Mutations in the epidermal growth factor receptor (EGFR) have been implicated in nearly one-third of non-small-cell lung cancers. For patients harboring non-traditional mutations, genomic and transcriptomic sequencing can help direct treatment. As cancer genomics evolves, novel driver mutations continue to be uncovered. We report on a unique EGFR-GRB2 fusion in a 48-year-old female never-smoker. This patient presented with stage IV lung adenocarcinoma (T2aN3M1) with metastatic disease in the iliac wing and liver. Despite systemic treatment, this patient continued to progress. On whole transcriptome sequencing, this patient was found to have a novel EGFR-GRB2 RNA fusion transcript similar to other EGFR fusions described in the literature. After treatment with osimertinib, this patient experienced remarkable clinical and radiological improvements. We believe that, especially for patients with metastatic lung cancer, the presence of novel driver mutations should be investigated. Potentially, patients harboring similar mutations may demonstrate analogous improvements with targeted treatment using the most recent generation of tyrosine kinase inhibitors.