Case Report: Dynamic TKI combination strategies for EGFR-mutant NSCLC with acquired ROS1 fusion and brain metastases

The development of a ROS1 fusion as a bypass signaling pathway mediating resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) is rare, with only sporadic cases reported in the literature. Consequently, no consensus exists on the optimal treatment sequencing for such patients. We report the case of a 61-year-old woman diagnosed with stage IV lung adenocarcinoma with brain metastasis harboring an EGFR exon 19 deletion (p.E746_A750del), who acquired resistance to osimertinib through a ROS1 fusion bypass pathway. The patient achieved a survival of over 6.5 years from initial diagnosis through ongoing adjustments to targeted therapy, including sequential treatment with crizotinib, entrectinib, and lorlatinib. Although all three agents target ROS1, they exhibited distinct side effect profiles in this patient. Notably, we observed an interesting phenomenon with both crizotinib and entrectinib: while initial treatment led to intolerable adverse reactions requiring discontinuation, subsequent reintroduction of the same agent was well-tolerated. This case report aims to provide potential treatment strategies for patients with similar complex co-mutations.