Abstract
BACKGROUND. 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. METHODS. Two clinical cohorts of overweight and obese patients with NSCLC — one undergoing surgical resection (n = 1,177, 71 GLP-1RA users) and another receiving immune checkpoint inhibitors (n = 300, 10 GLP-1RA users), were propensity score matched for relevant covariates and analyzed for clinical outcomes. RESULTS. 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. 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 antitumor immunity. Concurrent GLP-1RA and immunotherapy was also associated with improved overall (HR: 0.41, 95% CI: 0.16–1.01, P = 0.027) and progression-free survival (HR: 0.31, 95% CI: 0.10–0.94, P = 0.019) for patients with advanced NSCLC. CONCLUSIONS. In our cohort, GLP-1RAs enhanced lung cancer–specific clinical outcomes and augment immunotherapy efficacy. Preclinical evidence suggested this effect to be obesity restricted and mediated by immune modulation of the tumor microenvironment. FUNDING. George Duke, Department of Defense (W81XWH-21-1-0377), NIH/NIGMS (GM147497), American Cancer Society (RSG-22-071-01-TBE), NIH (1R01 CA255515-01A1), NIH/NCI (P30CA013696 and P30CA016056).
Authors
Akhil Goud Pachimatla, Bailey Fitzgerald, Joyce Ogidigo, Meera Bhatia, Randall J. Smith Jr., Kalyan Ratnakaram, Sukumar Kalvapudi, Yeshwanth Vedire, Deschana Washington, Robert Vethanayagam RR, Hua-Hsin Hsiao, Spencer Rosario, Viraj R. Sanghvi, Joseph Barbi, Sai Yendamuri
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