The Effect of Metformin on Atezolizumab/Bevacizumab Treatment in Patients with Hepatocellular Carcinoma and Diabetes.

[OBJECTIVES] The combination of atezolizumab plus bevacizumab (A+B) represents one of the standards first-line treatments for unresectable hepatocellular carcinoma (HCC). Metformin has garnered attention for its potential antitumour and immunomodulatory properties beyond glycaemic control. This study aimed to assess metformin's impact in patients with type 2 diabetes mellitus (T2DM) receiving A+B therapy.

[METHODS] This retrospective analysis of a prospectively-maintained multicentre database included 523 patients with HCC treated with A+B from the ARTE (Atezolizumab-bevacizumab Real-life Experience for Treatment of Hepatocellular Carcinoma) dataset across 18 Italian centres (May 2020-January 2024). We evaluated objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and time to progression (TTP) using Cox regression analysis and Inverse Probability of Treatment Weighting (IPTW) to address confounding.

[RESULTS] Among 523 patients, 341 (65.2%) did not have diabetes and 182 (34.8%) had T2DM. In the overall population, metformin showed no significant benefit for PFS (HR = 1.15, 95% CI [0.88-1.50], = 0.316) or OS (HR = 1.28, 95% CI [0.94-1.74], = 0.124). In the subgroup with T2DM (N = 180), metformin showed no significant benefit for PFS (HR = 1.41, 95% CI [0.97-2.05], = 0.069), OS (HR = 1.23, 95% CI [0.81-1.86], = 0.333), or TTP (HR = 0.82, 95% CI [0.53-1.26], = 0.363). IPTW analysis confirmed these negative findings.

[CONCLUSION] This study found no evidence of improved outcomes with metformin use in patients with HCC in particular with T2DM receiving A+B therapy. Routine metformin use should not be expected to enhance A+B efficacy based on current evidence.