Secondary biopsy of non‐oncogenic‐driven lung cancer may reveal a clinically sensible histologic change. A brief report of two paradigmatic cases

After an initial benefit, non‐small‐cell lung cancer (NSCLC) patients receiving therapy with tyrosine kinase inhibitors develop drug resistance through a variety of mechanisms. Among these, tumor histology changes are a mechanism of acquired resistance in epidermal growth factor receptor‐mutated and anaplastic lymphoma kinase‐rearranged NSCLC cases. The current availability of therapeutic approaches to overcome tyrosine kinase inhibitor resistance in oncogenic‐driven lung cancers justifies secondary tumor biopsy in these patients. On the other hand, little is known about the mechanism of disease progression in non‐oncogenic driven NSCLC. Nevertheless, NSCLC lacking “druggable” genetic alterations are not considered for secondary biopsy, as it is commonly believed that these tumors cannot develop histologic or molecular changes. Herein, we report two paradigmatic cases of wild‐type NSCLC showing histologic “change” on secondary biopsy, allowing for a successful switch in therapeutic strategy.