A challenging case of stage IV EGFR-mutant lung cancer with histologic transformation and multiple resistance mechanisms

•Molecular testing during progression is essential to identify resistance mechanism.•Acquired resistance events can lead to successful treatment strategies.•Neuroendocrine transformation is seen with biallelic LOF of TP53&RB1 in EGFR+ NSCLC. This clinical case presents a patient with NSCLC who experienced on-target resistant mutations and tumor cell transformation from adenocarcinoma to large cell neuroendocrine and small cell carcinoma. Our patient was successfully treated with a combination of targeted therapy, immunotherapy and chemotherapy based on genetic and histologic changes that occurred in a period of five years.