Efficacy of targeted therapy in advanced NSCLC patients with rare EGFR mutations and combinations of mutations

The efficacy of targeted therapy in rare epidermal growth factor receptor ( EGFR ) gene mutations in non-small cell lung cancer is debatable. However, due to introduction of NGS technology into clinical practice, patients with non-small cell lung cancer (NSCLC) harbouring rare EGFR mutations are being identified more often. We report here the case demonstrating the absence of EGFR mutations at the initial stage of diagnosis of metastatic lung adenocarcinoma in November 2024. The chemotherapy consisting of pemetrexed, carboplatin, and bevacizumab was initiated in December 2024. During treatment, a comprehensive genomic profiling test (Foundation One Liquid CDx Roche) was performed to evaluate a patient’s blood for circulating tumour DNA (ctDNA). A rare EGFR E114K extracellular domain mutation and mutations in the cell cycle checkpoint kinase 2 ( CHEK2 ) – V335fs*14, PTPN11 – G503V, and TP53 splice site 375G > T were identified. Osimertinib at a dose of 80 mg daily has been administered since April 2025. After the sixth course of polychemotherapy and targeted therapy (PCT+TT) in May 2025 and with due account for stabilization based on 18F-FDG PET-CT findings, the patient continued to receive the maintenance chemotargeted therapy with pemetrexed and osimertinib, showing disease stability. Most studies that led to the introduction of tyrosine kinase inhibitors excluded patients with rare EGFR mutations. Moreover, for many mutations, it is still unclear whether they are disease activating or merely incidental findings. Nevertheless, the available separate data suggest that osimertinib, EGFR tyrosine kinase inhibitor (EGFR-TKI), has clinical efficacy in rare EGFR mutations.