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

Abstract

4118 Background: Non-alcoholic steatohepatitis (NASH) is an emerging etiology for hepatocellular carcinoma (HCC) and contributes to the increasing incidence of HCC worldwide. Patients with NASH often have risk factors of metabolic syndrome including hypertension, obesity, and type 2 diabetes (T2DM). NASH induced HCC has been shown to be associated with less response to immune check point inhibitors (ICIs) in HCC. Anti-diabetic agent metformin has been shown to be associated with improved outcomes in patients treated with ICIs in melanoma and non-small cell lung cancer. However, the impact of metformin on the efficacy of ICIs is not well defined in HCC. The main purpose of this study was to examine the effect of metformin on clinical outcomes in patients with advanced HCC treated with ICIs. Methods: We performed a retrospective analysis of 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 Tumors (RECIST) version 1.1. Patients were stratified based on their usage of metformin. OS and PFS were analyzed using Cox proportional hazard models and Kaplan-Meier analysis with log-rank test. Results: A total of 111 patients met inclusion criteria, 18 patients in the metformin group and 93 patients in the non-metformin group. Most common cause of HCC was viral hepatitis (52%), followed by NASH (29%), alcohol (8%) and other (11%). Baseline characteristics between the two groups were similar except all patients in the metformin group had a diagnosis of T2DM. ORR was 5.6%. (1 partial response) in the metformin group vs 22.6% (5 complete responses, 16 partial responses) in the non-metformin group. Median OS was 45.9 months in the non-metformin group vs 10.8 months in metformin group (HR 1.99, 95% CI 0.95-4.21, p = 0.064). Median PFS of 6.6 months vs 2.5 months (HR 1.75, 95% CI 0.93-3.29, p = 0.077). Moreover, metformin usage was associated with shorter median OS of 10.8 months (HR 1.96, 95% CI 0.75-5.09, p = 0.16) vs 20.9 months among patients with T2DM. OS was significantly worse in patients with poor ECOG performance status 2-3, MELD score 10-23, higher grade tumor histology, AFP > = 400, and use of IO in later lines of therapy. Conclusions: In this retrospective study metformin use was associated with worse clinical outcomes in advanced HCC patients treated with ICIs.