Here, we describe a case report of a patient with metastatic NSCLC harboring <i>EGFR</i> mutation who developed two independent resistance mechanisms (<i>EGFR</i>-T790M and <i>TP53</i> + <i>RB1</i> mutations) to dacomitinib. This evidence concerns the gene EGFR and non-small cell lung carcinoma.