Metachronous development of L858R and T790M EGFR mutations following ALK inhibitor therapy in stage IV lung adenocarcinoma: a case report.

Background: Metachronous lung cancers with distinct driver mutations are rare, particularly following targeted therapy. This report presents a unique case of tumor evolution in non-small cell lung cancer (NSCLC).

Case description: A 73-year-old East Asian woman was diagnosed with stage IV anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinoma in the right middle lobe (RML). After 18 months of alectinib treatment, while the initial lesion regressed, a new nodule developed in the right upper lobe (RUL). Biopsy revealed adenocarcinoma with epidermal growth factor receptor (EGFR) L858R/T790M co-mutations without ALK rearrangement. We conducted a comparative analysis of genetic alterations in biopsies from 2022 and 2024 using targeted next-generation sequencing (NGS), revealing significant molecular evolution over time, with a marked increase in single nucleotide variants (SNVs) and copy number variants (CNVs) and distinct changes in key mutations such as ALK-EML4 and EGFR. The patient received stereotactic body radiotherapy (SBRT) for the new lesion while continuing alectinib, resulting in significant improvement until now.

Conclusions: This case represents the first documented occurrence of metachronous L858R and T790M EGFR mutations following ALK inhibitor therapy, highlighting the emergence of distinct driver mutations over time and reflecting temporal and spatial tumor heterogeneity. These findings underscore the importance of monitoring clonal evolution to guide tailored therapeutic strategies in NSCLC. Furthermore, re-biopsy is essential to assess tumor heterogeneity, identify potential drug resistance, and detect new mutations, ensuring that treatment strategies remain optimized for evolving disease conditions.