REVIEW article

Front. Oncol.

Sec. Thoracic Oncology

Volume 15 - 2025 | doi: 10.3389/fonc.2025.1624124

This article is part of the Research TopicReviews in Thoracic OncologyView all articles

HER2 Alterations in Non-Small Cell Lung Cancer (NSCLC): from Biology and Testing to Advances in Treatment Modalities

Provisionally accepted
Ahmed  IsmailAhmed IsmailAakash  DesaiAakash DesaiYanis  BoumberYanis Boumber*
  • O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, United States

The final, formatted version of the article will be published soon.

Lung cancer remains the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancers, is a biologically diverse disease characterized by a wide range of molecular alterations. Among these, HER2 (human epidermal growth factor receptor 2, or Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2)), a gene more commonly associated with breast cancer, has emerged as an important oncogenic driver in NSCLC, particularly within the adenocarcinoma subtype. HER2 alterations are notably more prevalent among non-smokers, with estimates suggesting that up to 50-80% of patients with HER2 mutations or amplifications have no smoking history. In our comprehensive review, we outline the molecular biology of HER2 in NSCLC, including distinctions between HER2 mutations, amplification, and overexpression, and we delve into the diverse diagnostic complexities. We also review NCCN guidelines and the performance of newer FDA-approved testing assays (such as Guardant360 and FoundationOne) in detecting HER2 alterations and circulating tumor DNA (ctDNA) as a tool for treatment response monitoring. Furthermore, we present updated clinical trial data for published HER2-targeted agents and explore ongoing clinical trials examining combinatorial therapies and next-generation HER2-targeted agents such as zongertinib, A166, ARX788, SHRA1811, and others. Given the rapid evolution in this field, our review offers a timely and comprehensive synthesis of the current state and future directions for HER2-altered NSCLC.

Keywords: non-small cell lung cancer (NSCLC), ErbB2 (HER2), HER2 testing, targeted therapy, Tyrosine kinase inhibitors (TKIs), Antibody-drug conjugates (ADCs), Immunotherapy

Received: 07 May 2025; Accepted: 05 Jun 2025.

Copyright: © 2025 Ismail, Desai and Boumber. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Yanis Boumber, O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, United States

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