Exceptional response to furmonertinib in lung adenocarcinoma harboring HER2 exon 20 insertion mutation: a case report

Background: The management of human epidermal growth factor receptor 2 (HER2)-mutant non-small cell lung cancer (NSCLC) remains a significant clinical challenge, with limited effective and accessible treatment options beyond antibody-drug conjugates such as trastuzumab deruxtecan (T-DXd). Furmonertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) with enhanced hydrophobic properties due to its trifluoroethoxy group, has shown activity against EGFR exon 20 insertions (ex20ins) but has not been explored in HER2-mutant NSCLC. Case description: A 65-year-old male smoker presented with progressive dyspnea and a performance status (PS) of 2. Initial computed tomography (CT) in March 2025 revealed bilateral pneumonic infiltrates. Biopsy confirmed T4N0M1 lung adenocarcinoma harboring the "ERBB2 p.Y772_A775dup" mutation. Administration of furmonertinib at a double standard dose of 160 mg/day resulted in symptomatic improvement and early radiological improvement within 5 days. Following chemotherapy and sintilimab failure in August 2025 due to progressive disease, furmonertinib rechallenge at 160 mg/day again induced a response within 5 days, with no grade ≥3 adverse events. Conclusion: This case provides the first clinical evidence of furmonertinib's activity against HER2 ex20ins mutations. The structural homology between HER2 p.Y772_A775dup and EGFR exon 20 "near-loop" insertions may facilitate TKI binding. Furmonertinib emerges as a potential, cost-effective oral therapeutic alternative for this patient population, especially when standard therapies are not feasible, warranting further prospective investigation.