Hua Feng ¹ Shuxian Shang ² Kun Chen ² Xuan Sun ³ Xueping Yue ^1*

• ¹ Department of Dermatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
• ² Hospital of Dermatology，Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
• ³ Interventional Neuroradiology Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

Background There is evidence of a modest reduction in skin cancer risk among metformin users. However, no studies have further examined the effects of metformin on melanoma survival and safety outcomes. This study aimed to quantitatively summarize any influence of metformin on the overall survival (OS) and immune-related adverse effects (irAEs) in melanoma patients. Methods Selection criteria: The inclusion criteria were designed based on the PICOS principles. Information sources: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for relevant literature published from the inception of these databases until November 2023 using ‘Melanoma’ and ‘Metformin’ as keywords. Survival outcomes were OS, progression-free survival (PFS), recurrence-free survival (RFS), and mortality; the safety outcome was irAEs. Risk of bias and data Synthesis: The Cochrane tool for assessing the risk of bias in randomized trial 2 (RoB2) and methodological index for non-randomized studies (MINORS) were selected to assess the risk of bias. The Cochrane Q and I2 statistics based on Stata 15.1 SE were used to test the heterogeneity among all studies. Funnel plot, Egger regression, and Begg tests were used to evaluate publication bias. The leave-one-out method was selected as the sensitivity analysis tool. Results A total of 12 studies were included, involving 111,036 melanoma patients. The pooled HR for OS was 0.64 (95% CI [ 0.42, 1.00], p = 0.004, I2= 73.7%), HR for PFS was 0.89 (95% CI [ 0.70, 1.12], p = 0.163, I2= 41.4%), HR for RFS was 0.62 (95% CI [ 0.26, 1.48], p = 0.085, I2= 66.3%), and HR for mortality was 0.53 (95% CI [0.46, 0.63], p = 0.775, I2= 0.0%). There was no significant difference in irAEs incidence (OR = 1.01; 95% CI [0.42, 2.41]; p = 0.642) between metformin and no metformin groups. Discussion The improvement in overall survival of melanoma patients with metformin may indirectly result from its diverse biological targets and beneficial effects on multiple systemic diseases. While we could not demonstrate a specific improvement in the survival of melanoma patients, the combined benefits and safety of metformin for patients taking the drug are worthy of recognition.