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Life sciences · Journal article
Frontiers in Oncology · September 23, 2026
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Acquired resistance to osimertinib in EGFR-mutant advanced non-small cell lung cancer is inevitable, and management following progression remains an evolving clinical challenge. HER2 amplification is a recognised but underreported off-target resistance mechanism, and its optimal management is not yet established. Trastuzumab deruxtecan has shown activity in HER2-altered NSCLC, but real-world data describing its use in this specific resistance context, particularly with respect to intracranial activity, remain scarce. We report the case of a 50-year-old man with metastatic NSCLC harbouring an EGFR exon 19 deletion who experienced disease progression through multiple lines of therapy, including 3 years of first-line osimertinib, platinum-based chemotherapy, atezolizumab-bevacizumab-paclitaxel-carboplatin, and repeated radiotherapy for intracranial metastases. Comprehensive genomic profiling at progression identified acquired HER2 (ERBB2) amplification, confirmed by immunohistochemistry (IHC 3+) and fluorescence in situ hybridisation, alongside persistence of the original EGFR mutation. Following a deliberate washout period to mitigate interstitial lung disease risk, the patient received trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, as fifth-line therapy, achieving a systemic partial response sustained over seven cycles, with concurrent regression of intracranial lesions. This case underscores HER2 amplification as a clinically actionable resistance mechanism and demonstrates T-DXd’s systemic and intracranial activity in this setting. It also highlights the value of serial molecular profiling at each point of progression in guiding personalised treatment strategies while acknowledging that the optimal testing strategy requires prospective validation.