177u - dotatate与大剂量长效奥曲肽治疗晚期1-2级分化良好的胃肠胰腺神经内分泌肿瘤（XT-XTR008-3-01）：一项开放标签、随机化的III期试验

IF 65.4 1区医学 Q1 ONCOLOGY

Annals of Oncology Pub Date : 2025-12-31 DOI:10.1016/j.annonc.2025.08.3758

J Xu, J Chen, S Song, L Song, R Wang, J Hao, X Du, D Cao, Y Gao, X Lan, A Yang, W Miao, H Xu, Y Chen, L Li, H Shi, X Yuan, F Ye, J Wang, N Xu, X Han, X Li, R Huang, T Zhang, E Li, R Wang, Y Zhou, H Chen, X Zhu, J Zhao, X Su, Y Cui, P Ren, P Wang

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引用次数: 0

摘要

背景：III期试验XT-XTR008-3-01是一项随机对照试验（RCT），评估了XTR008的有效性和安全性，XTR008是一种新型无载体添加的镥-177 (177Lu)-Dotatate，首次用于各种来源的胃肠胰神经内分泌肿瘤（GEP-NETs）的后期治疗设置。患者和方法：随机化前12个月内进展的1-2级，不可切除，局部晚期或转移性GEP-NETs患者被随机分配为1:1至XTR008（每8周4个周期）或奥曲肽60mg（每4周），根据原发肿瘤部位（胰腺与非胰腺），病理肿瘤分级（1与2）和既往生长抑素类似物治疗持续时间（≤6个月与bbb6个月）分层。主要终点是一个盲法独立审查委员会的无进展生存期（PFS）。主要次要终点包括总缓解率（ORR）；总生存期（OS）；生活质量，使用欧洲癌症研究和治疗组织生活质量问卷QLQ-C30和QLQ-GI.NET21进行评估；安全;药物动力学;和剂量测定法。结果：患者（N = 196）随机分为XTR008组（N = 99）和对照组（N = 97）。原发肿瘤部位：胰腺（59%），直肠（28%），中肠（7%）。中位随访：11.1个月[四分位数间距（IQR） 8.5-11.5, XTR008] vs . 10.2个月（IQR 8.5-11.9个月，对照组）。78例PFS事件，中位PFS未达到[95%置信区间（CI） 16.13个月至未估计]，而5.8个月（95% CI 5.65-8.41个月）；分层风险比（HR） 0.06 （P < 0.0001）。ORR: 43.4% (95% CI 33.50% ~ 53.77%) vs . 1.0% （95% CI 0.03% ~ 5.61%）。两组的OS数据均不成熟，XTR008表现出更长的生存趋势（HR 0.24, P = 0.0550）。治疗相关不良事件：98%对89%；严重不良事件：16.3%对12.5%（6.1%对3.1%与药物相关）。XTR008组中1%的患者出现骨髓增生异常综合征和≥3级肾毒性；未发生急性髓性白血病或药物相关死亡。结论：在所有来源的晚期GEP-NET肿瘤的后期治疗中，XTR008单药治疗与高剂量长效可重复（LAR）奥曲肽单药治疗相比，疗效更佳，安全性可控，支持其作为一种新的治疗选择。

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¹⁷⁷Lu-Dotatate versus high-dose long-acting octreotide for the treatment of patients with advanced, grade 1-2, well-differentiated gastroenteropancreatic neuroendocrine tumours (XT-XTR008-3-01): an open-label, randomised, phase 3 trial.

Background: The phase 3 XT-XTR008-3-01 trial evaluated the efficacy and safety of XTR008, a novel no-carrier-added ¹⁷⁷Lu-Dotatate, in later-line therapy setting for gastroenteropancreatic neuroendocrine tumours (GEP-NETs) of all origins for the first time.

Patients and methods: Patients with grade 1-2, unresectable, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs) who had progressed within the last 12 months before randomization were randomly allocated 1:1 to XTR008 (4 cycles every 8 weeks) or octreotide 60 mg LAR (every 4 weeks), stratified by primary tumour site (pancreatic vs non-pancreatic), pathological tumour grade (1 vs 2), and duration of prior somatostatin analogues treatment (≤6 vs >6 months). Primary endpoint was progression-free survival (PFS) by a blinded independent review committee (BIRC). The key second endpoints included overall response rate (ORR), overall survival (OS), quality of life by EORTC QLQ-C30 and QLQ-GI.NET21 questionnaires, safety, pharmacokinetics and dosimetry.

Results: 196 patients were randomized to XTR008 (n=99) or control (n=97). Primary tumour sites: pancreas (59%), rectum (28%), midgut (7%). Median follow-up: 11.1 months (IQR 8·5-11·5, XTR008) vs 10.2 months (IQR 8·5-11·9, control). With 78 PFS events, median PFS was not reached (95% CI 16.13-not estimated) vs 5.8 months (95% CI 5.65-8.41); stratified HR 0.06 (p<0.0001). ORR: 43.4% (95%CI 33.50-53.77) vs 1.0% (95% CI 0.03-5.61). Overall survival (OS) data was immature for both groups, with XTR008 showing longer survival trend (HR 0.24, p=0.0550). Treatment-related adverse events (TRAEs): 98% vs 89%; SAEs: 16.3% vs 12.5% (6.1% vs 3.1% drug-related). Myelodysplastic syndrome and grade ≥3 renal toxicity occurred in 1% patients in XTR008 group; no acute myeloid leukemia or drug-related deaths.

Conclusions: XTR008 monotherapy showed superior efficacy versus high-dose octreotide long-acting repeatable in advanced gastroenteropancreatic neuroendocrine tumors of all origins in later-line treatment setting, with manageable safety, supporting its use as a new treatment option.

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来源期刊

Annals of Oncology 医学-肿瘤学

CiteScore

63.90

自引率

1.00%

发文量

3712

审稿时长

2-3 weeks

期刊介绍： Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine. The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings. Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.