Dynamic clonal evolution of multiple bypass resistance mechanisms in EGFR-mutant lung adenocarcinoma: a case report

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved outcomes for patients with EGFR-mutant non-small-cell lung cancer (NSCLC). However, acquired resistance remains a critical clinical challenge.Here, we present the case of a 62-year-old male with stage IIB poorly differentiated lung adenocarcinoma harboring an EGFR L858R mutation. The patient received adjuvant aumolertinib following surgical resection. Serial sampling and dynamic next-generation sequencing (NGS) revealed a sequential bypass resistance clone evolution trajectory in this patient: initial MET amplification was followed by the detection of a BRAF V600E mutation concurrent with RET fusion, while in the terminal phase, MET amplification re-emerged alongside a progressively increasing TP53 variant allele frequency (VAF).Genotype-guided therapy adjustments yielded an 11-month progression-free survival (PFS) with aumolertinib plus savolitinib, whereas subsequent selpercatinib combined with chemotherapy provided only transient disease stabilization. Ultimately, the patient died of respiratory and circulatory failure due to progressive disease complicated by diffuse carcinomatous lymphangitis. Based on current evidence, we speculate that these bypass resistance alterations are driven by reactivation of the MAPK and PI3K/AKT signaling cascades. The progressive increase in TP53 mutant allele frequency was temporally concordant with the sequential emergence of bypass resistance mechanisms, suggesting an unfavorable prognosis. However, its utility in guiding therapeutic modifications requires further validation. This case illustrates that EGFR L858R-mutant lung adenocarcinoma can undergo stepwise clonal evolution of multiple bypass resistance mechanisms under aumolertinib selective pressure. Dynamic NGS profiling enables real-time tracking of resistant clone evolution to inform individualized treatment strategies.