Metformin as a booster or obstacle of immunotherapy in patients with non–small cell lung cancer and diabetes mellitus

Abstract

We read the article by Leshem et al. 1 with great interest. In a retrospective study, the authors estimated the impact of diabetes mellitus on the efficacy of pembrolizumab in patients with metastatic non-small cell lung cancer (NSCLC). They demonstrated significantly shorter overall survival (OS) and progression-free survival (PFS) for patients with diabetes versus those without diabetes, and diabetes mellitus was identified as an independent risk factor for shorter PFS and OS. It followed that immunotherapy might be less beneficial for patients with metastatic NSCLC. Despite inspiring and thoughtprovoking findings, we would like to raise the following comments.First, demographic and clinical characteristics associated with NSCLC, such as age, comorbidities, and body mass index (BMI), were included in the study, as presented in the article's Table 1. However, significant differences between diabetic and nondiabetic groups existed in age, the presence of hypertension, BMI, and so on. As is known to all, lung cancer is an age-related disease. 2 Current evidence suggests that BMI is strongly associated with OS in patients with advanced NSCLC. 3,4 In other words, these confounding variables between diabetic and nondiabetic groups indicated an unbalanced background.

Non-Invasive Predictive Biomarkers for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors

“…Chronic proton pump inhibitor use was also found to be adversely associated with GI irAEs in a cohort of 363 patients who received ICI (HR 13.22, 95% CI 3.11–56.10) [ 138 ]. Exposure to metformin, a drug used for type 2 diabetes mellitus, was recently shown to be associated with an increased risk of death compared to other non-insulin hypoglycemic agents despite its presumed antitumor and immunomodulating effects [ 139 , 140 , 141 ]. Further studies are needed to elucidate the causality of metformin and observed mortality, and whether this is associated with irAEs.…”