Acquired EML4-ALK fusion and BRAF V600G dual bypass activation following osimertinib resistance in lung adenocarcinoma and successful treatment with lorlatinib: a case report.

BACKGROUND: While osimertinib is the standard of care for EGFR-mutated advanced non-small cell lung cancer (NSCLC), acquired resistance is inevitable. Resistance mechanisms involving the simultaneous activation of dual bypass pathways, coupled with the complete loss of the primary EGFR mutation, are exceptionally rare and pose significant therapeutic challenges. CASE PRESENTATION: We report a clinically instructive case of a 64-year-old female with stage IV lung adenocarcinoma initially harboring an EGFR exon 19 deletion. She received uninterrupted first-line osimertinib for approximately five years, with good tolerability and no dose reduction or treatment interruption. During follow-up, a small asymptomatic central nervous system (CNS) oligoprogressive lesion was initially managed with continued osimertinib and close brain magnetic resonance imaging (MRI) surveillance because extracranial disease remained controlled. CyberKnife stereotactic radiosurgery (SRS) was subsequently performed after lesion enlargement, followed by systemic thoracic progression. A repeat biopsy, analyzed via immunohistochemistry and comprehensive next-generation sequencing, revealed a molecularly distinct clonal shift characterized by the simultaneous emergence of an EML4-ALK fusion and a BRAF V600G mutation, accompanied by the complete clearance of the original EGFR mutation. Confronted with this unique clonal evolution, the patient was transitioned to monotherapy with the third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib. This targeted intervention was associated with rapid regression of the thoracic lesions, while a reduction in the previously irradiated intracranial lesion was also observed. CONCLUSION: To our knowledge, this is the first documented case of concurrent acquisition of an EML4-ALK fusion and a BRAF V600G mutation after five years of first-line osimertinib therapy, in which the ALK fusion was prioritized as the predominant actionable driver. This case highlights the importance of longitudinal re-biopsy and comprehensive molecular profiling to distinguish conventional EGFR-TKI resistance from molecularly distinct clonal replacement or oncogenic driver switching after prolonged targeted therapy.