The synergic effect of metformin with atezolizumab/ bevacizumab in masld hcc patients: a retrospective study from arte multicentric Italian dataset

Background The standard treatment of advanced HCC is immune checkpoint inhibitor (ICI) therapy. Metabolic dysfunction-associated steatotic liver disease (MASLD) appears to adversely affect the efficacy of ICI. Recently, the antidiabetic drug metformin has garnered attention for its possible antitumor and immunomodulatory properties, such as reduction of proinflammatory cytokines and CD8+ T cells activation during immunotherapy. The aim of our study was to investigate the role of metformin in patients treated with atezolizumab/bevacizumab (A+B). Patients and Methods 159 HCC patients (82% males, mean age 64.5) treated with A+B were enrolled from ARTE dataset. Clinical and radiological factors associated with patients’ response to therapy were used to stratify objective response rate (ORR), overall survival (OS) and progression free survival (PFS) by Kaplan- Meier methodology, followed by Log-rank test in multivariate analysis. Results 53.3% patients had MASLD, with 31.9% being diabetic. No differences in OS, PFS and ORR were documented among the different etiologies. Considering 31 ORR patients, no differences between the two groups were underlined regarding sex, age, liver disease etiology. In the multistep multivariate model, diabetes was the only condition remained independently associate to ORR (OR 3.0, 95%CI 1.0-8.3; p=0.030). When diabetic patients were stratified based on antidiabetic treatments, those on metformin had a 12 months survival of 62% [44%-88%, 95% CI] vs insulin treatment with 21% [6%-72%, 95% CI], p<0.05. Conclusion Despite any clear difference in terms of ORR, OS and PFS between different etiologies, diabetic patients treated with metformin exhibited a better ORR and PFS, suggesting a potential immunological combination role of metformin with A+B treatment.