<i>HER2</i> mutations in advanced NSCLC: Prevalence, mutational context, and clinical outcomes from an Australian clinico-genomic database.

e20673 Background: ERBB2 mutations ( HER2 mut) are an emerging target in non-squamous non-small cell lung cancer (ns-NSCLC), with second-line response rates &gt;50% to tyrosine kinase inhibitors or antibody–drug conjugates (HER2tx). Their novelty necessitates large-scale studies to better define the clinico-molecular context. Methods: 1,257 ns-NSCLC patients in Australia underwent comprehensive genomic profiling (TSO-500, FoundationOne CDx, or Avenio). HER2 mut were curated for oncogenicity and co-mutation patterns. Logistic regression was conducted for raw prevalence values, accounting for sex, smoking status and ethnicity. Overall survival (OS) was assessed via Kaplan-Meier curves relative to 3:1 propensity-matched wild-type cases (matched by age, sex, histology). Results: HER2 mut prevalence was 6.2% (78/1,257), excluding 22 additional (1.8%) amplification-only cases. Never-smokers had a 4.43 odds ratio for HER2 mut after adjusting for ethnicity and sex (p &lt; .001). Sixty (77%) mapped to the kinase domain, with 54 (69%) in exon 20. Mutations were mutually exclusive for KRAS, BRAF, and EGFR (p &lt; .001). HER2 mut were less frequently TMB-high or PD-L1 high (p = .007) and were depleted for KEAP1/STK11 , enriched for ARID1A, and showed over-representation of 9p21/ MTAP loss (22% vs 9%; p &lt; .001). OS was shorter in HER2 mut vs wild-type patients (median 20.1 vs 28.7 mo; p = .01), while amplification-only tumours had an OS of 16.4 mo. HER2tx exposure in HER2 mut cases showed a trend for improved OS vs HER2tx-naïve patients (median 22.9 vs 19.3 mo; p = .176). Conclusions: HER2 mut was relatively common in non-smokers. While typically not TMB-H, an enrichment of other features provides opportunity for immunotherapy combination and potentially MTAP inhibition. HER2 mut had a poor prognosis relative to wild-type, with a trend to improved outcomes in those HER2tx exposed.