Purpose: No evidence exists as to whether type 2 diabetes (T2DM) impairs clinical outcome from Immune Checkpoint Inhibitors (ICI) in patients with solid tumors. Experimental Design: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose lowering medications (GLM) for T2DM had shorter OS and PFS. We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment of patients with/without diabetes. Results: A total of 1395 patients were included. Primary tumors included NSCLC (54.7%), melanoma (24.7%), renal cell (15.0%) and other carcinomas (5.6%). Following multivariable analysis, patients on GLM (n=226, 16.2%) displayed an increased risk of death (HR 1.29, 95%CI:1.07-1.56) and disease progression/death (HR 1.21, 95%CI:1.03-1.43) independent of number of GLM received. We matched 92 metformin exposed with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM was associated with an increased risk of death (HR 1.53, 95%CI:1.16-2.03) and disease progression/death (HR 1.34, 95%CI:1.04-1.72). T2DM patients with higher pre-treatment glycaemia had higher neutrophil-to-lymphocyte ratio (p=0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n=22) revealed differential regulation of innate and adaptive immune pathways in T2DM patients. Conclusions: In this study patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a pre-existing diagnosis of T2DM in influencing poorer outcomes in this population.

<p>Summary of baseline characteristics’ distribution between patients on metformin only and those who were not on diabetes medications.</p>

<p>Volcano plot of differentially regulated genes identified by Nanostring analysis. The Benjamini–Hockberg P-values are correlated to fold-changes in transcripts identified in diabetic samples (n = 11) versus non-diabetic controls (n = 11). The transcripts achieving the highest statistical significance (p value <0.05) are highlighted by the presence of the corresponding gene name. Significantly downregulated transcripts: HRAS, Ras oncogene family (p=0.009); GTF3C1, transcription factor of the TFIIIC complex (p=0.018); LAG3, key immune checkpoint for T cell modulation (p=0.023); BIRC5, survivin – modulator of programmed cell death (p=0.038); CXCL9 (p=0.038) and CXCL11 (p=0.048), two chemokines mediating inflammatory response; OAS3, interferon-induced enzyme (p=0.04). Significantly upregulated transcripts: IL22RA1, cytokine receptor (p=0.01); MME, transmembrane glycoprotein (p=0.02).</p>

<div>AbstractPurpose:<p>No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors.</p>Experimental Design:<p>In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose-lowering medications (GLM) for T2DM had shorter overall survival (OS) and progression-free survival (PFS). We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment (TME) of patients with or without diabetes.</p>Results:<p>A total of 1,395 patients were included. Primary tumors included non–small cell lung cancer (NSCLC; 54.7%), melanoma (24.7%), renal cell (15.0%), and other carcinomas (5.6%). After multivariable analysis, patients on GLM (<i>n</i> = 226, 16.2%) displayed an increased risk of death [HR, 1.29; 95% confidence interval (CI),1.07–1.56] and disease progression/death (HR, 1.21; 95% CI, 1.03–1.43) independent of number of GLM received. We matched 92 metformin-exposed patients with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM, was associated with an increased risk of death (HR, 1.53; 95% CI, 1.16–2.03) and disease progression/death (HR, 1.34; 95% CI, 1.04–1.72). Patients with T2DM with higher pretreatment glycemia had higher neutrophil-to-lymphocyte ratio (<i>P</i> = 0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (<i>n</i> = 22) revealed differential regulation of innate and adaptive immune pathways in patients with T2DM.</p>Conclusions:<p>In this study, patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a preexisting diagnosis of T2DM in influencing poorer outcomes in this population.</p></div>