# HER2 Alterations in Non-Small Cell Lung Cancer: Emerging Perspectives on the Therapeutic Landscape

## TL;DR

This paper reviews the role of HER2 alterations in non-small cell lung cancer and the emerging targeted therapies showing promise in treating these specific cancer subtypes.

## Contribution

The paper provides a comprehensive review of HER2-targeted therapies and their clinical outcomes in non-small cell lung cancer.

## Key findings

- HER2 alterations in NSCLC include protein overexpression, gene amplification, and activating mutations.
- Trastuzumab deruxtecan and selective tyrosine kinase inhibitors show robust efficacy and intracranial penetration.
- Further research is needed to understand resistance mechanisms and optimize treatment strategies for HER2-mutant NSCLC.

## Abstract

Over the past decade, significant achievements in elucidating the molecular pathogenesis of non–small cell lung cancer (NSCLC) have catalyzed a paradigm shift from empiric therapies to precision oncology. In this context, HER2 alterations, including protein overexpression, gene amplification, and activating mutations, constitute distinct molecular subsets within NSCLC. In the past few years, targeted therapeutic modalities such as antibody–drug conjugates (ADCs), particularly trastuzumab deruxtecan (the first agent to be granted FDA approval for HER2-mutant NSCLC), alongside selective tyrosine kinase inhibitors (TKIs), including zongertinib and sevabertinib, have demonstrated robust systemic efficacy and notable intracranial penetration. This comprehensive review delineates the molecular landscape and clinical phenotypes of HER2-altered NSCLC, synthesizes interim and mature data from ongoing clinical trials evaluating anti-HER2 therapies, and critically examines efficacy and safety results from different classes of targeted agents. Further research is crucial to uncover potential mechanisms of resistance in NSCLC with HER2 mutations and define sequencing or combinatorial strategies pertinent to optimizing individualized patient management.