Non-small cell lung cancer (NSCLC) is frequently associated with central nervous system metastases resulting in poor outcomes. As newer targeted therapies become available determining which patients can benefit from these therapies has remained challenging, and current molecular testing options rely on a panel of only a handful of known oncogenic drivers. Here, we demonstrate a targeted approach at uncovering clinically relevant variants in cancer-associated genes using genomic sequencing. Our patient underwent targeted sequencing of 212 cancer-associated genes, revealing mutations in six; two of which were in EGFR, an important target for therapy in NSCLC. A multidisciplinary approach involving surgical resection, radiation, and targeted therapy based on the genomic profile and tumor pathology ultimately lead to positive therapeutic response and stable disease. Our report provides a proof of principle for incorporating higher throughput genomic sequencing techniques directly into patient care. We also report an atypical response of an EGFR mutation positive metastatic tumor to immune checkpoint therapy, despite recent reports suggesting that these patients do not benefit from immune checkpoint inhibitors. A brief review of current literature is discussed here to explore links between EGFR mutations and PD-L1 expression, as well as response to targeted therapies.