Primary Resistance to Combination Therapy with First- and Third-Generation EGFR Tyrosine Kinase Inhibitors of Lung Adenocarcinoma Harboring EGFR 19Del/T790M/in Trans-C797S Mutations with Co-Occurring CTNNB1 Alteration

Background Epidermal growth factor receptor (EGFR) in trans-C797S alteration has been considered as one of the mechanisms, which leads to the resistance to third-generation tyrosine kinase inhibitors (TKI). Several reports have suggested that combination therapy with first- and third-generation TKIs might be effective for acquired trans-C797S alteration. Case Presentation Herein, we report a patient diagnosed with lung adenocarcinoma harboring EGFR 19Del/T790M/in trans-C797S mutations with co-occurring CTNNB1 alteration showing a negative response to combination therapy with first- and third-generation TKIs. Conclusion Our report highlights the importance of deploying more informed molecular diagnosis and real-time monitoring strategies to detect co-alterations that drive disease progression and drug resistance, in order to find more effective treatment.