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Clinical Trial
. 2023 Dec 14;16(1):119.
doi: 10.1186/s13045-023-01510-9.

Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2

Sara Pusceddu  1 , Francesca Corti  2   3 , Natalie Prinzi  2 , Federico Nichetti  2 , Silva Ljevar  4 , Adele Busico  5 , Tommaso Cascella  6 , Rita Leporati  2 , Simone Oldani  2 , Chiara Carlotta Pircher  2 , Jorgelina Coppa  7 , Veronica Resi  8 , Massimo Milione  9 , Marco Maccauro  10 , Rosalba Miceli  4 , Elena Tamborini  5 , Federica Perrone  5 , Carlo Spreafico  6 , Monica Niger  2 , Federica Morano  2 , Filippo Pietrantonio  2 , Ettore Seregni  10 , Luigi Mariani  4 , Vincenzo Mazzaferro  7   11 , Giorgia Di Liberti  2 , Giovanni Fucà  2 , Filippo de Braud #  2   11 , Claudio Vernieri #  12   13
Affiliations
Clinical Trial

Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2

Sara Pusceddu et al. J Hematol Oncol. .

Abstract

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.

Keywords: Antitumor activity; Metformin plus lanreotide; Phase Ib trial; Safety; Well-differentiated neuroendocrine tumors (WDNETs).

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Conflict of interest statement

SP received honoraria from Novartis, Ipsen, Pfizer, Merck Serono, and Advanced Accelerator Applications—AAA; received institutional research grant by Ipsen, Pfizer; MN received Travel expenses from Celgene and AstraZeneca, speaker honorarium from Accademia della Medicina and Incyte; honoraria from Sandoz, Medpoint SRL and Servier for editorial collaboration. Consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte, MSD Italia, Servier, Astrazeneca and Taiho. FP received honoraria from Amgen, Bayer, Servier, Merck-Serono, Lilly, MSD, BMS, Astrazeneca, Pierre-Fabre, Organon, Astellas; research grants from Bristol-Myers Squibb, AstraZeneca, Agenus, Incyte. MM received honoraria from Novartis, Ipsen, Roche, Merck Sharp & Dhome) research grant by Ignyta, Roche, Adopt bbmri-eric, Transcan2. NP received honoraria and travel accommodation from Novartis, Ipsen, Pfizer, MerckSerono, Italfarmaco, MSD, Advanced Accelerator Applications—AAA. CV received honoraria for advisory boards/speakers bureau from Novartis, Eli Lilly, Daiichi Sankyo, Pfizer and Istituto Gentili and research grants from Roche. FdB received honoraria for advisory boards/speakers bureau from Amgen, Novartis, Roche, Incyte, EMD Serono, Bristol-Myers Squibb, Roche, Pfizer, Menarini, Sanofi, Healthcare Research & Pharmacoepidemiology, Dephaforum and research funding from Novartis, Roche, Merck Sharp &Dohme, MerckSerono, Pfizer, Servier, NMS Nerviano Medical Science. All other authors have declared no conflicts of interest.

Figures

Fig. 1
Fig. 1
Kaplan–Meier curves for progression-free survival (PFS) (A) and time-to-progression (TTP) in the MetNET2 study cohort (B). Box plots depicting changes in the indicated metabolic parameters during the experimental treatment (C–H). The p value in panels C–H refers to the paired t test for the indicated comparisons
See this image and copyright information in PMC

References

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