Author information

¹Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy.

²Vita-Salute University San Raffaele, Milan, Italy.

³Liver Unit-CHTMAD, Vila Real, Portugal.

⁴Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Higashiosaka, Japan.

⁵Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan.

⁶Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.

⁷Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 830-0011, Japan.

⁸Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.

⁹Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.

¹⁰Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy.

¹¹Clinical Oncology Unit, Careggi University Hospital, Florence, Italy.

¹²Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

¹³Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

¹⁴Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.

¹⁵Department of Internal Medicine, Ospedale degli Infermi di Faenza, Faenza, Emilia Romagna, Italy.

¹⁶Department of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.

¹⁷Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, Foggia, Puglia, Italy.

¹⁸Medical Oncology Unit, IRST IRCCS, Meldola, Italy.

¹⁹Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy.

²⁰Department of Oncology, ASUFC University Hospital, Udine, Italy.

²¹Hepato-Biliary Surgery Department, IRCCS San Raffaele Hospital, Milan, Italy.

²²Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

²³Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy. casadeigardini@gmail.com.

²⁴Vita-Salute University San Raffaele, Milan, Italy. casadeigardini@gmail.com.

Abstract

Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1-3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1-3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0-2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1-2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group.