Abstract
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 EGFR 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 CCDC6-RET fusion in a liver metastasis, two novel RET fusions (IL6ST-RET and SLC41A3-RET), and an ALK fusion with a mutation allele frequency of 0.19% in circulating tumor DNA (ctDNA), including the known EGFR 19del. Pralsetinib was added to osimertinib, resulting in a response lasting 4 months. Molecular detection of both liver and ctDNA revealed the presence of ALK fusions, while EGFR 19del still existed, but RET 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 (EGFR 19del, EGFR C797S, MET amplification, and RET fusions), cabozantinib-gefitinib combination was initiated, leading to rapid deterioration. Interestingly, an FGFR3-TACC3 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 FGFR3-TACC3 fusion may represent a novel resistance mechanism contributing to the limited efficacy of EGFR-TKI.