Targeting HER2 Alterations in Non–Small-Cell Lung Cancer

A Comprehensive Review

Jing Zhao, MD; Yang Xia, MD, PhD


JCO Precis Oncol. 2020;4:411-425. 

In This Article

Abstract and Introduction


Purpose: HER2 is a critical gene that drives various solid tumors in addition to those of breast cancer. For example, HER2 plays a role in non–small-cell lung cancer (NSCLC). Overexpression, amplification, and point mutations in HER2 have been described in patients with NSCLC; however, the potential roles of these alterations remain unclear.

Methods: We summarize the evidence regarding the distinct impacts of different HER2 aberrations on antitumor agents. Also, we update the therapeutic efficacy of HER2-targeted agents, including anti-HER2 antibodies, antibody-drug conjugates, and small-molecule tyrosine kinase inhibitors, tested in HER2-aberrant NSCLC.

Results: Although these drugs are not yet standard treatments, certain patients may benefit from these therapies. In this review, we aim to provide an improved understanding of HER2 aberrations in NSCLC, including NSCLC biology and the impacts of each aberration on prognosis and standard treatment. We also highlight the potential of novel anti-HER2 therapies approved by regulatory bodies and those in clinical development.

Conclusion: Compared with HER2 amplification or overexpression, HER2 mutations, especially HER2 exon 20 mutations, are emerging as the most clear targetable driver for HER2-directed therapies in lung cancer. De novo and inducible HER2 pathway activation need to be differentially managed. Further investigations with new strategies are needed.


Lung cancer is the leading cause of cancer-related death worldwide. Non–small-cell lung cancer (NSCLC), which accounts for 85% of all lung cancer cases,[1] is a group of heterogeneous diseases driven by a spectrum of molecular alterations. Targeted therapies directed toward specific molecular alterations, such as a mutation in epidermal growth factor receptor (EGFR) or a rearrangement in the genes encoding anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1), have had tremendous success in improving the prognosis of patients and their quality of life. Therefore, these therapies are routinely recommended for all patients with advanced NSCLC that harbor specific genomic alterations.[2] The use of next-generation sequencing (NGS) has resulted in the discovery of several aberrations that are potential oncogenic drivers.[3] For example, the gene encoding human epidermal growth factor 2 (HER2 erbB-2/neu) is a driver gene that is regarded as a new therapeutic target for treating NSCLC.

HER2 is encoded by the HER2 gene, which is located on the long arm of chromosome 17 (17q21). HER2 is a member of the erbB receptor tyrosine kinase family. HER2 amplification and overexpression have been well documented to play a role in the development of breast cancer and gastric cancer.[4,5]

Anti-HER2 therapies, particularly the monoclonal antibody trastuzumab in combination with cytotoxic agents, are considered the standard first-line regimen for HER2-positive breast and gastric cancers.[6,7] However, anti-HER2 strategies for treating NSCLC, including monoclonal antibodies, chemotherapy, tyrosine kinase inhibitors (TKIs), and combinations of these, have shown conflicting results in treating NSCLC. Thus, the value of anti-HER2 therapy in NSCLC is still questioned. In this article, we aim to enhance the understanding of HER2 aberrations in NSCLC, including the biology of NSCLC, the impact of the aberrations on prognosis and treatment, and their use as targets in approved and investigational anti-HER2 therapies.