ecancermedicalscience

Clinical Study

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

31 Mar 2022
João Glasberg, Aley Talans, Thomás Rivelli Giolo, Débora Zachello Recchimuzzi, João Evangelista Bezerra Neto, Rossana Veronica Mendonza Lopez, Paulo Marcelo Gehm Hoff, Rachel P Riechelmann

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).

Aim(s): 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.

Related Articles

Dana Narváez, Federico Waisberg, Tomas Soule, Martín Angel, Luisina Bruno, Maria Romina Girotti, Carmen Pupareli, Matías Chacón, Fernando E Petracci
Debdeep Dey, Bhagat Singh Lali, Paromita Roy, Divya Midha, Indu Arun, Lateef Zameer, Anand Bardia, Geetashree Mukherjee
Suresh Kumar Bondili, Ravindra Nandhana, Aditya Dhanawat, Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Nandini Menon, Rajiv Kumar Kaushal, Anuradha Choughule, Sabita S Jiwnani, Amit Janu, Kumar Prabhash
João Glasberg, Aley Talans, Thomás Rivelli Giollo, Débora Zachello Recchimuzzi, João Evangelista Bezerra Neto, Rossana Veronica Mendonza Lopez, Paulo Marcelo Gehm Hoff, Rachel P Riechelmann
Ajaykumar Singh, Akhil Kapoor, Vanita Noronha, Vijay Patil, Nandini Menon, Abhishek Mahajan, Amit Janu, Nilendu Purandare, Rajiv Kaushal, Kumar Prabhash