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

Yanjie Han; Yuanyuan Xiong; Tao Lu; Rongrong Chen; Yuan Liu; Hui Tang; Ruixuan Geng; Yingyi Wang

doi:10.3389/fonc.2023.1121708

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

Front Oncol. 2023 Apr 3:13:1121708. doi: 10.3389/fonc.2023.1121708. eCollection 2023.

Authors

Yanjie Han^{1

2}, Yuanyuan Xiong³, Tao Lu⁴, Rongrong Chen³, Yuan Liu², Hui Tang², Ruixuan Geng⁵, Yingyi Wang¹

Affiliations

¹ Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² 4 + 4 Medical Doctor (MD) Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ Geneplus-Beijing, Beijing, China.
⁴ Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁵ Department of International Medical Services, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

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

Methods: HER2-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 HER2 alterations, 64.8% harbored HER2 mutations with/without HER2 amplification, and 35.2% carried HER2 amplification only. Molecular characterization was correlated with tumor stage that late-stage NSCLC with HER2 oncogenic mutations showed a higher prevalence of TP53 mutations and a higher tumor mutation burden. However, this correlation was not found in patients with HER2 amplification only. Twenty-one patients with HER2 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], P = 0.06) in these patients. Analysis of the genomic profiles before and after anti-HER2 targeted therapies identified de novo HER2 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: HER2-mutant NSCLC had different molecular features from HER2-amplified NSCLC, and its genomic profile was dependent of tumor stage. Pyrotinib had superior therapeutic effects than afatinib in HER2-altered NSCLC, although larger cohorts are warranted to validate it. HER2-dependent and -independent resistance mechanisms to afatinib and pyrotinib were unveiled.

Keywords: HER2; HER2-TKI; non-small cell lung cancer; resistance mechanism; targeted sequencing.

Grants and funding

This work was supported by National High Level Hospital Clinical Research Funding (2022-PUMCH-A-213) and the Beijing Municipal Science and Technology Commission (Z211100003021034).