This report describes the management of small cell lung cancer (SCLC) transformation in a patient with untreated ALK-mutated advanced disease and a minimal smoking history, and a separate case of a de novo SCLC in a lifelong nonsmoker found to have a potentially targetable ERBB2 alteration. In the first case, chemotherapy followed by a targeted inhibitor was chosen due to the presence of the ALK rearrangement, as well as a somewhat discordant response to induction chemotherapy, suggesting possible progression of the ALK inhibitor–sensitive component. Molecular testing for the identification of driver mutations should be considered in patients with SCLC who have light/never smoking histories in order to help understand the incidence and ultimate optimal management strategies.
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