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Background: Treatment paradigms for metastatic non-small cell lung cancer are increasingly based on biomarker-driven therapies, with the most common alteration being mutation in the epidermal growth factor receptor (EGFR). Change in expression of such biomarkers could have a profound impact on the choice and efficacy of a selected targeted therapeutic, and hence the objective of this study was to analyze discordance in EGFR status in patients with lung cancer brain metastasis (LCBM). Methods: Using PRISMA guidelines, a systematic review was performed of series in the Medline database of biopsied or resected LCBM published before May, 2020. Key words included “lung cancer” and “brain metastasis” combined with “epidermal growth factor receptor/EGFR,” and “receptor conversion/discordance or concordance.” Weighted random effects models were used to calculate pooled estimates. Results: We identified 501 patients from 19 full-text articles for inclusion in this study. All patients underwent biopsy or resection of at least one intracranial lesion to compare to the primary tumor. On primary/LCBM comparison, the weighted pooled estimate for overall EGFR receptor discordance was 10% (95% CI 5–17%). The weighted effects model estimated a gain of an EGFR mutation in a brain metastases in patients with negative primary tumors was 7% (95% CI 4–12%). Alternatively, the weighted effects model estimate of loss of an EGFR mutation in patients with detected mutations in the primary tumor was also 7% (95% CI 4–10%). KRAS testing was also performed on both primary tumors and LCBM in a subset of 148 patients. The weighted effects estimate of KRAS-mutation discordance among LCBM compared to primary tumors was 13% (95% CI 5–27%). The weighted effects estimated of KRAS gain and loss in LCBM was 10% (95% CI 6–18%) and 8% (95% CI 4–15%), respectively. Meta-regression analysis did not find any association with any factors that could be associated with discordances. Conclusions: EGFR and KRAS mutation status discordance between primary tumor and LCBM occurs in approximately 10% and 13% of patients, respectively. Evaluation of LCBM receptor status is key to biomarker-driven targeted therapy for intracranial disease and awareness of subtype switching is critical for those patients treated with systemic therapy alone for intracranial disease.