There are currently no standard first-line treatment options for patients with higher grade 2–3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [Lu]Lu-DOTA-TATE (Lu-Dotatate) treatment. NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 3) and origin (pancreas other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with , , and is active and not recruiting. Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7–13·8) in the control group and 22·8 months (19·4–not estimated) in the Lu-Dotatate group (stratified hazard ratio 0·276 [0·182–0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. First-line Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. Advanced Accelerator Applications, a Novartis Company.

中文翻译：

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[177Lu]Lu-DOTA-TATE 加长效奥曲肽与高剂量长效奥曲肽治疗新诊断的晚期 2-3 级、分化良好的胃肠胰神经内分泌肿瘤 (NETTER-2)：开放式标签、随机、3 期研究


对于 2-3 级、分化良好的晚期胃肠胰神经内分泌肿瘤患者，目前尚无标准的一线治疗选择。我们的目的是研究一线 [Lu]Lu-DOTA-TATE (Lu-Dotatate) 治疗的有效性和安全性。 NETTER-2 是一项开放标签、随机、平行组、优效性 3 期试验。我们纳入了新诊断的较高 2 级（Ki67 ≥10% 且≤20%）和 3 级（Ki67 >20% 且≤55%）、生长抑素受体阳性（在所有目标病变中）、来自北美、欧洲和亚洲 9 个国家 45 个中心的晚期胃肠胰腺神经内分泌肿瘤。我们使用交互式响应技术随机分配 (2:1) 患者接受四个周期（周期间隔为 8 周 ± 1 周）静脉注射 Lu-Dotatate 加肌肉注射奥曲肽 30 mg 长效可重复 (LAR)，然后奥曲肽 30 mg LAR每 4 周一次（Lu-Dotatate 组）或每 4 周一次高剂量奥曲肽 60 mg LAR（对照组），按神经内分泌肿瘤分级（2-3）和来源（胰腺其他）分层。在基线、第 16 周和第 24 周进行肿瘤评估，然后每 12 周进行一次，直到疾病进展或死亡。主要终点是通过盲法、独立、中心放射学评估得出的无进展生存期。我们对 101 个无进展生存事件进行了初步分析，作为最终的无进展生存分析。 NETTER-2 已在 、 、 注册，并且处于活动状态且未招募。 2020年1月22日至2022年10月13日期间，我们筛查了261名患者，其中35名（13%）被排除在外。我们将 226 名 (87%) 患者（121 [54%] 男性和 105 [46%] 女性）随机分配至 Lu-Dotatate 组 (n=151 [67%]) 和对照组 (n=75 [33%]) ）。 对照组的中位无进展生存期为 8·5 个月（95% CI 7·7–13·8），Lu-Dotatate 组的中位无进展生存期为 22·8 个月（19·4 - 未估计）（分层风险比为 0） ·276 [0·182–0·418]；p<0·0001)。治疗期间，Lu-Dotatate 组 147 名治疗患者中有 136 名（93%）发生不良事件（任何级别），对照组 73 名治疗患者中有 69 名（95%）发生不良事件。治疗期间没有发生与研究药物相关的死亡。一线 Lu-Dotatate 联合奥曲肽 LAR 显着延长 2 级或 3 级晚期胃肠胰腺神经内分泌肿瘤患者的中位无进展生存期（延长 14 个月）。 Lu-Dotatate 应被视为该人群一线治疗的新护理标准。高级加速器应用，诺华公司。