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Case Reports
. 2022 Mar 31:16:1369.
doi: 10.3332/ecancer.2022.1369. eCollection 2022.

METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours

João Glasberg  1   2 , Aley Talans  3   4 , Thomás Rivelli Giollo  1 , Débora Zachello Recchimuzzi  1 , João Evangelista Bezerra Neto  1 , Rossana Veronica Mendonza Lopez  5 , Paulo Marcelo Gehm Hoff  1 , Rachel P Riechelmann  2   6
Affiliations
Case Reports

METNET: a phase II trial of metformin in patients with well-differentiated neuroendocrine tumours

João Glasberg et al. Ecancermedicalscience. .

Abstract

Background: Preclinical studies have suggested that metformin has anti-tumour effects, likely due to blockage of mammalian target of rapamycin pathway through adenosine monophosphate-activated protein kinase and decreased insulin levels. A retrospective study showed that metformin added to everolimus to treat type 2 diabetes mellitus offered longer progression-free survival (PFS) in patients with pancreatic neuroendocrine tumours (NET).

Aims: To evaluate the efficacy and safety of metformin monotherapy in patients with advanced/metastatic well-differentiated NET (WD-NET) of gastroenteropancreatic (GEP) or pulmonary origin.

Patients and methods: Single-arm phase II trial of metformin 850 mg PO twice daily until progression or intolerance for patients with progressive metastatic well-differentiated GEP or pulmonary NET. The primary endpoint was disease control rate (DCR) by RECIST 1.1 at 6 months. Secondary endpoints were response rate, PFS, toxicity and variations in glycaemic profiles (glycaemia, glycated haemoglobin and peptide C and insulin) at baseline, at 30 and 90 days.

Results: From 2014 to 2019, 28 patients were enrolled: median age was 50 years; 84% had non-functional NET, 86% were of GEP origin and 62% had G2 NET. At the time of last follow-up, 26 patients had progression, with 13 (46%) presenting DCR at 6 months and a median PFS of 6.3 months (95% confidence interval: 3.2-9.3). There was no objective response, but one patient with refractory carcinoid syndrome had complete symptom relief, lasting for more than 5 years. Variations in glycaemic profiles were not associated with DCR at 6 months. Diarrhoea was the most common adverse event, being grade 3 or 4 in 10% of the cases.

Conclusion: Metformin monotherapy offers modest anti-tumour activity in well-differentiated GEP or lung NET.

Keywords: cancer treatment; metformin; neuroendocrine tumours.

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Conflict of interest statement

R P Riechelmann: honoraria for lectures from Novartis. J Glasberg, A Talans, T Rivelli Giollo, D Zachello Recchimuzzi, J E Bezerra Neto, R V Mendonza Lopez and P M Gehm Hoff: none.

Figures

Figure 1.
Figure 1.. Kaplan–Meier plot of progression-free survival.
Figure 2.
Figure 2.. Kaplan–Meier plot according to baseline body mass index.
Figure 3.
Figure 3.. Waterfall plot.
Figure 4.
Figure 4.. Boxplot of fasting glycemic profiles.
See this image and copyright information in PMC

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