Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-12-01
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| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13045-023-01510-9 |
| _version_ | 1797388112206233600 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sara Pusceddu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T22:36:08Z |
| format | Article |
| id | doaj.art-1fcb7b069e624b61b3c438f1291779ca |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-03-08T22:36:08Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-1fcb7b069e624b61b3c438f1291779ca2023-12-17T12:27:37ZengBMCJournal of Hematology & Oncology1756-87222023-12-011611510.1186/s13045-023-01510-9Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2Sara Pusceddu0Francesca Corti1Natalie Prinzi2Federico Nichetti3Silva Ljevar4Adele Busico5Tommaso Cascella6Rita Leporati7Simone Oldani8Chiara Carlotta Pircher9Jorgelina Coppa10Veronica Resi11Massimo Milione12Marco Maccauro13Rosalba Miceli14Elena Tamborini15Federica Perrone16Carlo Spreafico17Monica Niger18Federica Morano19Filippo Pietrantonio20Ettore Seregni21Luigi Mariani22Vincenzo Mazzaferro23Giorgia Di Liberti24Giovanni Fucà25Filippo de Braud26Claudio Vernieri27Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceClinical Epidemiology and Trial Organization, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori Di MilanoDepartment of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Radiology Foundation IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceHepato-Biliary-Pancreatic and Upper G.I. Surgery, Liver Transplantation and Hepato-Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceEndocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoDepartment of the Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartement of Nuclear Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceClinical Epidemiology and Trial Organization, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori Di MilanoDepartment of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Radiology Foundation IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartement of Nuclear Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceClinical Epidemiology and Trial Organization, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori Di MilanoHepato-Biliary-Pancreatic and Upper G.I. Surgery, Liver Transplantation and Hepato-Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of ExcellenceAbstract 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.https://doi.org/10.1186/s13045-023-01510-9Well-differentiated neuroendocrine tumors (WDNETs)Metformin plus lanreotideSafetyAntitumor activityPhase Ib trial |
| spellingShingle | 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 Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2 Journal of Hematology & Oncology Well-differentiated neuroendocrine tumors (WDNETs) Metformin plus lanreotide Safety Antitumor activity Phase Ib trial |
| title | Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2 |
| title_full | Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2 |
| title_fullStr | Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2 |
| title_full_unstemmed | Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2 |
| title_short | Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2 |
| title_sort | safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro intestinal or lung neuroendocrine tumors the phase ib trial metnet2 |
| topic | Well-differentiated neuroendocrine tumors (WDNETs) Metformin plus lanreotide Safety Antitumor activity Phase Ib trial |
| url | https://doi.org/10.1186/s13045-023-01510-9 |
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