fusion as a potential primary resistance mechanism to EGFR-TKI in lung adenocarcinoma harboring co-driven mutations: a case report.

Oncogenic driver mutations were once considered mutually exclusive in non-small cell lung cancer (NSCLC), and the optimal management for these patients with co-mutations of driver genes remains controversial. We report a 66-year-old never-smoking female patient with exon 19 deletion (19del) metastatic NSCLC. Progression occurred after around seven months of first-line treatment with osimertinib. After the progression, the molecular testing revealed fusion in a liver metastasis, two novel fusions ( and ), and an fusion with a mutation allele frequency of 0.19% in circulating tumor DNA (ctDNA), including the known 19del. Pralsetinib was added to osimertinib, resulting in a response lasting 4 months. Molecular detection of both liver and ctDNA revealed the presence of fusions, while 19del still existed, but fusions disappeared. After one month with alectinib only, osimertinib was added due to the progression, resulting in another response of more than two months. Upon progression with quadruple alterations ( 19del, C797S, amplification, and fusions), cabozantinib-gefitinib combination was initiated, leading to rapid deterioration. Interestingly, an 3 fusion was detected at baseline before EGFR-TKI initiation and persisted throughout the patient's treatment course. The patient died about 18 months after the initial diagnosis of metastatic NSCLC. This case demonstrates that iterative molecular profiling in metastatic NSCLC identifies actionable alterations to optimize clinical management. At the same time, comprehensive genomic testing remains essential for therapeutic decision-making, with ctDNA analysis complementing tissue-based approaches. Notably, the fusion may represent a novel resistance mechanism contributing to the limited efficacy of EGFR-TKI.