Sequential EGFR T790M, MET c.3010C>G-Associated Exon 14 Alteration, and RET-CCDC6 Fusion in EGFR-Mutant NSCLC: A Case Report.

Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) is heterogeneous, and serial re-biopsy may uncover actionable mechanisms. We report a 55-year-old man with stage IVB lung adenocarcinoma harboring EGFR L858R and TP53 R282W. First-line icotinib produced a partial response (PR) with progression-free survival (PFS) of 7 months. Rebiopsy at progression identified acquired EGFR T790M together with a MET c.3010C>G exon 14-related alteration. Almonertinib induced a second PR lasting 7 months. After renewed progression, almonertinib plus savolitinib achieved another PR for 8 months, supporting MET-dependent bypass resistance. Biopsy of a newly progressive iliac metastasis then showed emergence of RET-CCDC6 fusion, whereas T790M and the MET alteration were no longer detected. Because selective RET inhibition was initially unaffordable, the patient received pemetrexed-carboplatin plus continued almonertinib, followed by selpercatinib plus almonertinib. Local radiotherapy to oligoprogressive bone and lung lesions prolonged benefit from systemic therapy. At the latest follow-up in January 2026, the patient remained alive nearly 50 months after diagnosis. This case illustrates clonal evolution under treatment pressure and highlights three practical lessons: repeat molecular testing at each clinically meaningful progression, matched combination targeted therapy for actionable bypass alterations, and local ablative radiotherapy for oligoprogression.