Acquired EGFR L858R mutation following ALK-TKI resistance in lung adenocarcinoma: a case report

Reports of secondary mutations in mutual exclusive driver genes after resistance to targeted therapy are rare. We present a patient with Anaplastic lymphoma kinase (<i>ALK</i>) fusion lung adenocarcinoma who received sequential treatment with ALK tyrosine kinase inhibitor (TKI) (crizotinib, PFS:32.3 months and then conteltinib, PFS: 29 months). Upon further disease progression, a lung biopsy and next-generation sequencing (NGS) revealed acquired secondary driver mutations including Epidermal Growth Factor Receptor (<i>EGFR)</i> L858R and <i>ALK</i> mutation of F1174L. Subsequently, the patient switched to third generation <i>EGFR</i>-TKI treatment with almonertinib. This case suggests <i>EGFR</i> mutation is one of the mechanisms of <i>ALK</i>-TKI resistance, highlights the value of re-biopsy in identifying potentially targetable resistance mechanisms and underscores the spatiotemporal heterogeneity of tumors under the selective pressure of <i>ALK</i>-TKI.