ERBB2 Exon 20 Mutation-Guided Trastuzumab Deruxtecan Therapy in Metastatic Lung Adenocarcinoma with Low HER2 Expression: A Case Report

Abstract: HER2 mutations are uncommon in lung adenocarcinoma, and treatment options become limited after failure of standard systemic therapies. We report a 69-year-old woman with metastatic lung adenocarcinoma involving multiple lymph nodes, bone, and the left adrenal gland. Histopathological and immunohistochemical examinations strongly supported a diagnosis of primary pulmonary adenocarcinoma. Targeted next-generation sequencing (NGS) performed at initial diagnosis in January 2024 identified an ERBB2 exon 20 in-frame insertion mutation (p.Y772_A775dup). The patient received six sequential treatment regimens, including platinum-based chemotherapy, PD-1 inhibitor therapy, antiangiogenic therapy, and palliative radiotherapy. Initial tumor regression was observed, but sustained disease control was not achieved. Following further disease progression, the previously identified ERBB2 mutation was reassessed by the multidisciplinary team in 2025. HER2 immunohistochemistry showed an IHC score of 1+. Based on the activating ERBB2 mutation, trastuzumab deruxtecan (T-DXd) was initiated in June 2025 at a fixed dose of 200 mg per administration (approximately 3.2 mg/kg), lower than the standard starting dose for HER2-mutant NSCLC. Five doses were administered between June and November 2025. Serum carcinoembryonic antigen and carbohydrate antigen 19– 9 levels decreased markedly after treatment. Serial chest computed tomography indicated radiological disease stabilization for approximately 5 months, with no clinically significant treatment-related adverse events documented. This case highlights the value of molecular profiling in identifying actionable ERBB2 mutations despite low HER2 protein expression. It also provides a real-world observation of disease stabilization with a lower-than-standard initial dose of T-DXd, although conclusions regarding reduced-dose efficacy cannot be drawn from a single case. Keywords: lung adenocarcinoma, HER2 mutation, trastuzumab deruxtecan, targeted therapy, case report