Recent Advances in the Development and Clinical Use of HER2 Inhibitors in Non-Small Cell Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Alterations in the human epidermal growth factor receptor 2 (HER2) gene are key drivers in non-small cell lung cancer (NSCLC).
• HER2-targeting therapies have advanced, with approvals for both inhibitors and antibodies in various cancers.
• While HER2-targeting agents are more developed in breast cancer, their potential in NSCLC is increasingly recognized.

Purpose of the Study:

• To review the latest research on HER2 signaling biology and alterations in NSCLC.
• To summarize the current landscape of HER2-targeting therapies for NSCLC.
• To discuss the challenges and future directions in treating HER2-altered NSCLC.

Main Methods:

• This narrative review synthesizes current scientific literature on HER2 in NSCLC.
• It examines the biological basis of HER2 alterations and their role in oncogenesis.
• The review analyzes clinical data from HER2-targeting therapies, comparing advancements in NSCLC and breast cancer.

Main Results:

• HER2 mutations are present in 2-4% of NSCLC cases and are targetable oncogenic drivers.
• Trastuzumab-deruxtecan is approved for previously treated advanced NSCLC with HER2 mutations.
• HER2-specific tyrosine kinase inhibitors (TKIs), like zongertinib, show encouraging efficacy, with zongertinib approved in 2025.
• While pan-HER TKIs have shown limited benefit, HER2-specific agents represent a significant advancement.

Conclusions:

• Targeting HER2 is a viable strategy for a subset of NSCLC patients.
• The development of HER2-targeting therapies for NSCLC lags behind breast cancer, but recent approvals and ongoing research show significant promise.
• Insights from breast cancer treatment paradigms may inform future strategies for HER2-altered NSCLC.