Genomic landscape and efficacy of HER2-targeted therapy in patients with -mutant non-small cell lung cancer.

Background: HER2-targeted therapy provides survival benefits to -mutant non-small cell lung cancer (NSCLC). A better understanding of the clinical and genomic characterization of treatment-naïve -positive NSCLC, as well as the efficacy of and resistance to HER2-targeted therapy in -altered NSCLC, could promote further improvement of HER2 targeted therapy.

Methods: -altered NSCLC patients was retrospectively included and their genomic profiles were performed by next-generation sequencing. The clinical outcomes included overall response rate, disease control rate and progression-free survival.

Results: Among 176 treatment-naïve patients with alterations, 64.8% harbored mutations with/without amplification, and 35.2% carried amplification only. Molecular characterization was correlated with tumor stage that late-stage NSCLC with oncogenic mutations showed a higher prevalence of mutations and a higher tumor mutation burden. However, this correlation was not found in patients with amplification only. Twenty-one patients with alterations treated with pyrotinib or afatinib were retrospectively enrolled. Pyrotinib yielded a longer median progression-free survival than afatinib (5.9 [95% CI, 3.8-13.0] vs. 4.0 months [95% CI, 1.9-6.3], = 0.06) in these patients. Analysis of the genomic profiles before and after anti-HER2 targeted therapies identified copy number gain and G518W mutation, as well as mutations involving DNA damage repair signaling, SWI-SNF complex, and epigenetic regulations as potential resistance mechanisms.

Conclusion: -mutant NSCLC had different molecular features from -amplified NSCLC, and its genomic profile was dependent of tumor stage. Pyrotinib had superior therapeutic effects than afatinib in -altered NSCLC, although larger cohorts are warranted to validate it. -dependent and -independent resistance mechanisms to afatinib and pyrotinib were unveiled.