In retrospective studies, metformin use has been associated with better clinical outcomes in diabetic patients with advanced, well-differentiated neuroendocrine tumors (WDNETs). However, prospective evidence of metformin safety and activity is lacking. Here, we conducted the first-in-human phase Ib MetNET2 trial to investigate the safety and antitumor activity of metformin in combination with the somatostatin analog lanreotide autogel (ATG) in both diabetic and non-diabetic patients with advanced WDNETs of the gastrointestinal (GI) or thoracic tract. Enrolled patients received lanreotide ATG 120 mg plus oral metformin, up to a maximum dosage of 2550 mg/day. We enrolled 20 patients, of whom 18 (90%) and 2 (10%) had WDNETs of the GI and thoracic tract, respectively. Fourteen patients (70%) were non-diabetic. With a 5% incidence of SAEs, the study met its primary objective of demonstrating treatment safety. With a median follow-up of 39 months (95% CI 28-NE), median PFS was 24 months (95% CI 16-NE), with 12-month and 24-month PFS probability of 75% (95% CI 58–97) and 49% (95% CI 31–77), respectively. We found no statistically significant PFS differences between diabetic and non-diabetic patients. Among exploratory analyses, the presence of tumor genomic alterations in DNA damage pathways was associated with trend towards worse PFS, whereas a precocious reduction of HOMA-IR index and plasma cholesterol concentration showed a trend towards an association with better PFS. In conclusion, metformin plus lanreotide ATG is a safe and well tolerated combination treatment that is associated with promising antitumor activity in both non-diabetic and diabetic patients with WDNETs, and that warrants further investigation in larger clinical trials.

中文翻译：

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二甲双胍加兰瑞肽治疗晚期胃肠道或肺神经内分泌肿瘤患者的安全性和抗肿瘤活性：Ib 期试验 MetNET2


在回顾性研究中，二甲双胍的使用与患有晚期高分化神经内分泌肿瘤（WDNET）的糖尿病患者更好的临床结果相关。然而，缺乏二甲双胍安全性和活性的前瞻性证据。在这里，我们进行了首次人体 Ib 期 MetNET2 试验，以研究二甲双胍联合生长抑素类似物兰瑞肽自凝胶 (ATG) 在患有晚期胃肠道 WDNET (GI) 的糖尿病和非糖尿病患者中的安全性和抗肿瘤活性。 ）或胸腔。入组患者接受兰瑞肽 ATG 120 毫克加口服二甲双胍治疗，最大剂量为 2550 毫克/天。我们招募了 20 名患者，其中 18 名 (90%) 和 2 名 (10%) 分别患有胃肠道和胸腔 WDNET。十四名患者（70%）没有糖尿病。该研究的 SAE 发生率为 5%，达到了证明治疗安全性的主要目标。中位随访时间为 39 个月 (95% CI 28-NE)，中位 PFS 为 24 个月 (95% CI 16-NE)，12 个月和 24 个月 PFS 概率为 75% (95% CI 58) –97) 和 49% (95% CI 31–77)。我们发现糖尿病患者和非糖尿病患者之间的 PFS 没有统计学上的显着差异。在探索性分析中，DNA 损伤途径中肿瘤基因组改变的存在与较差的 PFS 趋势相关，而 HOMA-IR 指数和血浆胆固醇浓度的过早降低则显示出与更好的 PFS 相关的趋势。总之，二甲双胍联合兰瑞肽 ATG 是一种安全且耐受性良好的联合治疗方法，在患有 WDNET 的非糖尿病和糖尿病患者中都具有良好的抗肿瘤活性，值得在更大规模的临床试验中进行进一步研究。