Real-world retrospective analysis of the mutation and co-mutation landscape of ERBB2 in advanced NSCLC.

Abstract

<p><strong>Background:</strong> ERBB2 oncogenic mutations (ERBB2m) have emerged as a significant actionable driver in non-small cell lung cancer (NSCLC) with approved targeted therapies. Improving the understanding of the mutational landscape of ERBB2 along with its’ co-mutations is critical for optimising targeted therapies and improving patient outcomes. <strong>Methods:</strong> This study analysed data from a large multicentre retrospective cohort gathered from 7 public hospitals in Hong Kong from January 2021 until October 2024; 1094 patients were identified. FoundationOne CDx and FoundationOne Liquid CDx target-panel next-generation sequencing were employed to identify ERBB2 alternations including mutations and amplifications. We characterized the clinicopathological features of patients, examined co-occurring mutations and analysed the survival outcomes after different first-line treatments. <strong>Results:</strong> The overall incidence of ERBB2 alterations in this Asian population was 11.8% which can be further classified into ERBB2m, ERBB2 amplification (ERBB2 amp) and both (7.2%, 3.7% and 0.9% respectively). Notably, the most common ERBB2 mutation was an exon 20 insertion (A775_G776insYVMA) which accounted for 19% of all mutations. Co-mutations with TP53 (67%) and common EGFR (31%) were frequently observed, highlighting the complex genetic interplay in ERBB2-altered NSCLC. ERBB2 mutations were associated with increased brain metastases (p=0.01), and lower tumour mutation burden (TMB) p=0.017. Interestingly, patients with ERBB2 mutation had an improved overall survival (OS) (ERBB2m vs. ERBB2 amp: 31.3 vs. 10.6 months; p = 0.046) and progression-free survival (PFS) (ERBB2m vs ERBB2 amp: 6.2 vs. 2.2 months; p= 0.016) when treated with first-line chemotherapy compared to patients with ERBB2 amplification. The presence of EGFR co-mutation with ERBB2 led to a better OS compared to EGFR WT (ERRBm-EGFRm vs. ERBB2m-EGFRwt: NR vs. 21.7 months; p= 0.004) and conversely the presence of TP53 co-mutation had a worse OS (ERBB2-TP53m vs. ERBB2m-TP53wt; 27.7 months vs. NR; p=0.043). <strong>Conclusions:</strong> This comprehensive analysis reveals the diverse mutational landscape of ERBB2 in NSCLC, emphasising the need for tailored therapeutic strategies. Currently ERBB2 targeted treatment are approved in second line setting, our study confirms patients with ERBB2 mutation has an improved survival outcome with first-line chemotherapy alone, possibly due to the low TMB. Future studies are warranted to validate these findings.<br></p>