Abstract：
BACKGROUND: 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 [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment.
METHODS: 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 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs 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 ClinicalTrials.gov, NCT03972488, and is active and not recruiting.
RESULTS: 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 177Lu-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 177Lu-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 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period.
CONCLUSIONS: First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population.
BACKGROUND: Advanced Accelerator Applications, a Novartis Company.
METHODS: 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 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs 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 ClinicalTrials.gov, NCT03972488, and is active and not recruiting.
RESULTS: 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 177Lu-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 177Lu-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 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period.
CONCLUSIONS: First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population.
BACKGROUND: Advanced Accelerator Applications, a Novartis Company.
摘要：
背景：对于2-3级较高，分化良好的患者，目前尚无标准的一线治疗选择，先进,胃肠胰腺神经内分泌肿瘤。我们旨在研究一线[177Lu]Lu-DOTA-TATE（177Lu-Dotatate）治疗的疗效和安全性。
方法：NETTER-2是一个开放标签，随机化，平行组，优越性,第三阶段试验。我们招募了新诊断为2级以上（Ki67≥10％且≤20％）和3级（Ki67>20％且≤55％）的患者（年龄≥15岁），生长抑素受体阳性（在所有靶病变中），来自北美9个国家45个中心的晚期胃肠胰腺神经内分泌肿瘤，欧洲,和亚洲。我们使用交互式反应技术随机分配（2：1）患者接受四个周期（周期间隔为8周±1周）的静脉177Lu-Dotatate加肌内奥曲肽30mg长效可重复（LAR），然后奥曲肽30mgLAR每4周（177Lu-Dotatate组）或高剂量奥曲肽60mgLAR每4周（对照组），按神经内分泌肿瘤分级（2比3）和起源（胰腺与其他）分层。肿瘤评估是在基线时进行的，第16周和第24周，然后每12周一次，直到疾病进展或死亡。主要终点是盲法无进展生存期，独立,中央放射学评估。我们对101例无进展生存事件进行了主要分析，作为最终的无进展生存分析。NETTER-2在ClinicalTrials.gov注册，NCT03972488，并且是活跃的，没有招募。
结果：在2020年1月22日至2022年10月13日之间，我们筛选了261名患者，35人（13%）被排除在外。我们将226例（87％）患者（男性121例[54％]，女性105例[46％]）随机分为177Lu-Dotatate组（n=151例[67％]）和对照组（n=75例[33％]）。对照组的中位无进展生存期为8·5个月（95％CI7·7-13·8），177Lu-Dotatate组为22·8个月（19·4-未估计）（分层风险比0·276[0·182-0·418]；p<0·0001）。在治疗期间,177Lu-Dotatate组147例接受治疗的患者中有136例(93%)发生了不良事件(任何级别),对照组73例接受治疗的患者中有69例(95%)发生了不良事件.在治疗期间没有研究药物相关的死亡。
结论：一线177Lu-Dotatate联合奥曲肽LAR可显著延长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）。177Lu-Dotatate应被视为该人群一线治疗的新标准。
背景：高级加速器应用，诺华公司。
方法：NETTER-2是一个开放标签，随机化，平行组，优越性,第三阶段试验。我们招募了新诊断为2级以上（Ki67≥10％且≤20％）和3级（Ki67>20％且≤55％）的患者（年龄≥15岁），生长抑素受体阳性（在所有靶病变中），来自北美9个国家45个中心的晚期胃肠胰腺神经内分泌肿瘤，欧洲,和亚洲。我们使用交互式反应技术随机分配（2：1）患者接受四个周期（周期间隔为8周±1周）的静脉177Lu-Dotatate加肌内奥曲肽30mg长效可重复（LAR），然后奥曲肽30mgLAR每4周（177Lu-Dotatate组）或高剂量奥曲肽60mgLAR每4周（对照组），按神经内分泌肿瘤分级（2比3）和起源（胰腺与其他）分层。肿瘤评估是在基线时进行的，第16周和第24周，然后每12周一次，直到疾病进展或死亡。主要终点是盲法无进展生存期，独立,中央放射学评估。我们对101例无进展生存事件进行了主要分析，作为最终的无进展生存分析。NETTER-2在ClinicalTrials.gov注册，NCT03972488，并且是活跃的，没有招募。
结果：在2020年1月22日至2022年10月13日之间，我们筛选了261名患者，35人（13%）被排除在外。我们将226例（87％）患者（男性121例[54％]，女性105例[46％]）随机分为177Lu-Dotatate组（n=151例[67％]）和对照组（n=75例[33％]）。对照组的中位无进展生存期为8·5个月（95％CI7·7-13·8），177Lu-Dotatate组为22·8个月（19·4-未估计）（分层风险比0·276[0·182-0·418]；p<0·0001）。在治疗期间,177Lu-Dotatate组147例接受治疗的患者中有136例(93%)发生了不良事件(任何级别),对照组73例接受治疗的患者中有69例(95%)发生了不良事件.在治疗期间没有研究药物相关的死亡。
结论：一线177Lu-Dotatate联合奥曲肽LAR可显著延长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）。177Lu-Dotatate应被视为该人群一线治疗的新标准。
背景：高级加速器应用，诺华公司。
