Unravelling the complexity of

Background: Osimertinib, a third-generation tyrosine kinase inhibitor that targets epidermal growth factor receptor (EGFR), specifically inhibits both EGFR tyrosine kinase inhibitor-sensitive mutations and T790M resistance mutations. Despite initial positive responses to EGFR tyrosine kinase inhibitors, nearly all patients eventually experience disease progression. Mechanisms of resistance are classically divided into EGFR-dependent and EGFR-independent mechanisms, such as the activation of alternative pathways and histological changes. We report a case of histological transformation into large cell carcinoma associated with the subsequent acquisition of an anaplastic lymphoma kinase (ALK) rearrangement after osimertinib exposure. Case Description: A 67-year-old female with no smoking history presented with supraclavicular lymphadenopathy and asthenia, which led to a diagnosis of stage IVB lung adenocarcinoma. Next generation sequencing (NGS) identified an Conclusions: To our knowledge, this case is the first reported incidence of transformation into large cell carcinoma coupled with a second acquisition of alterations in ALK. These findings underscore the necessity of monitoring patients with oncogenic addiction through both liquid biopsy for on-target mechanism detection and tissue sampling to detect histological transformations. These mechanisms can occasionally be combined, thereby providing comprehensive panels at each stage of tumour progression.