Background: As the number of approved molecularly-targeted therapies for the treatment of lung cancer increases, the debate continues as to whether a clinical strategy leveraging next-generation sequencing (NGS) comprehensive genomic profiling (CGP) to match patients to targeted treatments is advantageous versus a narrow/single-gene (N/S) panel testing. We examined clinical and economic outcomes of patients with advanced lung cancer (aLC) in the United States (US). Methods: In this retrospective study, newly diagnosed aLC patients aged 65-89 years were identified from a US Medicare Advantage plan from 2018-2020. Patients receiving genomic testing within 90 days of diagnosis and an FDA-approved pharmacotherapy cancer treatment after diagnosis were categorized by initial sequencing with NGS CGP (51+ genes) vs N/S (≤50 genes) panel testing using administrative claims based on previously validated algorithms. We assessed the proportion of patients with an inpatient or emergency department (INP/ED) visit for select outcomes (e.g., neutropenia) within 6 months of start of treatment, all-cause mortality, and PPPM (per patient per month) total healthcare costs through all available follow-up. Genomic testing costs within 90 days of cancer diagnosis were estimated using the Medicare fee schedule. Among patients with treatment within 30 days of testing, we assessed the proportion who did not switch treatment and were alive within 6 months. Descriptive analyses were conducted, and average effects were estimated using inverse probability weighted regression models. Results: We identified 3,532 patients who received genomic testing and pharmacotherapy cancer treatment (NGS CGP, n = 968; N/S, n = 2,564). Characteristics were similar between testing groups. The proportion of patients with INP/ED for outcomes of interest was similar following NGS CGP vs. N/S panels (15.0% vs. 17.8%; IRR [95% CI]: 0.76 [0.57 – 1.02]; p = 0.066), as were mortality (56.2% vs. 59.2%; HR: 1.05 [0.95 - 1.16]; p = 0.323) and PPPM costs (PPPM median cost difference -$575; ratio from regression 0.99, 0.94-1.04; p = 0.228). Among a subgroup of patients treated within 30 days of testing, a higher proportion receiving NGS CGP did not switch treatment and were alive after 6 months (47.6%) vs those receiving N/S panels (39.8%) (OR [95% CI]: 1.33 [1.12 - 1.59]; p = 0.001). Median genomic testing costs were $3,049 for NGS CGP vs. $218 for N/S testing. Conclusions: Outcomes were similar between patients receiving NGS CGP and N/S panel testing. Among patients with treatment within 30 days of testing, upfront NGS CGP was associated with fewer patients switching treatment and 6-month survival. Upfront testing with NGS CGP may represent a beneficial genomic profiling strategy as part of the initial management of patients with aLC.