Background: Guidelines (NCCN, CAP/IASLC/AMP) recommend clinical molecular testing of patients with advanced NSCLC to inform therapy decisions. We investigated the testing and treatment patterns of patients with stage 4 NSCLC treated in the real-world setting. Methods: This retrospective observational study included de-identified stage 4 NSCLC patients from the Integra Connect PrecisionQ database (ICD) enriched with information obtained by curation. Patients with a positive mutation for EGFR, ALK, ROS1, BRAF, MET, RET, HER2, or NTRK and who initiated treatment for stage 4 NSCLC between 01/01/2018 and 12/31/2021 were included with follow-up through 05/31/2022. Also included were demographics, ECOG score, time of ordering test, and date of death. Genomic test data were classified by method and type of test. Overall survival (OS) was calculated using Kaplan-Meier curves and data are presented using descriptive statistics. Results: Of 5195 patients in the ICD with stage 4 NSCLC, 3532 patients initiated first line of therapy (LOT1), and 2899 had somatic molecular testing ordered, specifically via tissue-based next-generation sequencing (NGS, 30%), plasma-based NGS (26%), or non-NGS methods (44%). A total of 934 patients tested positive for a driver mutation at any time during the study observation period, and 671 patients (72%) had test results available before initiating treatment. Of those treated after receiving biomarker results, 407 (61%) initiated treatment with a tyrosine kinase inhibitor (TKI), 43 (6%) with chemotherapy (chemo), 156 (23%) with chemo + immuno-oncology (IO), and 65 (10%) with IO. The median OS (95% confidence interval [CI]) was 24.46 (21.90-29.18) months for patients treated with TKI and 14.2 (11.6-16.5) months for patients treated without TKI (unadjusted hazard ratio [95% CI], 1.56 [1.26, 1.92]; P < 0.001). Conclusions: Among patients with stage 4 NSCLC treated in the real-world setting, patients treated with TKI after receiving test results had better overall survival than patients treated without TKI. While subject to the limitations of a retrospective observational real-world data study, this study suggests that, with regard to utilizing genomic testing and appropriate selection of targeted treatment, adherence to treatment guidelines may improve patient outcomes. As new targeted agents continue to emerge in NSCLC, these data encourage utilization of genomic testing data to guide treatment selection. We acknowledge the significant contributions of our dear friend, Dr. Robert E. Smith, whose cheerful enthusiasm and deep expertise were a driving force of this work.