Acquired CCDC6-RET Fusion After First-Line Osimertinib in Epidermal Growth Factor Receptor (EGFR)-Mutant Lung...

Osimertinib is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with sensitizing epidermal growth factor receptor (EGFR) mutations. Despite initial responses, most patients eventually develop acquired resistance through heterogeneous molecular mechanisms, including activation of bypass signaling pathways. RET gene fusions represent a rare and still underreported cause of acquired resistance, for which clinical evidence supporting combined targeted treatment remains limited. We report a case of EGFR exon 19-mutant lung adenocarcinoma that developed an acquired CCDC6-RET fusion following treatment with first-line osimertinib, identified through repeat molecular profiling at disease progression. Radiological assessment revealed a heterogeneous pattern of response, with sustained control of the primary lung lesion and improvement in some metastatic sites, alongside progression in others, predominantly in the liver, supporting the hypothesis of intratumoral heterogeneity. A combined strategy with continued osimertinib and addition of the selective RET inhibitor selpercatinib was pursued based on biological rationale; however, the short duration of combined treatment precluded a meaningful assessment of clinical benefit. This case highlights the importance of molecular reassessment at progression to identify rare but actionable resistance mechanisms that may significantly influence therapeutic strategy in EGFR-mutant NSCLC.