Promising Response to Pyrotinib in Non-Small-Cell Lung Cancer with the Rare HER2 R456C Mutation: A Case Report

Background: HER2 exon 20 insertions exhibit relative resistance to chemothera-py and covalent HER2-targeted tyrosine kinase inhibitors (TKIs) in non-small-cell lung can-cer (NSCLC). Furthermore, specific missense mutations in the extracellular domain of the HER2 protein have been identified as oncogenic drivers in NSCLC. However, their structur-al properties and clinical response to HER2-targeted inhibitors remain poorly understood, warranting further investigation. R456C represents a rare exon 12 missense mutation in the HER2 extracellular domain, with limited documentation in NSCLC. Case Presentation: This study presents an atypical case of NSCLC with a HER2 R456C mutation, where the patient experienced a favorable response and substantial survival bene-fit from the HER2-targeted inhibitor pyrotinib. A patient, a 65-year-old man diagnosed with stage IIIB lung adenocarcinoma, initially underwent radical concurrent chemoradiotherapy. Upon disease recurrence, polymerase chain reaction assay detected no oncogenic alterations, and programmed cell death ligand 1 (PD-L1) expression was negative. Chemotherapy in combination with bevacizumab resulted in stable disease, providing a progression-free sur-vival (PFS) benefit of 6 months. However, anlotinib proved ineffective against brain metas-tasis, necessitating brain radiotherapy. A subsequent lung biopsy confirmed adenocarcinoma and next-generation sequencing identified a somatic HER2 exon 12 missense mutation, p.R456C. Following pyrotinib administration, the patient's pulmonary metastases signifi-cantly diminished, and the brain metastasis regressed, resulting in a partial response and a PFS benefit of 13 months. Conclusion: To the best of our knowledge, this study represents the first reported case demonstrating the promising efficacy of pyrotinib in HER2-altered NSCLC harboring the ra-re exon 12 R456C mutation. Heterogeneous alterations in the HER2 extracellular segment, such as R456C, may be targetable and could confer survival benefits with HER2-targeted inhibitors.