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

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.


| INTRODUC TI ON
Hepatocellular carcinoma (HCC) represents a major global health challenge as the sixth most common cancer and the third leading cause of cancer-related mortality worldwide. 1,2 Although the incidence rates of most cancers are declining, the incidence rate of HCC continues to increase, resulting in more than 900 000 new cases per year. 1 The major risk factor for HCC is chronic viral infection due to hepatitis B (HBV) and hepatitis C (HCV) viruses, followed by chronic alcohol consumption, non-alcoholic fatty liver disease (NAFLD)/ non-alcoholic steatohepatitis (NASH), and environmental toxins. 3,4 The prognosis of HCC is mainly determined by the stage at diagnosis in addition to performance status and baseline liver function.
Surgical resection and liver transplantation are potentially curative treatment options offered to patients with earlier stages of HCC and may result in over 70% 5-year survival rates. 2 Patients ineligible for surgery with localised disease can be considered for tumour ablation and transarterial therapies such as transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT). 5 Unfortunately, HCC patients with earlier stages of disease often recur after definitive treatment or present with an advanced-stage disease requiring systemic therapy, which generally results a in modest survival benefit of 1-1.5 years. 2 The multi-targeted tyrosine kinase inhibitor (TKI) sorafenib represented the first major breakthrough in systemic therapy for advanced HCC in the landmark SHARP trial, 6 leading to the development and approval of other similar TKIs including regorafenib, 7 lenvatinib, 8 and cabozantinib. 9 More recently, immunotherapy has dramatically expanded the scope of treatment for many cancers, including HCC. The phase III IMbrave 150 trial established an immunotherapy-based regimen as the new standard first-line treatment for HCC after the combination of immune checkpoint inhibitor (ICI) atezolizumab (anti-programmed death-ligand 1 [PD-L1]) plus bevacizumab improved survival outcomes compared to sorafenib. 10 Dual ICI blockade using durvalumab (anti-PD-L1) plus tremelimumab (anti-cytotoxic T-lymphocyte-associated protein [CTLA]-4) may be poised to become another first-line therapy option following the recent presentation of the HIMALAYA trial. 11 Despite the promising prospect of immunotherapy in HCC, only about 30% of patients with advanced HCC respond to ICI-based therapy in clinical trials, irrespective of the underlying aetiology of HCC. Emerging literature suggests that NASH-induced cirrhosis may be associated with decreased response to ICIs and thus the underlying aetiology of HCC should be considered for appropriate treatment selection. 12 Many patients with NAFLD/NASH are prescribed metformin, a widely used drug to treat diabetes as well as other conditions such as metabolic syndrome, obesity, and polycystic ovarian syndrome.
Besides its well-known anti-hyperglycemic effects, growing evidence indicates that metformin also has anti-cancer properties that may be effective in both preventative and therapeutic settings. 13 One systematic review of case-control and cohort studies found that metformin use correlates with a significantly lower risk of HCC development in diabetic patients, whereas the use of insulin and sulfonylureas is associated with a higher risk. 14 Numerous studies have also now demonstrated an association between metformin use and improved clinical outcomes of multiple malignancies including bladder, colon, lung, ovarian, and breast cancer. [15][16][17][18][19] Most of the contemporary literature evaluated patient outcomes with the combination of metformin and standard chemotherapy, so the interaction between metformin and ICIs is an active area of interest in the current era of immunotherapy. Emerging studies have shown that the anti-diabetic agent is associated with improved outcomes in patients treated with ICIs in melanoma 20 and non-small cell lung cancer (NSCLC). 21 However, the impact of metformin on the efficacy of ICIs in HCC is not well defined, particularly given the potential association between NASH-HCC and reduced response to immunotherapy.
Thus, the main purpose of this study is to examine the effect of metformin on clinical outcomes in patients with advanced HCC treated with ICIs.

| Statistical analysis
Clinical and demographic characteristics of the patients were sum-

| Treatment response and survival outcomes
Metformin use was associated with a lower ORR of 5.6% with 0 complete responses (CR) and 1 partial response (PR) compared to an ORR of 22.6% (5 CR, 16 PR) in patients not on metformin (P = .0987) ( Table 3). Survival outcomes were also worse in MG com- Child-Pugh score) did not significantly impact survival (Table 5).

F I G U R E 2
Overall survival by metformin status.

| DISCUSS ION
In recent years, mounting evidence has suggested that the antidiabetic agent metformin has anti-cancer activity in multiple cancer types. [15][16][17][18][19] Various mechanisms by which metformin enhances antitumour immunity have been described. A preclinical study showed that metformin helps restore CD8+ tumour infiltrating lymphocytes (TILs) from immune exhaustion via AMPK-mTOR signalling, resulting in enhanced effector activity of TILs to destroy cancer cells. 22 Metformin has also demonstrated the ability to reduce hypoxia in the tumour microenvironment and consequently improve intratumoral T cell function and tumour clearance. 23

AUTH O R CO NTR I B UTI O N S
LK was involved in conceptualization, data curation, formal analysis, investigation, project administration, supervision, validation and writing-review and editing. SK was involved in conceptualization, data curation, formal analysis, investigation, project administration, supervision, validation and writing -review and editing. YL/AV was involved in data curation, methodology, software and writing. JG was involved in data curation and manuscript review and editing. MD was involved in data curation, methodology and software. WLS was involved in the methodology, investigation, original draft and writing-review and editing. OBA was involved in the methodology, investigation, original draft and writing-review and editing. OG was involved in the methodology, investigation, original draft and writing-review and editing.
BFER was involved in the methodology, investigation, original draft and writing-review and editing. MA was involved in conceptualization, data curation, formal analysis, investigation, project administration, supervision, validation and writing-review and editing. All authors read and approved the final manuscript.

ACK N O WLE D G E M ENTS
This data was presented in part as a poster at the 2022 ASCO Annual

FU N D I N G I N FO R M ATI O N
There was no specific funding for this study and there are no competing financial disclosures.

CO N FLI C T O F I NTER E S T S TATEM ENT
Dr. Akce has collaborated with the following companies in research:

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available within the article.