南宫体育：ASCO GI 2024丨[177Lu]Lu-DOTATATE是高分化神经内分泌肿瘤潜在一线治疗（NETTER-2研究）南宫体育官方网站

　　编者按

　　2024年美国临床肿瘤学会胃肠道肿瘤研讨会（2024 ASCO Gastrointestinal Cancers Symposium，ASCO GI 2024）已于美国当地时间1月18～20日在旧金山召开。现介绍入选肝胆胰口头报告专场的探索胃肠胰神经内分泌肿瘤一线治疗的3期随机NETTER-2研究的初步分析结果（LBA588），以飨读者！

　　背景

　　目前，对于高级别、高分化的胃肠胰神经内分泌肿瘤（GEP-NETs），还没有普遍接受的一线（1L）治疗方法，这些患者的医疗需求仍未得到满足。放射配体治疗（RLT）是一种创新的癌症治疗方法，跨越了传统的全身、放射或手术治疗领域。3期NETTER-2研究（NCT03972488）评估[177Lu]Lu-DOTA-TATE（以下简称177Lu-DOTATATE）作为（G）2级和G3级晚期GEP-NETs患者的1L治疗。这是第一个评估 RLT在实体肿瘤中的1L应用的试验。

　　方法

　　入组前6个月内新诊断为生长抑素受体阳性高G2或G3（Ki-67≥10%和≤55%）晚期GEP-NETs为符合条件的患者。患者随机（2:1）接受4个周期的177Lu-DOTATATE（4×7.4 GBq）加30 mg奥曲肽长效释放剂（LAR）（在177Lu-DOTATATE治疗期间每8周一次），然后每4周一次（177Lu-DOTATATE组），或每4周60 mg奥曲肽长效释放剂（对照组），按级别（G2 vs. G3）和肿瘤起源（胰腺 vs. 其他）分层。主要终点是无进展生存期（PFS），使用RECIST 1.1进行评估。客观缓解率（ORR）是一个关键的次要终点，在PFS后进行分层测验。

　　结果

　　226例患者被随机分配到177Lu-DOTATATE组(n=151)或对照组(n=75)。大多数肿瘤起源于胰腺（54.4%）或小肠（29.2%）；35.0%的患者报告G3肿瘤。177Lu-DOTATATE的中位累积剂量为29.2 GBq, 87.8%的患者接受了所有4次剂量。中位PFS（95%CI）显著延长约14.3个月，从对照组的8.5个月（7.7～13.8个月）延长至177Lu-DOTATATE组的22.8个月（19.4个月～NE）；分层风险比0.276 (95%CI：0.182~0.418；P<0.0001)。177Lu-DOTATATE组的ORR（43.0%）显著高于对照组（9.3%）；分层优势比7.81 (95%CI：3.32~18.4；P<0.0001)。PFS和ORR结果在所有预先指定的人口和预后亚组中是一致的。在RLT特别关注的不良事件中，在177Lu-DOTATATE组中，G3/4型白细胞减少症、贫血和血小板减少症各发生≤3例。报告1例骨髓增生异常综合征（177Lu-DOTATATE组）。

　　结论

　　与大剂量奥曲肽长效释放剂相比，177Lu-DOTATATE可显著延长新诊断的晚期G2和G3 GEP-NETs患者的PFS，并显示出具有临床意义的ORR。安全性符合177Lu-DOTATATE的既定特征。这是第一个证明RLT治疗任何恶性肿瘤疗效的随机研究，将改变临床实践。在其他情况下，RLT作为治疗选择的进一步研究是有必要的。临床试验信息：NCT03972488。

　　摘要原文

　　[177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study

　　Background:Currently, there is no universally accepted first line (1L) therapy for higher grade, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and an unmet medical need remains in these patients (pts). Radioligand therapy (RLT) is an innovative cancer treatment that crosses the traditional domains of systemic, radiation or surgical therapies. The Phase 3 NETTER-2 study (NCT03972488) evaluated [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) as 1L treatment in pts with Grade (G) 2 and G3 advanced GEP-NETs. This is the first trial to assess 1L RLT in any solid tumor.

　　Methods:Eligible pts were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki-67 ≥10% and ≤55%) advanced GEP-NETs within the last 6 months prior to enrollment. Pts were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq) plus 30 mg octreotide long-acting release (LAR) at 8-weekly intervals during 177Lu-DOTATATE treatment then every 4 weeks (177Lu-DOTATATE arm), or 60 mg octreotide LAR every 4 weeks (control arm), stratified by grade (G2 vs G3) and tumor origin (pancreas vs other). The primary endpoint was progression-free survival (PFS), centrally assessed using RECIST 1.1. Objective response rate (ORR), a key secondary endpoint, was tested hierarchically after PFS.

　　Results:Overall, 226 pts were randomized to the 177Lu-DOTATATE (n = 151) or control (n = 75) arms. Most tumors originated in the pancreas (54.4%) or small intestine (29.2%); G3 tumors were reported in 35.0% of pts. Median cumulative dose of 177Lu-DOTATATE was 29.2 GBq, with 87.8% of pts receiving all 4 doses. Median PFS (95% confidence interval [CI]) was significantly prolonged by ~14.3 months from 8.5 months (7.7, 13.8) in the control arm to 22.8 months (19.4, not estimable) in the 177Lu-DOTATATE arm; stratified hazard ratio 0.276 (95% CI: 0.182, 0.418; p < 0.0001). The ORR was significantly higher in the 177Lu-DOTATATE arm (43.0%) vs the control arm (9.3%); stratified odds ratio 7.81 (95% CI: 3.32, 18.4; p < 0.0001). PFS and ORR results were consistent across all pre-specified demographic and prognostic subgroups. Among adverse events of special interest to RLT, G3/4 leukopenia, anemia and thrombocytopenia occurred in ≤3 pts each in the 177Lu-DOTATATE arm. One case of myelodysplastic syndrome was reported (177Lu-DOTATATE arm).

　　Conclusion:177Lu-DOTATATE significantly prolonged PFS and demonstrated a clinically meaningful ORR, compared with high-dose octreotide LAR, in pts with newly diagnosed advanced G2 and G3 GEP-NETs. Safety was in line with the established profile of 177Lu-DOTATATE. This is the first randomized study to demonstrate efficacy of RLT as 1L treatment in any malignancy and will change clinical practice. Further investigations of RLT as a therapeutic option in other settings is warranted. Clinical trial information: NCT03972488.