The effect of glucagon-like peptide-1 (GLP-1) receptor agonists on outcomes in metastatic non-small cell lung cancer (mNSCLC) patients treated with tyrosine kinase inhibitors (TKIs): Real-world retrospective analysis.

8636 Background: The therapeutic landscape of mNSCLC has rapidly evolved, with multiple oncogenic alterations now targetable by approved TKIs used in first-line settings, leading to substantial survival gains. However, several TKIs are associated with metabolic toxicities, including weight gain and hyperlipidemia, particularly with ALK inhibitors (e.g., lorlatinib) and selective RET inhibitors. As use of GLP-1 has increased among patients with cancer, their impact on outcomes in oncogene-driven mNSCLC treated with TKIs remains unknown. We evaluated the association between GLP-1 use and survival outcomes in TKI-treated mNSCLC using real-world data. Methods: We conducted a retrospective analysis using TriNetX, a Global Collaborative electronic health record with > 190 million patients and > 170 healthcare organizations, from 2010-2025. Adults (≥18 years) with mNSCLC, metabolic comorbidities (T2DM, obesity, or hyperlipidemia), and treatment with first line-approved TKIs (EGFR, ALK, ROS1, RET, NTRK, BRAF, MET) were included. Patients were stratified by concomitant GLP-1 use and matched 1:1 using propensity scores based on demographics, ECOG performance status, cardiometabolic comorbidities, tobacco and alcohol use, and outpatient healthcare utilization. 5 year overall survival (OS) was assessed. Results: A total of 25,008 patients met inclusion criteria, including 24,459 (97.8%) non-GLP1 users and 549 (2.2%) in GLP-1 users. After 1:1 propensity score matching (PSM), 546 patients were included per group. Amongst both cohorts average age was 64, 61% were female, 60% were White, 13% were Asian. In the overall mNSCLC TKI-treated patients, GLP-1 use was associated with significantly improved 5-year OS compared with non-use (63% vs 40%; HR 0.45, 95% CI 0.36-0.57; p < 0.001). In subgroup analyses, patients treated with ALK TKIs (lorlatinib or alectinib; n = 128/group) demonstrated improved 5 year OS with GLP-1 use 85% vs 48% in non-users (HR, 0.18; 95% CI, 0.09 - 0.36; p < 0.0001). Furthermore, GLP-1 use was also associated with improved 5-year OS among EGFR TKI-treated patients (54% vs 44%; HR 0.60, 95% CI 0.44-0.82; p = 0.001) and BRAF TKI-treated patients (41% vs 35%; HR 0.52, 95% CI 0.30-0.91; p = 0.02). Other TKI groups comprised relatively small numbers of patients and therefore were not analyzed separately. Conclusions: In this large real-world analysis, GLP-1 use was associated with significantly improved survival in patients with oncogene-driven mNSCLC treated with TKIs, with consistent benefit across ALK, EGFR, and BRAF-driven mNSCLC. To our knowledge, this is the first study to link the impact of the GLP-1 agonists on the outcomes of TKI treated mNSCLC. Further prospective studies are needed to validate these findings and to identify underlying mechanisms.