SPARK-Lung: A study of patterns and outcomes in young-onset lung cancer.

8070 Background: Young onset lung cancer patients diagnosed before age 50 appear to have distinct features compared to their older counterparts, including a higher proportion of never-smokers and increased frequency of targetable driver mutations. Yet, the molecular characteristics and survival outcomes of young-onset non-small cell lung cancer (NSCLC) remain poorly defined in U.S. populations. Improved understanding of the demographic and molecular profile of this distinct disease is needed to guide diagnostic testing strategies and personalize treatment. Methods: We conducted a retrospective cohort study using the US-based, electronic health record-derived deidentified Flatiron Health Research Database, which included adults diagnosed with NSCLC between 2013 and 2025 who underwent next-generation sequencing. Young-onset NSCLC was defined as age < 50 years and older-onset as ≥50 years. Demographics, stage at diagnosis, and prevalence of driver mutations and fusions were compared between age groups. Differences are reported using standardized mean differences (SMD) with SMD ≥0.2 indicating significant difference. Treatment patterns and overall survival (OS) were evaluated in metastatic patients adjusting for sex, histology, smoking status, performance status, insurance, and TP53 status. Results: Among 3792 young-onset and 120,161 older-onset patients with NSCLC across all stages, young-onset patients were more often female (54.2% vs 51.2%), Asian (5.3% vs 2.4%), Black (12.4% vs 8.1%), or Hispanic/Latino (8.5% vs 3.6%) (SMD 0.38). They were more often treated in academic settings (24.8% vs 16.0%; SMD 0.26) and more likely to have no tobacco history (36.6% vs 13.8%; SMD 0.65). Non-squamous histology predominated in younger patients (85.1% vs 73.1%; SMD 0.29) and actionable driver alterations were more common (47.8% vs 40.5%), particularly ALK (9.3% vs 1.2%; SMD 0.66) and EGFR (17.6% vs 11.0%; SMD 0.21). Young-onset patients were more likely to present with metastatic disease (69.8% vs 49.2%; SMD 0.43). After adjustment, treated young-onset patients received more lines of therapy than older patients (median no. 2 vs 1; incident rate ratio 1.16; 95% CI 1.12–1.20; p < 0.0001) and had longer median treatment duration (23.7 vs 14.3 mos, p < 0.0001). Among patients with metastatic disease at diagnosis, unadjusted median OS was longer in young-onset versus older-onset patients (2.0 vs 1.1 years), with higher 1-year (72.6% vs 57.2%) and 2-year (56.7% vs 41.8%) OS rates. Conclusions: Young-onset NSCLC represents a clinically distinct population in the United States, characterized by higher rates of advanced stage at diagnosis, a higher percentage of actionable molecular alterations and improved survival in the metastatic setting. Recognition of these differences may inform screening, testing, treatment, and survivorship strategies for younger adults with NSCLC.