Acquired BRAF-AGK Fusion Following Osimertinib Plus Savolitinib in EGFR-Mutated MET-Amplified Non-Small-Cell Lung Cancer: Durable Response to Gefitinib and Trametinib in a Case Report.

Background: Osimertinib is one of the standard first-line treatments for advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Approximately 25% of patients acquire MET amplification upon disease progression on osimertinib and may respond to combined EGFR-MET inhibition (e.g, osimertinib plus savolitinib). However, whether secondary targetable alterations emerge after dual EGFR/MET inhibition, and whether existing targeted agents retain therapeutic relevance in this setting, remain insufficiently characterized. Case Presentation: We report a 59-year-old female non-smoker with stage IV EGFR Leu858Arg-mutated lung adenocarcinoma who sequentially received first-line osimertinib (~9 months), second-line osimertinib plus savolitinib for MET amplification (~20 months), third-line platinum-based chemotherapy with local ablative therapy for oligo-progression, and fourth-line docetaxel. Comprehensive genomic profiling (CGP) of an archival cervical lymph node specimen (resected June 2019) subsequently identified an acquired BRAF-AGK fusion alongside the original EGFR Leu858Arg mutation; MET amplification was no longer detected in this specimen. Fifth-line gefitinib plus trametinib (initiated July 2020) was administered for approximately 19 months. Serial thoracic computed tomography, reassessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, showed a best overall response of stable disease, with the dominant target thoracic lesion decreasing from 16.8 mm at baseline to a nadir of 13.8 mm (17.9% maximum reduction). The course was complicated by central nervous system (CNS) progression managed with brain tumor resection and whole-brain radiotherapy, by transient thoracic re-progression during a 48-day treatment interruption that resolved on retreatment, and by trametinib dose reductions for grade 2 toxicities. Conclusion: This case illustrates that an acquired BRAF fusion may emerge as a potentially targetable bypass alteration in EGFR-mutated MET-amplified NSCLC after progression on combined EGFR-MET inhibition and that the combination of a first-generation EGFR-TKI and a MEK inhibitor can be associated with prolonged systemic disease control. The findings are hypothesis-generating and support the value of CGP at sequential progression points to guide mechanism-based therapy in oncogene-driven NSCLC.