Comprehensive molecular profiling in advanced non–small cell lung cancer (NSCLC): Measurable survival and value impacts of implementation.

11054 Background: Comprehensive molecular profiling (CMP) is key to precision oncology in advanced non–small cell lung cancer (NSCLC), enabling identification of actionable driver alterations and delivery of matched targeted therapies that improve survival. CMP has been universally recommended by international guidelines for over a decade. Despite mature evidence and widespread availability, real-world adoption remains strikingly low. We evaluated the real-world impact of molecular profiling on survival, healthcare utilization, and cost in NSCLC, and quantified the magnitude of its ongoing underuse. Methods: We analyzed NSCLC patients aged ≥18 years treated between January 2019 and December 2025 using two independent real-world datasets: TriNetX and Highmark Health. Patients were categorized based on receipt of broad-panel molecular profiling consistent with guideline-directed indications. Outcomes included overall survival (OS), emergency department (ED) visits, inpatient admissions, and healthcare costs. Survival was assessed using Kaplan–Meier methods, with multivariable regression to adjust for clinical factors. Results: Among 33,977 NSCLC patients in TriNetX, only 2,354 (6.9%) underwent molecular profiling, despite the majority of NSCLC patients presenting with advanced disease. Molecularly profiled patients experienced a substantial survival advantage, with median OS of 1,784 days versus 1,074 days in untested patients (adjusted hazard ratio 0.61; p<0.001). Molecular profiling was also associated with significantly fewer inpatient admissions (0.651 vs 0.875; p<0.001) and ED visits (0.437 vs 0.583; p=0.047). Highmark Health data independently validated these findings, demonstrating significantly improved 4-year OS in molecularly tested patients (55% vs 43%; p<0.001). Importantly, these survival gains were achieved without a statistically significant increase in total cost per patient per month at follow-up (p=0.083). Conclusions: Across two large, independent real-world datasets, comprehensive molecular profiling in NSCLC was associated with meaningful improvements in survival and reductions in healthcare utilization, even when applied primarily in advanced disease. These benefits were achieved without a significant increase in overall costs, supporting the value-based impact of precision oncology. Yet fewer than 1 in 15 eligible NSCLC patients underwent molecular profiling between 2019 and 2025, revealing a profound and persistent failure to implement guideline-concordant care. This underuse directly translates into avoidable mortality and unnecessary healthcare utilization. System-level solutions, including standardized and reflexive molecular testing at diagnosis, are urgently needed to ensure precision medicine is delivered as standard care in advanced NSCLC patients.