Journal of Hematology & Oncology (Dec 2023)

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,
  • Francesca Corti,
  • Natalie Prinzi,
  • Federico Nichetti,
  • Silva Ljevar,
  • Adele Busico,
  • Tommaso Cascella,
  • Rita Leporati,
  • Simone Oldani,
  • Chiara Carlotta Pircher,
  • Jorgelina Coppa,
  • Veronica Resi,
  • Massimo Milione,
  • Marco Maccauro,
  • Rosalba Miceli,
  • Elena Tamborini,
  • Federica Perrone,
  • Carlo Spreafico,
  • Monica Niger,
  • Federica Morano,
  • Filippo Pietrantonio,
  • Ettore Seregni,
  • Luigi Mariani,
  • Vincenzo Mazzaferro,
  • Giorgia Di Liberti,
  • Giovanni Fucà,
  • Filippo de Braud,
  • Claudio Vernieri

DOI
https://doi.org/10.1186/s13045-023-01510-9
Journal volume & issue
Vol. 16, no. 1
pp. 1 – 5

Abstract

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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.

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