Glucagon-like peptide-1 receptor agonism is associated with improved lung cancer outcomes and tumor growth control

Emerging evidence indicates a reduced incidence of multiple cancers in users of Glucagon-like peptide-1 receptor agonists (GLP-1RAs), drugs widely used for glycemic control and weight reduction that modulate several key regulators of metabolism. We sought to examine their association with non-small cell lung cancer (NSCLC) outcomes in overweight and obese patients and gain mechanistic insights from mouse models. Two clinical cohorts of overweight and obese NSCLC patients—one undergoing surgical resection (n=1,177, 71 GLP-1RA users) and another receiving immune checkpoint inhibitors (ICIs; n=300, 10 GLP-1RA users), were propensity score matched for relevant covariates and analyzed for clinical outcomes. GLP-1RA use was associated with increased recurrence-free survival in overweight and obese patients (HR=0.41 [95%CI=0.16-1.04], p=0.026) after lobectomy. Further, GLP-1RA treatment reduced tumor burden in obese but not normal-weight mice and altered the frequency and phenotypes of leukocyte populations and gene expression patterns in obese tumors, crucial to cancer progression and anti-tumor immunity. Concurrent GLP-1RA and immunotherapy was associated with improved overall (0.41 [0.16-1.01], 0.027) and progression-free survival (HR=0.31, [0.10-0.94], 0.019) for patients with advanced NSCLC. GLP-1RAs may enhance lung cancer-specific clinical outcomes and augment immunotherapy efficacy. Preclinical evidence suggests this effect is obesity-restricted and mediated by immune modulation of the tumor microenvironment.