Background: Prognostic determinants in metastatic non-small cell lung cancer (mNSCLC) include numerous sociodemographic and clinical characteristics. We provide granular, real-world survival data in different cohorts of this heterogeneous population, stratifying by: age, Charlson/Deyo scoring (CDS) of comorbidity, tumor histology, and use of immunotherapy. Methods: This retrospective analysis uses the National Cancer Database (NCDB) to explore patterns of survival in patients diagnosed between 2010-2016 with mNSCLC involving the brain. Kaplan-Meier (KM) modeling was used to evaluate for differences in overall survival (OS) between 3 cohorts of patients: those undergoing 1) stereotactic radiosurgery (SRS), 2) whole-brain radiotherapy (WBRT), and 3) those not undergoing brain radiotherapy (NR) as part of the first course of treatment. As per Table, we ran 8 KM models to generate median OS (mOS) data across stratifications for age (<70 vs. ≥70), CDS (0-1 vs. 2-3), tumor histology (adenocarcinoma vs. squamous), and use of immunotherapy (yes vs. no). We provide a ranked order of these 3 cohorts by mOS (‘survival sequence’, or ‘SS’), as well as differences in mOS (‘ΔmOS’) between NR and WBRT – the two cohorts most comparable in life expectancy. Results: A total of n=38,119 patients were included in this study. Most received WBRT (n=18,052, 47.4%), n=6,562 (17.2%) received SRS, while n=13,505 (35.4%) did not receive brain radiation as part of their first course of treatment. In all subgroups, patients treated with SRS for brain metastasis had the highest mOS. Survival for those receiving WBRT was better or comparable (difference in mOS <0.5 months) to those that did not receive radiotherapy, except in patients aged ≥70 (SS: NR > WBRT; KM p-value <0.05; ΔmOS of 1.6 months), those with Charlson-Deyo comorbidity scores of 2-3 (SS: NR > WBRT; KM p-value <0.05; ΔmOS: 0.6 months), those with squamous carcinoma (SS: NR > WBRT; KM p-value <0.05; ΔmOS: 0.7 months), and those already receiving immunotherapy (SS: NR > WBRT; KM p-value <0.05; ΔmOS: 0.6 months). Conclusions: SRS for de novo brain metastases is associated with improved OS in mNSCLC. In contrast, the burden of WBRT may outweigh the survival benefit it affords in patients ≥70, and those with comorbidities. Squamous cell carcinomas may be associated with more radio-resistance than adenocarcinomas to WBRT. Finally, as previously described in melanoma, the survival benefit afforded by brain radiotherapy may be lower in patients on immunotherapy.