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 III trial.

patients_and_methods

Patients with grade 1-2, unresectable, locally advanced or metastatic GEP-NETs who had progressed within the last 12 months before randomisation were randomly allocated 1 : 1 to XTR008 (four cycles every 8 weeks) or octreotide 60 mg (every 4 weeks), stratified by primary tumour site (pancreatic versus non-pancreatic), pathological tumour grade (1 versus 2), and duration of prior somatostatin analogues treatment (≤6 versus >6 months).

在随机分组前12个月内疾病进展的1-2级、不可切除的局部晚期或转移性GEP-NETs患者，被随机1:1分配接受XTR008（每8周四个周期）或奥曲肽60毫克（每4周一次），根据原发肿瘤部位（胰腺与非胰腺）、病理肿瘤分级（1级与2级）以及先前使用生长抑素类似物治疗的持续时间（≤6个月与>6个月）进行分层。

The primary endpoint was progression-free survival(PFS) by a blinded independent review committee.

主要终点是由双盲独立评审委员会评估的无进展生存期（PFS）

The key secondary endpoints included overall response rate (ORR); overall survival(OS); quality of life, evaluated using the European Organisation for Research and Treatment of Cancer quality of life questionnaires QLQ-C30 and QLQ-GI.NET21; safety; pharmacokinetics; and dosimetry.

关键次要终点包括总体反应率（ORR）；总生存（OS）；生活质量，使用欧洲癌症研究与治疗组织的生活质量问卷QLQ-C30和QLQ-GI.NET21进行评估；安全性；药物动力学；以及剂量测定。

Results

Patients (N = 196) were randomized to XTR008 (n = 99) or control (n = 97).

患者（N = 196）被随机分配到XTR008（n = 99）或对照组（n = 97）。

Primary tumour sites: pancreas (59%), rectum (28%), midgut (7%).

原发肿瘤部位：胰腺（59%），直肠（28%），中肠（7%）。

Median follow-up: 11.1 months [interquartile range (IQR) 8.5-11.5, XTR008] versus 10.2 months (IQR 8.5-11.9 months, control).

中位随访时间：XTR008组为11.1个月[四分位数范围（IQR）8.5-11.5]，对照组为10.2个月（IQR 8.5-11.9个月）。

With 78 PFS events, median PFS was not reached [95% confidence interval(CI) 16.13 months to not estimated] versus 5.8 months (95% CI 5.65-8.41 months); stratified hazard ratio(HR) 0.06 (P < 0.0001).

在发生78次无进展生存（PFS）事件的情况下，XTR008组的中位无进展生存期未达到[95%置信区间（CI）16.13个月至未估计]，而对照组为5.8个月（95% CI 5.65-8.41个月）；分层风险比（HR）为0.06（P < 0.0001）。

ORR: 43.4% (95% CI 33.50% to 53.77%) versus 1.0% (95% CI 0.03% to 5.61%).

客观缓解率（ORR）：43.4%（95%置信区间 33.50% 至 53.77%）对比 1.0%（95%置信区间 0.03% 至 5.61%）。

OS data were immature for both groups, with XTR008 showing a longer survival trend (HR 0.24, P = 0.0550).

两组的总生存（OS）数据尚未成熟，但XTR008显示出更长生存期的趋势（风险比 HR 0.24，P = 0.0550）。

Treatment-related adverse events: 98% versus 89%; serious adverse events: 16.3% versus 12.5% (6.1% versus 3.1% drug-related).

治疗相关不良事件：98%对比89%；严重不良事件：16.3%对比12.5%（其中药物相关为6.1%对比3.1%）。

Myelodysplastic syndrome and grade ≥3 renal toxicity occurred in 1% of patients in the XTR008 group; no acute myeloid leukaemia or drug-related deaths occurred.

XTR008组中有1%的患者出现骨髓增生异常综合征和3级或以上的肾毒性；没有发生急性髓细胞性白血病或与药物相关的死亡事件。

Conclusions

XTR008 monotherapy showed superior efficacy versus high-dose long-acting repeatable (LAR) octreotide monotherapy in advanced GEP-NET tumours of all origins in a later-line treatment setting, with manageable safety, supporting its use as a new treatment option.

XTR008单药治疗在晚期胃肠道神经内分泌肿瘤（GEP-NET）的所有起源中显示出比高剂量长效可重复（LAR）奥曲肽单药治疗更好的疗效，在后期治疗环境中，安全性可控，支持其作为新的治疗选择。