的交互作用作为自变量。由于基线后数据缺失不可忽视，我们进行了事后敏感性分析包括采用无条件跳转至参照和差值调整拐点分析比较两组从基线至第25周的变化，这些分析不依赖于随机缺失假设（补充数字内容1； http://links.lww.com /CORR /A904）。本研究的第二个目标是探讨在ENLIVEN试验第1部分中疼痛缓解与客观肿瘤缓解之间的关联。为此我们采用Pearson相关分析，评估从基线至治疗第25周的每周平均最严重疼痛NRS评分的变化与通过RECIST1.1版标准测量的肿瘤大小变化及肿瘤体积评分变化之间的相关性。本研究的最终目标是探讨疼痛缓解的持续性。通过分析在ENLIVEN开放标签扩展期（第2部分）接受培西达替尼治疗患者的疼痛缓解情况进行评估。为此，我们提供了第2部分中接受培西达替尼治疗25周和50周后，每周平均最严重疼痛NRS评分较基线变化的描述性统计数据。结果在ENLIVEN研究中培西达替尼治疗达到了何种程度的疼痛缓解？在疼痛缓解的主要评估指标上，培西达替尼组与安慰剂组之间未检测到统计学差异。该疼痛缓解定义为：从基线至第25周，每周平均疼痛NRS评分下降≥30%且麻醉性镇痛药使用增加<30%（培西达替尼组：31%[19/61][95%CI21%–44%]；安慰剂组：15%[9/59][95%CI8%–27%]；单侧p=0.03；显著性阈值为0.025）（表1）。在预设的探索性分析中采用最严重疼痛NRS评分下降≥50%的替代阈值（培西达替尼组：26%[16/61][95%CI17%–38%]比安慰剂组：10%[6/59][95%CI5%–20%]；单侧p=0.02）或下降达到MCID（≥2分）的阈值（培西达替尼组：31%[19/61][95%CI21%–44%]比安慰剂组：14%[8/59][95%CI7%–25%]；单侧p=0.02）时，培西达替尼组患者的缓解率均高于安慰剂组。从基线至第25周，每周平均最严重疼痛NRS评分的最小二乘均值变化在培西达替尼治疗组中大于安慰剂组（-2.5[95%CI-3.0至-1.9]比-0.3[95%CI-0.9至0.3]；p<0.001），尽管两组之间的均值差异（-2.2[95%CI-3.0至-1.4]）仅略大于下降2分的MCID（表1）。这一结果得到了事后敏感性分析的支持，包括采用无条件跳转至参照法处理缺失数据（最小二乘均值：-2.3[95%CI-2.9至-1.6]比-0.5[95%CI-1.2至0.2]；p<0.0001）同时也得到了转折点分析的支持。转折点分析显示使统计显著性丧失所需的Δ值（1.9）大于基于观测数据估计的治疗效应。表1：ENLIVEN试验第1部分结束时（第25周）疼痛评估较基线的变化：主要分析与探索性分析疼痛缓解与客观肿瘤缓解之间有何关联？每周平均最严重疼痛NRS评分的变化与RECIST1.1版标准测量的肿瘤缩小（r=0.44；p<0.001）及肿瘤体积评分（r=0.61；p<0.001）均呈中度相关性（图2）。相关图及个体最严重疼痛NRS评分随时间变化的蛛网图显示接受培西达替尼治疗的患者中出现疼痛增加的比例低于接受安慰剂的患者（补充图1；http://links.lww.com /CORR /A905）。图2 A-B这些图显示了最严重疼痛NRS评分变化与肿瘤缓解之间的相关性。肿瘤缓解采用RECIST1.1版进行评估，分别以（A）肿瘤直径之和和（B）肿瘤体积评分在第1部分试验结束时的结果作为指标；r=皮尔逊相关系数。疼痛缓解的持续性如何？在试验的第2部分中第1部分接受安慰剂的患者可以转为接受开放标签的培西达替尼治疗而第1部分接受培西达替尼的患者可以继续接受开放标签的培西达替尼治疗。总体而言，对于所有纳入第2部分的患者，在接受培西达替尼治疗25周后（91例中的51例），每周平均最严重疼痛NRS评分较基线的变化为-2.7±2.5；治疗50周后（91例中的32例）该变化为-3.2±2.3（表2）。当仅限于在第1部分即开始接受培西达替尼并继续治疗的患者时治疗25周后（61例中的33例）每周平均最严重疼痛NRS评分变化为-2.7±2.2，治疗50周后（61例中的22例）变化为-3.3±1.7。同样当仅限于第1部分接受安慰剂后转为培西达替尼治疗的患者时，接受培西达替尼治疗25周后（30例中的18例）变化为-2.6±3.1，治疗50周后（30例中的10例）变化为-2.8±3.4。表2：研究扩展期（第2部分）后疼痛缓解持久性的探索性分析讨论疼痛是TGCT患者的主要主诉之一，缓解疼痛是该肿瘤性及炎症性疾病管理中的迫切需求之一。鉴于培西达替尼能够为腱鞘巨细胞瘤患者带来客观的肿瘤缓解并改善其身体功能和关节僵硬，我们推测该药可能有助于缓解这些患者的疼痛。这项对ENLIVENIII期试验数据的二次分析显示在不适合从手术中获益的患者中培西达替尼带来的疼痛减轻总体上幅度较小，但偶尔也可见显著缓解。这表明适度的疼痛减轻可能是培西达替尼为这些患者带来的额外获益；然而由于这一结果基于一项随机试验的探索性评估，尚不足以支持将培西达替尼常规用于疼痛缓解。该结果也表明未来针对腱鞘巨细胞瘤疼痛缓解的研究应探讨患者自身认为有意义的改善指标以此替代或补充外部验证的评估工具。局限性本研究有两个主要局限性：一是未能在主要疼痛评估中显示出差异；二是最严重疼痛NRS评分在ENLIVEN研究中是次要结局指标。这意味着本研究的结果仅具有提示性而非结论性。另一个局限性是近半数患者的完整疼痛数据缺失，主要原因包括早期停药、电子数据采集的技术问题、研究机构及患者的依从性以及因肝毒性问题导致入组在接近目标时提前终止。结合样本量较小的因素，本研究因此评估最严重疼痛NRS评分差异的把握度不足。此外本研究的另一局限在于：由于高达80%接受培西达替尼治疗的患者会出现可逆的头发变浅现象，可能导致盲法设计受到干扰。同样研究扩展期的开放标签设计也可能影响了支持疼痛缓解持续性的结果。最后非甾体抗炎药（NSAID）使用的影响尚不明确，因其未纳入缓解定义中。因此要验证当前结果，需要一项专门设计用于评估疼痛并同时限制潜在偏倚影响的研究。此外本研究纳入的人群总体具有TGCT患者的代表性特征包括女性比例较高、平均年龄大于40岁以及膝关节为最常受累关节。然而TGCT是一种罕见疾病因此本研究人群规模较小，无法按亚组（例如按性别或年龄）分析缓解率的差异。在ENLIVEN研究中培西达替尼治疗达到了何种程度的疼痛缓解？总体而言当前结果表明，对于选择不接受手术或不适合手术的TGCT患者，培西达替尼可能提供适度的疼痛缓解，其程度略大于最小临床重要性差值（MCID）。靶向集落刺激因子-1受体的单克隆抗体Emactuzumab以及集落刺激因子-1受体酪氨酸激酶抑制剂甲磺酸伊马替尼在回顾性研究中也显示出可改善TGCT症状，但疼痛缓解的具体程度尚未见报道。事实上，据我们所知，ENLIVEN是唯一一项纳入了针对疼痛的患者报告结局指标的随机临床试验。主要分析与探索性分析的不同结果提示，疼痛缓解的阈值需要谨慎选择。具体而言虽然根据疼痛NRS评分改善≥30%的主要阈值，培西达替尼并未显示出优于安慰剂的获益，但根据改善≥50%以及改善≥2分（即MCID）的探索性阈值，培西达替尼确实显示出优于安慰剂的获益。重复测量分析及相关的敏感性分析也支持培西达替尼与安慰剂之间存在差异。主要阈值与探索性阈值之间的这种差异，很可能是由于显著的安慰剂效应（这在临床疼痛研究中很常见）加之相对较小的样本量所致。因此，针对该人群的临床试验可能需要采用更高的疼痛缓解阈值。这些结果也凸显了单维度测量指标（如最严重疼痛NRS评分及其他指标）及汇总报告疼痛的局限性。可能需要更精细、多维度的疼痛评估方法以更好地捕捉患者的体验。疼痛缓解与客观肿瘤缓解之间有何关联？接受培西达替尼治疗患者的疼痛缓解与客观肿瘤缓解呈中度相关性。同样我们近期在ENLIVEN研究中发现，僵硬感和身体功能的改善与客观肿瘤缓解也存在相关性。在少数接受培西达替尼治疗的患者中（33例中的3例）疼痛无明显变化或略有加重，这可能源于残留肿瘤对周围组织的影响、继发性骨关节炎、持续性滑膜炎、基础退行性关节疾病或既往手术的后遗症。然而未发现与疾病进展相关的疼痛加重。疼痛缓解的持续性如何？基于开放标签扩展期的结果，疼痛缓解似乎至少可持续50周。在交叉接受活性药物治疗的患者中最初25周治疗期间的疼痛缓解程度与最初随机分配至培西达替尼组的患者相似。因此接受半年的安慰剂治疗似乎并未影响患者在开始接受研究药物后的疼痛缓解效果。然而由于研究扩展期开放标签设计的局限性，这些结果仅具有提示性。结论疼痛是TGCT患者最重要的症状且常因继发性退行性关节炎而加剧。特别是当TGCT患者选择不接受手术或不适合手术时缩小肿瘤和缓解疼痛的需求尤为迫切。临床医生必须考虑系统性药物治疗的替代方案包括手术（具有实际风险）、对疾病进展和关节破坏采取观察等待策略以及放射治疗（可能引起局部并发症甚至继发性肉瘤）。这些替代方案的局限性使得全身性治疗具有吸引力，尽管目前尚缺乏其长期保护关节能力及潜在不良反应的数据。当TGCT不适合手术（否则将导致不可接受的并发症）时应考虑使用培西达替尼因其具有使肿瘤缩小、改善身体功能和僵硬感的能力，但这必须与其肝毒性风险相权衡。基于本项研究适度的疼痛减轻（程度仅略大于MCID）可能是培西达替尼为这些患者带来的额外获益然而目前的研究结果尚不足以支持将培西达替尼常规用于疼痛缓解。 PMID：36001000 DOI：10.1097/CORR.0000000000002335 原文链接： https://pubmed.ncbi.nlm.nih.gov/36001000/（可点击左下角阅读原文进行查看）翻译：付美红校对：陈挺编辑：黄静赞终审：商冠宁付美红锦州医科大学 2023级学术型研究生盛京医院骨与软组织肿瘤科知名专家门诊信息商冠宁周一上午：知名专家门诊4楼B区29诊室周三上午：知名专家门诊4楼A区09诊室门诊信息门诊地址：南湖院区(和平区三好街36号 )： 1号楼B座6楼外科门诊D区8诊室病房地址：滑翔院区(铁西区滑翔路39号 )： 2号楼5楼骨与软组织肿瘤科病房

2026-04-13

·EndPoints

Neomorph raises $100M for molecular glues; Spyre's ulcerative colitis data

Plus, news about AbbVie, SynOx, Eli Lilly’s Jaypirca, ImageneBio, Nxera Pharma, Neurocrine and Novartis: Neomorph raises $100M more for molecular glues : San Diego-based Neomorph has raised a $100 million Series B round led by its founding investor, Deerfield Management. The startup dosed its first patient in February in a trial of NEO-811, its lead molecular glue degrader that targets a hard-to-drug driver of a type of kidney cancer. Neomorph has also signed research deals with Biogen, AbbVie and Novo Nordisk since emerging from stealth in December 2020 with a $109 million Series A round. — Andrew Dunn Spyre’s positive ulcerative colitis results: Spyre Therapeutics’ experimental antibody SPY001 met the primary endpoint in the first part of a Phase 2 trial, showing a statistically significant reduction from baseline on a scale used to measure ulcerative colitis disease activity. The first part of the trial was an open-label induction period testing three of Spyre’s antibodies as monotherapies. Induction data from the other two candidates, SPY002 and SPY003, are expected later this year. The next phase of the trial will test the antibodies alone and in combinations against a placebo. SPY001 is designed to improve on Takeda’s blockbuster Entyvio, which has been approved for ulcerative colitis since 2014. Spyre’s stock $SYRE climbed 26% Monday morning. — Nicole DeFeudis AbbVie licenses non-opioid pain drugs from China: The US drugmaker is paying $30 million upfront for the ex-China rights to two analgesic candidates developed by Haisco Pharmaceutical Group. Haisco is also eligible for up to $705 million in milestones and tiered royalties on sales. The two assets, known as HSK55718 and HSK51155, have been engineered to target the Nav1.8 sodium channel. — Ayisha Sharma SynOx plans FDA filing for rare tumor type: The biotech announced on Monday that its drug emactuzumab passed a Phase 3 trial in tenosynovial giant cell tumor, or TGCT. The non-malignant growths typically occur in the knee, hip or ankle joints, and cause loss of function, pain or stiffness. Emactuzumab met the primary endpoint of objective response rate, as well as key secondary endpoints such as improvement in pain and physical function. The drug was designed to be a “short-course” alternative to chronic treatment, and patients in the Phase 3 trial were given five doses over an eight-week period. SynOx said it will bring the results to the FDA in the second half of this year. — Nicole DeFeudis Lilly touts new Jaypirca data in CLL: Adding Eli Lilly’s BTK inhibitor Jaypirca to Venclexta (venetoclax) and rituximab significantly improved patients’ progression-free survival compared to the venetoclax and rituximab combination alone, Lilly said on Monday. The open-label trial enrolled patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Treatment in both arms was “time-limited,” meaning it had an end date. Patients received treatment for up to two years, then took no treatment until their disease progressed. Lilly didn’t spell out the full data, but its oncology president Jacob Van Naarden said in a news release that Jaypirca “outperformed our expectations.” Lilly said it plans to submit the data to regulators later this year in hopes of a label expansion. — Nicole DeFeudis ImageneBio raises $30M: The private placement will fund the development of Imagene’s lead drug IMG-007 in alopecia areata and atopic dermatitis. The monoclonal antibody is currently in a Phase 2b trial for atopic dermatitis. Coastlands Capital led the financing, with participation from other investors including Trails Edge Capital Partners, Omega Funds and OrbiMed. — Nicole DeFeudis Nxera secures $22.5M milestone from Neurocrine: The payment was triggered by Neurocrine Biosciences dosing the first patient in a Phase 2 schizophrenia trial testing a drug called NBI-570, which was discovered using Nxera’s NxWave platform. The two companies entered a collaboration in 2021 that could be worth up to $2.7 billion. — Ayisha Sharma Novartis to lay off 114 staffers in New Jersey: The Swiss drugmaker disclosed the staff cuts in East Hanover, which will take effect from June to November, in a WARN notice for the state. Novartis did not immediately respond to a request for comment. — Ayisha Sharma

2026-04-13

·FierceBiotech

BioNTech, SynOx plot paths to FDA as trials hit goals in competitive tumor types

BioNTech and SynOx plan to file for FDA approvals this year.\n The fight for two tumor types is poised to intensify, with BioNTech lining up a challenge to AstraZeneca, while SynOx Therapeutics is planning to enter a market served by companies including Daiichi Sankyo.BioNTech’s data come from a phase 2 trial of its Duality Biologics-partnered antibody-drug conjugate (ADC) trastuzumab pamirtecan. The biotech reported a 49.3% response rate to the HER2-targeted ADC in a phase 2 cohort of 73 patients with HER2-expressing, advanced endometrial cancer who progressed on or after first-line chemotherapy and checkpoint inhibitor therapy, hitting its primary endpoint.The primary analysis cohort was part of a broader study that included people without prior exposure to checkpoint inhibitor therapy. Across all 96 centrally tested patients, BioNTech reported a response rate of 47.9% and median progression-free survival of 8.1 months. The response rate fell to 44.1% in the full, 143-patient cohort, which included patients tested for HER2 at their trial site or local laboratory. BioNTech said the safety profile was manageable and as expected for HER2-targeted ADCs. Almost 47% of patients had grade 3 or greater treatment-related adverse events. Almost 5% of patients had grade 3 or greater interstitial lung disease (ILD) or pneumonitis. AstraZeneca and Daiichi’s HER2-directed ADC Enhertu carries a boxed warning for ILD and pneumonitis. The FDA approved Enhertu in adults with unresectable or metastatic HER2-positive solid tumors in 2024. The tumor-agnostic authorization was supported (PDF) by data including a 56.3% response rate in 16 endometrial cancer patients. BioNTech, which hailed its trial as the largest in the indication, plans to file for FDA approval this year.Separately, SynOx aims to file for FDA approval of emactuzumab in tenosynovial giant cell tumor (TGCT) patients in the second half of the year. SynOx outlined the plan as part of the release of phase 3 data on the CSF1R inhibitor, which achieved a significantly better response rate than placebo at Month 6 to hit the primary endpoint. The biotech also reported hits on secondary endpoints.Daiichi won FDA approval for a CSF1R inhibitor, Turalio, in TGCT in 2019. Last year, Ono Pharmaceutical got the green light to sell a rival drug, Romvimza, that it acquired in its $2.4 billion takeover of Deciphera. Merck KGaA filed for FDA approval of another CSF1R inhibitor, pimicotinib, in the indication in January. Having ceded a head start to rivals, SynOx is positioning the former Roche antibody emactuzumab as a differentiated, short-course treatment. Phase 3 participants received emactuzumab intravenously every two weeks for eight weeks. Turalio (PDF) and Romvimza (PDF) are given orally, respectively twice daily and twice weekly. Merck tested once-daily pimicotinib in its phase 3 trial.

临床结果上市批准临床3期抗体药物偶联物临床2期

100 项与 Emactuzumab 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D11234	Emactuzumab	-	DB14905

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
腱鞘巨细胞瘤	临床3期	美国	Synox Therapeutics Ltd.	2024-10-09
腱鞘巨细胞瘤	临床3期	比利时	Synox Therapeutics Ltd.	2024-10-09
腱鞘巨细胞瘤	临床3期	加拿大	Synox Therapeutics Ltd.	2024-10-09
腱鞘巨细胞瘤	临床3期	法国	Synox Therapeutics Ltd.	2024-10-09
腱鞘巨细胞瘤	临床3期	意大利	Synox Therapeutics Ltd.	2024-10-09
腱鞘巨细胞瘤	临床3期	荷兰	Synox Therapeutics Ltd.	2024-10-09
腱鞘巨细胞瘤	临床3期	韩国	Synox Therapeutics Ltd.	2024-10-09
腱鞘巨细胞瘤	临床3期	西班牙	Synox Therapeutics Ltd.	2024-10-09
腱鞘巨细胞瘤	临床3期	瑞典	Synox Therapeutics Ltd.	2024-10-09
腱鞘巨细胞瘤	临床3期	瑞士	Synox Therapeutics Ltd.	2024-10-09

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02323191 (Pubmed \| J Immunother Cancer)	临床1期	晚期恶性实体瘤	221	Emactuzumab + Atezolizumab	積廠願鏇構齋願網築窪(糧製衊蓋醖淵醖襯膚範) = Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each) 顧蓋範構製築糧壓築遞 (襯襯範鹽鏇窪範衊鹹繭 )	积极	2022-05-01
NCT01494688 (Pubmed \| Eur J Cancer Care (Engl) \| Eur J Cancer) 人工标引	临床1期	色素沉着的绒毛结节性滑膜炎	63	Emactuzumab	廠構艱艱構鏇衊製鏇鑰(鑰範蓋鏇齋艱積遞鏇網) = pruritus, asthenia and oedema 觸餘獵觸簾憲製鏇選鬱 (願積網築製廠壓願糧蓋 )	积极	2020-12-01
NCT01494688 (Pubmed \| Ann Oncol) 人工标引	临床1期	实体瘤	99	paclitaxel+emactuzumab	鏇選網簾糧積網憲壓壓(製壓鏇構選壓齋築鹹繭) = No maximum tolerated dose was reached in either study arm 夢膚蓋醖願鬱鹽觸獵夢 (蓋築獵鹽製選衊餘遞鬱 )	不佳	2019-08-01
NCT01494688 (Pubmed \| Ann Oncol) 人工标引	临床1期	实体瘤	99	emactuzumab		不佳	2019-08-01
NCT01494688 (Pubmed \| Lancet Oncol) 人工标引	临床1期	巨细胞瘤	25	emactuzumab	衊憲獵遞餘膚觸網糧壓(憲鏇構構獵獵選膚壓鬱) = 5 events in 5 pts [lupus erythematosus（2 pts）, periorbital oedema（1 pt）, erythema（1 pt）, dermohypodermitis（1 pt）] 範獵夢衊窪獵觸鏇餘齋 (構簾網範範衊膚鬱築願 ) 更多	积极	2015-08-01