Advances in the Treatment of HER2-Mutant Advanced Non-Small Cell Lung Cancer

HER2 (ERBB2) mutations are increasingly recognized as a distinct molecular subtype in advanced non-small cell lung cancer (NSCLC).

Approximately 3%–5% of NSCLC patients harbor HER2 mutations, with exon 20 insertions being the most common. These mutations primarily occur within the tyrosine kinase domain (TKD).

Patients with HER2-mutant NSCLC tend to exhibit unique clinical characteristics:

• More common in females
• More frequent in non-smokers
• Median diagnosis age ~62 years
• Higher risk of brain metastases

The NCCN guidelines recommend HER2 mutation testing for metastatic non-squamous NSCLC to guide treatment decisions.

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Antibody–Drug Conjugates (ADCs): Leading the First Breakthrough

Antibody–drug conjugates (ADCs) have driven major breakthroughs in HER2-mutant NSCLC.

Trastuzumab Deruxtecan (Enhertu)

• Approved in China for previously treated patients
• DESTINY-Lung01:
  • ORR: 55%
  • OS: 17.8 months

⚠️ Key risk: interstitial lung disease (ILD)

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Trastuzumab Rezetecan

• HORIZON-Lung study:
  • ORR: 74.5%
  • mPFS: 11.5 months

👉 Strong activity even in:

• Brain metastases
• Prior HER2-TKI patients

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Oral Tyrosine Kinase Inhibitors (TKIs): Expanding Precision Therapy

Zongertinib

• FDA-approved HER2 TKI
• Beamion LUNG-1:
  • ORR: 71% (pretreated)
  • ORR: 76% (first-line)
  • mPFS: 12.4 months

👉 Some patients achieved complete response

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Sevabertinib

• Dual HER2/EGFR inhibitor

SOHO-01 study:

• ORR: 64% (no prior HER2 therapy)
• ORR: 38% (post-ADC)
• mPFS: 8.3 months

⚠️ Common AE: diarrhea

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Treatment Landscape Evolution

Current NCCN recommendations:

• First-line: chemotherapy ± immunotherapy
• After progression:
  • ADCs (trastuzumab deruxtecan, disitamab vedotin)
  • TKIs (zongertinib, sevabertinib)

👉 Treatment is shifting toward precision targeted sequencing strategies

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Conclusion

The treatment landscape of HER2-mutant NSCLC is rapidly evolving.

From ADCs to next-generation TKIs:

• Response rates significantly improved
• Survival outcomes extended
• Personalized therapy becoming feasible

Future directions:

• Combination therapy
• Earlier-line targeted use
• Brain metastasis optimization

DengYueMed will continue to track global advances and support access to innovative oncology therapies.