HER-2 Altered Early-Stage Non-Small Cell Lung Cancer Had Better Survival than Triple-Negative Disease

Background: A unique group of non-small cell lung cancer (NSCLC) is driven by alterations in HER2. Early studies, mostly from advanced NSCLC, suggest that NSCLC with HER2 alterations confers a poor prognosis. However, modern studies are scant. Methods: We performed an analysis of a United States-based database on stage I–III NSCLC patients diagnosed during 2019–2024. Cases with complete data on EGFR, ALK, and HER 2 alterations were included. Study cohorts were divided into: EGFR or ALK alterations (EGFR/ALK group), HER2 alterations (HER2 group), or negative for these alterations (triple-negative group). Outcomes of interest were survival. Results: Analyses were performed on data from 3486 patients: 515 patients (15%) in the EGFR/ALK group, 173 patients (5%) in the HER2 group, and 2798 patients (80%) in the triple-negative group. Median disease-free survival (DFS) was 41.3 months, 26.6 months, and 21.2 months, respectively. Median overall survival (OS) was 62.5 months, 63.7 months, and 40.1 months, respectively. Multivariable analysis showed that DFS and OS were significantly worse among the triple-negative group than HER2 group: adjusted HRs 1.44 (95% CI: 1.08–1.90, p = 0.01) and 1.94 (95% CI: 1.25–3.01, p = 0.003), respectively. In the subgroup of patients with HER2 alterations, no significant difference in DFS or OS was found among patients with HER2 mutation, HER2 amplification, or HER2 overexpression in this exploratory analysis. Conclusions: When classified by the status of EGFR, ALK and HER2, early-stage NSCLC patients with HER2 alterations had significantly better DFS and OS than those with triple-negative biomarkers.