[177Lu]Lu-dota-tate versus sunitinib in patients with metastatic progressive neuroendocrine tumours of the pancreas (OCLURANDOM): a randomised, controlled, phase 2 trial.

We aimed to evaluate the antitumour activity and safety of [177Lu]Lu-dota-tate in this setting.

我们旨在评估[177Lu]Lu-dota-tate在这种环境下的抗肿瘤活性和安全性。

Methods

OCLURANDOM is a randomised, open-label, non-comparative, phase 2 trial conducted in ten academic centres in France.

OCLURANDOM 是在法国十个学术中心进行的一项随机、开放标签、非比较性的2期试验。

Patients aged 18 years and older with pretreated, progressive, somatostatin receptor-positive, metastatic pancreatic neuroendocrine tumours and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1) using web-based software to receive intravenous [177Lu]Lu-dota-tate (7·4 GBq every 8 weeks up to four cycles) with concomitant amino acid infusion or oral sunitinib (37·5 mg once daily).

年龄在18岁及以上的患者，患有经过治疗的、进展性的、生长抑素受体阳性的、转移性的胰腺神经内分泌肿瘤，并且东部肿瘤协作组（ECOG）表现状态为0-2，通过基于网络的软件随机分配（1:1），接受静脉注射[177Lu]Lu-dota-tate（每8周7.4 GBq，最多四个周期）伴随氨基酸输注或口服苏尼替尼（每日一次37.5 mg）。

Amino acid infusion was for at least 4 h starting 30 min before [177Lu]Lu-dota-tate infusion and included 16·8 g of arginine and 22 g of lysine in 2 L until May, 2018, and, from that date, a solution of 25 g of arginine and 25 g of lysine in 2 L.

氨基酸输注至少持续4小时，从[177Lu]Lu-dota-tate输注前30分钟开始，直至2018年5月，包括在2升溶液中加入16.8克精氨酸和22克赖氨酸。从该日期起，改为在2升溶液中加入25克精氨酸和25克赖氨酸。

Randomisation was stratified according to Ki-67, liver involvement, and previous therapies.

随机分组根据Ki-67指数、肝脏受累情况以及既往治疗进行分层。

The primary endpoint was progression-free survivalat 12 months assessed by real-time central review using Response Evaluation Criteria in Solid Tumours version 1.1 in the intention-to-treatpopulation.

主要终点是通过实时中心审查使用实体瘤反应评估标准版本1.1评估的意向治疗人群中12个月无进展生存。

Cross-over was allowed.

允许交叉研究。

Adverse events in the as-treated population were assessed continuously during the active phase of treatment and then every 3 months.

在治疗活跃期间，对接受治疗人群的不良事件进行了持续评估，之后每3个月评估一次。

Patients and the public were not involved in the design, conduct, reporting, or dissemination plans of this research.

患者和公众没有参与本研究的设计、实施、报告或传播计划。

This trial was registered with ClinicalTrials.gov, NCT02230176, and is closed to enrolment.

该试验已在ClinicalTrials.gov注册，编号为NCT02230176，目前不再接受患者入组。

Results

Between Feb 13, 2015, and July 16, 2020, 84 patients were enrolled and randomly assigned to the [177Lu]Lu-dota-tate group (n=41) or the sunitinib group (n=43). 44 (52%) patients were women and 40 (48%) were men.

在2015年2月13日至2020年7月16日期间，共有84名患者被纳入研究并随机分配至[177Lu]Lu-dota-tate组（n=41）或舒尼替尼组（n=43）。其中44名（52%）为女性，40名（48%）为男性。

Median follow-up was 72·5 months (IQR 61·4-88·4).

中位随访时间为72.5个月（四分位数间距61.4-88.4个月）。

Progression-free survivalrate at 12 months was 33 (80·5% [90% CI 67·5-89·9]) of 41 patients in the [177Lu]Lu-dota-tate group versus 18 (41·9% [29·1-55·5]) of 43 patients in the sunitinib group.

在[177Lu]Lu-dota-tate组的41名患者中，12个月无进展生存率为33（80.5% [90% 置信区间 67.5-89.9]），而在舒尼替尼组的43名患者中，12个月无进展生存率为18（41.9% [29.1-55.5]）。

Grade 3-4 adverse events occurred in 18 (44%) of 41 patients in the [177Lu]Lu-dota-tate group and 31 (72%) of 43 patients in the sunitinib group.

在[177Lu]Lu-dota-tate组的41名患者中，有18名（44%）发生了3-4级不良事件，在sunitinib组的43名患者中，有31名（72%）发生了3-4级不良事件。

The most common grade 3-4 adverse events for all treatment groups were neutropenia (two [5%] of 41 in the [177Lu]Lu-dota-tate group vs 13 [30%] of 43 in the sunitinib group) and hypertension (four [10%] in the [177Lu]Lu-dota-tate group vs eight [19%] in the sunitinib group).

所有治疗组中最常见的3-4级不良事件是中性粒细胞减少症（[177Lu]Lu-dota-tate组的41名患者中有2名（5%），sunitinib组的43名患者中有13名（30%））和高血压（[177Lu]Lu-dota-tate组的41名患者中有4名（10%），sunitinib组的43名患者中有8名（19%））。

Drug-related serious adverse events occurred in six (15%) patients in the [177Lu]Lu-dota-tate group (transaminase increase, neutropenia, thrombosis, and fever) and ten (23%) in the sunitinib group (gastrointestinal, general disorders, and sepsis).

在[177Lu]Lu-dota-tate组中，有六名（15%）患者发生了与药物相关的严重不良事件（转氨酶升高、中性粒细胞减少、血栓形成和发热），而在sunitinib组中有十名（23%）患者（胃肠道、一般性疾病和败血症）。

There was a 10·3-point (95% CI 2·4-18·2) difference in the Global Health Status score between the two groups in favour of [177Lu]Lu-dota-tate.

两组之间的全球健康状况评分差异为10.3分（95% 置信区间 2.4-18.2），有利于[177Lu]Lu-dota-tate。

Late adverse events (grade 2 or worse) were reported in 24 (60%) patients in the [177Lu]Lu-dota-tate group and in three (43%) of seven patients in the sunitinib group.

在[177Lu]Lu-dota-tate组中有24名（60%）患者报告了晚期不良事件（2级或更严重），而在sunitinib组的七名患者中有三名（43%）报告了此类事件。

One treatment-related death (acute leukaemia) occurred in the [177Lu]Lu-dota-tate group.

在[177Lu]Lu-dota-tate组中发生了一例与治疗相关的死亡（急性白血病）。

interpretation

Using sunitinib as an internal control, our results show clinically significant antitumour efficacy of [177Lu]Lu-dota-tate in pretreated, progressive, somatostatin receptor-positive, metastatic pancreatic neuroendocrine tumours, and a better quality of life during the treatment phase.

以舒尼替尼作为内部对照，我们的结果显示[177Lu]Lu-dota-tate在既往治疗、进展期、生长抑素受体阳性、转移性胰腺神经内分泌肿瘤中具有显著的抗肿瘤疗效，并在治疗期间提高了患者的生活质量。

Late adverse events were reported in the [177Lu]Lu-dota-tate group that might affect the tolerance of subsequent lines of treatment.

[177Lu]Lu-dota-tate组报告了晚期不良事件，这可能影响后续治疗线的耐受性。

funding

French Ministry of Health, through the National Institute for Cancer.

法国卫生部，通过国家癌症研究所。