Cortellini and colleagues have reported a detrimental effect of metformin on outcomes of immune checkpoint inhibition (ICI) therapy for advanced solid tumors (54% non–small cell lung cancer, NSCLC) in patients with type 2 diabetes mellitus (DM; ref. 1). The same group of investigators has previously noted that overweight and obese patients—body mass index (BMI) ≥ 25—with advanced solid tumors (65% NSCLC; type 2 DM status not reported) responded better to programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) ICI than those with a smaller BMI (2), in agreement with conclusions of other similar studies. We therefore request the authors to report in their new study the influence of BMI on the association of metformin use and ICI outcome. There are enough observations today to warrant stratified analyses of outcomes of ICI and other targeted therapies by overweight and obesity, including ours suggesting that metformin use reduces expression of immune checkpoint genes, including those encoding PD-1 and PDL-1, in NSCLC tumors of only the overweight or obese but not others (3). Indeed, a lack of consideration of obesity in the outcome analysis may explain why the harmful effect of metformin on ICI that is reported in this study is at discordance with studies reporting either a beneficial effect (4) or no effect (5) of metformin on response of patients with type 2 DM to ICI therapy for advanced NSCLC.
S. Yendamuri reports grants from Lumeda Inc outside the submitted work. No disclosures were reported by the other author.