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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
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Evolving treatment strategies for HER2-altered non-small-cell lung cancer: the rise of TKIs and ADCs

Sevinc Balli1, Tugba Basoglu2, Mustafa Ozdogan2,3

  • 1Department of Medical Oncology, Samsun City Hospital, Samsun, Türkiye.

Frontiers in Oncology
|April 10, 2026
PubMed

Insights

Novel HER2-targeted therapies, including antibody-drug conjugates and tyrosine kinase inhibitors, are transforming outcomes for non-small cell lung cancer (NSCLC) patients with HER2 mutations. Research is ongoing to optimize treatment sequencing and manage resistance for these rare NSCLC cases.

Area of Science:

  • Oncology
  • Translational Medicine
  • Pharmacology

Background:

  • Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver in a subset of non-small cell lung cancer (NSCLC).
  • Historically, HER2-driven NSCLC lacked targeted therapies, relying on conventional chemotherapy and immunotherapy.
  • The therapeutic landscape for HER2-driven NSCLC has significantly evolved with new targeted agents.

Purpose of the Study:

  • To provide a comprehensive update on emerging HER2-targeted therapies for NSCLC.
  • To review clinical trial data, mechanisms of action, and comparative benefits of new HER2-directed agents.
  • To discuss challenges, resistance mechanisms, and future directions in HER2-targeted NSCLC treatment.

Main Methods:

  • Review of clinical trial data for novel HER2-targeted therapies, including antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs).
  • Analysis of mechanisms of action and comparative efficacy against older pan-HER agents.
  • Discussion of emerging therapeutic scope, immunotherapy challenges, and resistance mechanisms.

Main Results:

  • The approval of fam-trastuzumab deruxtecan (T-DXd) and new oral HER2 TKIs (zongertinib, sevabertinib) has expanded treatment options for HER2-mutant NSCLC.
  • Emerging data supports the efficacy of these novel agents in HER2-driven NSCLC, including those with HER2-low expression.
  • Challenges remain in managing immunotherapy, resistance, and CNS metastases.

Conclusions:

  • Recent breakthroughs in HER2-targeted TKIs and ADCs are transforming outcomes in rare NSCLC subsets.
  • Optimizing treatment sequencing, managing resistance, and improving patient selection via biomarkers are critical priorities.
  • Ongoing trials are expected to further refine first-line standards for HER2-targeted NSCLC.
Keywords:
HER2-mutant NSCLCantibody–drug conjugatebrain metastasesresistance mechanismstargeted therapytyrosine kinase inhibitor

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