Department of Medical Oncology, Multidisciplinary NET Group, Umbria Regional Cancer Network and University of Perugia, Perugia, Italy.
Department of Oncology, San Luigi Hospital, Orbassano, Italy.
Lancet Oncol. 2017 Dec;18(12):1652-1664. doi: 10.1016/S1470-2045(17)30681-2. Epub 2017 Oct 23.
There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus.
LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0-2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing.
Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2-55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6-49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1-73·7) in the combination group. The most common grade 1-2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3-4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related.
The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids.
Novartis Pharma AG.
目前尚无专门针对晚期肺和胸腺类癌患者的前瞻性研究数据。我们旨在评估长效帕瑞肽和依维莫司单药或联合应用于晚期肺或胸腺类癌患者的疗效和安全性。
LUNA 是一项前瞻性、多中心、随机、开放标签、Ⅱ期临床试验，纳入年龄（年龄＞18 岁）＞18 岁）晚期（不可切除或转移性）、分化良好的肺或胸腺类癌患者，在随机分组前 12 个月内有影像学进展，且世界卫生组织（WHO）体能状态为 0-2 级。在每个中心，研究者或其指定人员使用交互式语音识别系统将每位患者登记到三个治疗组之一。随机分配序列由外部公司生成；患者随机分为三组（1:1:1）：长效帕瑞肽（每 28 天肌肉注射 60 mg）、依维莫司（每天口服 10 mg）或两者联合治疗，核心治疗期为 12 个月。患者按类癌类型（典型与非典型）和研究治疗线（一线与其他）分层。主要终点是第 9 个月时无进展患者比例，定义为根据实体瘤反应评价标准 1.1（RECIST1.1），在第 9 个月时总体病变评估中，完全缓解、部分缓解或疾病稳定的患者比例，在意向治疗人群中进行评估。对至少接受一剂研究药物且至少有一次基线后安全性评估的所有患者进行安全性评估。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01563354。研究的扩展阶段正在进行中。
2013 年 8 月 16 日至 2014 年 9 月 30 日，从 9 个国家的 36 个中心共纳入 124 例患者：41 例分配至长效帕瑞肽组，42 例分配至依维莫司组，41 例分配至联合组。在第 9 个月时，长效帕瑞肽组、依维莫司组和联合组的完全缓解、部分缓解或疾病稳定患者比例分别为：41 例患者中 16 例（39.0%，95%CI 24.2-55.5）、42 例患者中 14 例（33.3%，19.6-49.5）和 41 例患者中 24 例（58.5%，42.1-73.7）。与长效帕瑞肽单药治疗相关的最常见 1-2 级不良事件包括腹泻（41 例患者中 15 例[37%]）、高血糖症（17 例[41%]）和体重减轻（8 例[20%]）；与依维莫司单药治疗相关的最常见不良事件为口腔炎（42 例患者中 26 例[62%]）和腹泻（16 例[38%]）；与联合治疗相关的最常见不良事件为高血糖症（41 例患者中 27 例[66%]）、腹泻（19 例[46%]）和乏力（8 例[20%]）。与长效帕瑞肽单药治疗相关的最常见 3-4 级不良事件为γ-谷氨酰转移酶升高（41 例患者中 4 例[10%]）、腹泻（3 例[7%]）和高血糖症（3 例[7%]）；与依维莫司治疗相关的最常见不良事件为高血糖症（42 例患者中 7 例[17%]）、口腔炎（4 例[10%]）和腹泻（3 例[7%]）；与联合治疗相关的最常见不良事件为高血糖症（41 例患者中 9 例[22%]）和腹泻（4 例[10%]）。11 例患者在核心 12 个月治疗期间或末次研究治疗后 56 天内死亡：长效帕瑞肽组 2 例（5%）、依维莫司组 6 例（14%）和联合组 3 例（7%）。没有死亡被怀疑与长效帕瑞肽治疗有关。依维莫司组 1 例死亡（与腹泻相关的急性肾损伤），联合组 2 例死亡（1 例腹泻和尿路感染，1 例急性肾衰竭和呼吸衰竭）被怀疑与依维莫司治疗有关。在后一种情况下，急性肾衰竭被怀疑与依维莫司治疗无关，但呼吸衰竭被怀疑与依维莫司治疗有关。
所有三组治疗的研究均达到了主要终点。安全性与这些药物的已知安全性一致。需要进一步研究以证实生长抑素类似物联合依维莫司在肺和胸腺类癌中的抗肿瘤疗效。
诺华制药公司。
