Lung cancer is uncommon among people with cystic fibrosis (pwCF). We describe the case of a 35-year-old man with mild, stable CF disease who presented with severe respiratory distress, systemic symptoms, elevated liver enzymes and hypereosinophilia along with a lung mass and pleural effusion. The patient was subsequently diagnosed with non-small cell lung carcinoma (NSCLC), featuring anaplastic lymphoma kinase (ALK) translocation. Following treatment with a targeted tyrosine kinase inhibitor (TKI) there was a rapid tumor regression, however, his dyspnea and hypoxemia subsequently worsened. A trial of Elexacaftor/Tezacaftor/Ivacaftor (ETI) led to significant clinical improvement and enhanced pulmonary function.