Never-smoker non-small cell lung cancer (NSCLC) represents a distinct molecular subtype enriched for actionable driver mutations, including ERBB2 (HER2) exon 20 insertions, which occur in approximately 2-4% of cases and are more common in women and individuals of Asian ancestry. We report a 75-year-old never-smoking, asymptomatic Asian-American woman with incidentally discovered stage IV (cT1cN0M1a) lung adenocarcinoma. Imaging demonstrated innumerable bilateral solid, part-solid, ground-glass, and cavitary pulmonary nodules, with the largest measuring 29 × 25 mm, without nodal or distant metastases. Lung biopsy confirmed TTF-1 and Napsin A-positive adenocarcinoma, and genomic profiling identified an ERBB2 (HER2) exon 20 insertion mutation (p. A775G776insYVMA; VAF 3. 9%). She enrolled in a clinical trial of the selective HER2 tyrosine kinase inhibitor zongertinib (60 mg twice daily) in February 2025 and tolerated therapy well, with mild diarrhea, lactose intolerance, brittle nails, and intermittent muscle cramps. Serial imaging demonstrated an early partial response by RECIST 1. 1 at six weeks, followed by sustained radiographic stability with cavitary changes consistent with treatment effect. As of January 2026, she has maintained lung-confined disease control for over 11 months without extrapulmonary progression and remains fully functional without symptoms. This case highlights the clinical benefit and tolerability of selective HER2-targeted therapy in HER2-mutant NSCLC and adds to emerging evidence supporting consideration of risk-based lung cancer screening strategies in high-risk never-smoking populations.
Kyle S Yang (Sat,) studied this question.