Abstract B041: GLP-1 receptor agonists associated with improved response to immune checkpoint inhibitors in solid tumors: a multi-institutional retrospective cohort study

Abstract Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly utilized for Type 2 Diabetes Mellitus (T2DM), obesity, and non-alcoholic steatohepatitis (NASH). Despite growing prevalence, data regarding their safety and influence on clinical outcomes in patients with malignancies treated with immune checkpoint inhibitors (ICIs) remain scarce. This study evaluated the safety and impact of concurrent GLP-1 receptor agonist use on ICI efficacy in a multi-cohort population. Methods: We conducted a retrospective, propensity score-matched (PSM) analysis using the TriNetX global federated health research network. Patients with Renal Cell Carcinoma (RCC), Melanoma, Lung Cancer, and Breast Cancer treated with ICIs were identified. Cohorts stratified by concurrent GLP-1 receptor agonist use vs non-use were matched (1:1) for covariates including demographics, comorbidities, cancer stage, and medications altering ICI response. Primary endpoints were 3-year all-cause mortality and immune-related adverse events (irAEs). To investigate metabolic/cardiovascular mechanisms, we analyzed mean Hemoglobin A1c (HbA1c) levels and Major Adverse Cardiovascular Events (MACE) over 3 years. Surveillance bias was evaluated using Ondansetron and Sucralfate as negative controls. Results: Matched cohorts included Breast (n=294), Melanoma (n=547), RCC (n=443), and Lung (n=964) per arm. GLP-1 receptor agonist use was associated with significantly lower 3-year mortality: Melanoma (HR 0.309, 95% CI 0.23–0.42), RCC (HR 0.338, 95% CI 0.26–0.45), Breast (HR 0.326, 95% CI 0.20–0.53), and Lung (HR 0.399, 95% CI 0.34–0.46). Negative controls showed no benefit. Ondansetron HRs: Lung 0.96 (0.90–1.03), RCC 0.95 (0.83–1.10), Melanoma 1.08 (0.95–1.22), Breast 0.95 (0.69–1.30). Sucralfate HRs: Lung 0.96 (0.91–1.02), RCC 0.95 (0.81–1.11), Melanoma 1.11 (0.93–1.32), Breast 1.28 (0.99–1.64). GLP-1 receptor agonist users exhibited higher mean HbA1c levels vs non-users: RCC (7.18±1.62 vs 6.52±1.46, p<0.0001), Lung (7.21±1.57 vs 6.76±1.44, p<0.0001), Breast (6.90±1.72 vs 6.46±1.24, p=0.01), and Melanoma (7.08±1.56 vs 6.86±1.51, p=0.09). Most irAEs (e.g., colitis, thyroiditis) did not differ significantly. However, MACE was significantly increased in Lung (OR 1.585) and Breast (OR 2.000) cohorts, but unchanged in RCC and Melanoma. Conclusion: Concurrent GLP-1 receptor agonist use is associated with improved survival in ICI-treated patients. Elevated HbA1c across cohorts and higher MACE specifically in Lung/Breast cohorts suggest higher baseline metabolic/cardiovascular risk ("sick user bias") persisting despite matching. This indicates survival benefits are not attributable to improved cardiovascular outcomes or glycemic control. Instead, data support potential direct immunomodulatory enhancement of ICI efficacy by GLP-1 receptor agonists. Due to the retrospective nature, prospective studies are needed to address this, alongside preclinical studies to unveil mechanisms. Citation Format: Mostafa Eysha, Mohanad Elchouemi, Malak Fouani, Bayan Khasawneh, Mariah Black, Wanyu Zhang, Daniel Schrum, Islam Abdelmoeti, Afreen Idris . Shariff, Erika Crosby, Jeffrey Marks, Jatin Roper, Jose Conejo-garcia, Nicholas. Devito. GLP-1 receptor agonists associated with improved response to immune checkpoint inhibitors in solid tumors: a multi-institutional retrospective cohort study [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B041.