The Effects of HER2 Alterations in EGFR Mutant Non-small Cell Lung Cancer

HER2 alteration can mediate resistance to EGFR tyrosine kinase inhibitors. 12,946 NSCLC samples that under-went NGS were analyzed. 321 patients had HER2 alterations: 197 mutation and 134 amplification. Among EGFR mutations, 1.5% had concurrent HER2 alteration. EGFR mutated patients with HER2 amplification had longer time on EGFR TKI(s). Background: HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors. Methods: We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data. Results: Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 ampli-fication had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplifi-cation (HR 2.284, P = .004). Conclusion: A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.

Automated summary

HER2 alterations can lead to resistance to EGFR tyrosine kinase inhibitors in NSCLC patients. Among the 12,946 samples analyzed, 2.5% had HER2 alterations, with 1.5% of EGFR mutated patients also having concurrent HER2 alterations. Patients with both EGFR mutation and HER2 amplification had longer time on treatment with EGFR TKIs compared to those with EGFR mutation alone. It is important to continue gathering clinical data for further analysis of real-world outcomes.