Impact of metformin on clinical outcomes in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors

Abstract

Background and Aims Non‐alcoholic steatohepatitis (NASH) is a common cause of hepatocellular carcinoma (HCC) worldwide. Emerging data suggests NASH‐induced HCC could be associated with less response to immune checkpoint inhibitor (ICI)‐based therapy. Metformin has been associated with improved outcomes in cancers like melanoma treated with ICIs, but its impact on HCC is not well defined. The purpose of this study was to examine the effect of metformin on clinical outcomes in patients with advanced HCC treated with ICIs. Methods We retrospectively analysed patients with advanced HCC treated with ICIs in first and later‐line settings between 2015 and 2021. The primary endpoints were overall survival (OS), progression‐free survival (PFS), and objective response rate (ORR) as assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Patients were stratified based on their usage of metformin. Results Our study included 18 patients in the metformin group and 93 patients in the non‐metformin group. The most common causes of HCC were viral hepatitis (52%), NASH (29%), and alcohol (8%). ORR was 5.6% in the metformin group vs 22.6% in the non‐metformin group (P = .0987). Median OS was 10.8 months versus 45.9 months (HR = 1.99, 95% CI = 0.95–4.21, P = .065) and median PFS was 2.5 months versus 6.6 months (P = .077) in the metformin and non‐metformin groups, respectively. Regardless of metformin usage, OS was significantly worse in patients with poor ECOG performance status, HCC aetiology of NASH, MELD score 10–23, AFP >= 400, and use of ICIs in later lines of therapy. Conclusions Metformin use was associated with a trend, although not statistically significant, toward a worse ORR, OS and PFS in advanced HCC patients treated with ICIs.

Impact of metformin, statin, aspirin and insulin on the prognosis of uHCC patients receiving first line Lenvatinib or Atezolizumab plus Bevacizumab

“…Conversely, the utilization of metformin was found to have no prognostic impact in a cohort of patients with advanced HCC who received Lenvatinib as a rst-line treatment. Recently, Kang and colleagues performed an analysis on a cohort of patients treated with immunotherapy for advanced HCC and highlighted worse survival outcomes in patients included in the metformin group compared to those in the no-metformin groups, even without reaching the statistical signi cance (11). Our study encompassed a larger patient sample receiving rst-line treatment for advanced HCC (Atezolizumab plus Bevacizumab or Lenvatinib), whereas the previous study focused exclusively on patients who received immunotherapy in either the rst or subsequent lines of treatment.…”

“…Discordant evidences about the metformin's antineoplastic properties have been highlighted (8-10). Recently, Kang and collaborators conducted a retrospective analysis on 111 patients affected by advanced HCC who received immune checkpoint inhibitors (ICIs) and demonstrated that the use of metformin was associated with a trend towards worse objective response rates (ORR), overall survival (OS), and progression-free survival (PFS), even without reaching statistical signi cance (11). Building upon these ndings, the aim of the present study was to investigate the potential prognostic role of metformin use and other concomitant medications (such as statins, insulin, and aspirin) in a cohort of advanced HCC patients who received Lenvatinib or Atezolizumab plus Bevacizumab as rst-line treatment.…”