Acquired ROS1 Intragenic Rearrangements as a Resistance Mechanism in EGFR-Mutant Non-Small Cell Lung Cancer: A Case Series

Lung cancer is a leading cause of global cancer mortality, with EGFR mutations serving as a primary therapeutic target. Although EGFR tyrosine kinase inhibitors (TKIs) are initially effective, acquired resistance inevitably develops. While ROS1 rearrangements are well-known baseline drivers, they are exceptionally rare as acquired resistance mechanisms. We utilized next-generation sequencing (NGS) to identify a rare ROS1 intragenic rearrangement (exons 35–37) in three never-smoking women with EGFR-mutant lung adenocarcinoma following progression on EGFR TKIs. Clinical courses were heterogeneous: one patient achieved a durable partial response using combined osimertinib and crizotinib. A second patient, intolerant to dual TKI therapy due to QTc prolongation and grade 3 edemas, achieved a sustained partial response with platinum-pemetrexed chemotherapy. The third patient exhibited polyclonal resistance, including EGFR C797S and TP53 mutations, with fatal central nervous system progression. In this three-patient case series, ROS1 exon 35–37 RNA-level intragenic rearrangements were repeatedly detected after EGFR-TKI progression, suggesting a rare transcript-level alteration within heterogeneous resistance evolution. However, its biological significance, driver versus passenger role, and therapeutic relevance remain uncertain. Combined EGFR and ROS1 inhibition may be considered in selected cases, but further validation is required.