HER2-Mutated NSCLC: Testing and Emerging Treatment Approaches

Joshua Sabari, MD and Isabel Preeshagul, DO, MBS, discuss how comprehensive biomarker testing for HER2 mutations in non–small cell lung cancer (NSCLC) enables targeted treatment with emerging therapies including antibody-drug conjugates such as trastuzumab deruxtecan and promising oral tyrosine kinase inhibitors such as zongertinib and sevabertinib, which offer improved tolerability and central nervous system penetration compared with traditional chemotherapy approaches.

EP. 1: HER2 Alteration Testing In Advanced and Metastatic NSCLC

June 13th 2025

Panelists discuss how comprehensive next-generation sequencing testing is essential for identifying HER2 mutations in patients with stage IV non–small cell lung cancer, distinguishing between HER2 mutations (detected by DNA sequencing) and HER2 overexpression/amplification (detected by immunohistochemistry).

EP. 2: Clinical Implications and Frontline Treatment of HER2-Mutated NSCLC

June 13th 2025

Panelists discuss how patients with HER2-mutated lung cancer represent a high-risk population with aggressive biology and propensity for brain metastases, currently treated with standard chemotherapy in the frontline setting while awaiting clinical trials that may move HER2-targeted agents to first-line treatment.

EP. 3: Antibody-Drug Conjugate Efficacy and Safety in HER2-Mutated NSCLC

June 13th 2025

Panelists discuss how antibody drug conjugates like trastuzumab deruxtecan work as “Trojan horses” to deliver chemotherapy directly to tumor cells, providing effective second-line treatment for patients with HER2-mutated disease but requiring careful management of chemotherapy-like adverse effects, including significant toxicities.

EP. 4: Recognizing and Treating Interstitial Lung Disease Associated With Trastuzumab Deruxtecan

June 13th 2025

Panelists discuss how interstitial lung disease represents a critical and potentially cryptic toxicity occurring in 10% to 15% of patients receiving HER2 antibody-drug conjugates, requiring vigilant monitoring, prompt recognition of subtle symptoms like dry cough, and aggressive management with steroids and pulmonary consultation.

EP. 5: Emerging Oral HER2-Targeted TKIs (Zongertinib and Sevabertinib): Efficacy and Safety in HER2-Mutated NSCLC

June 13th 2025

Panelists discuss how emerging oral tyrosine kinase inhibitors like zongertinib (HER2-selective) and sevabertinib (HER2/EGFR dual inhibitor) offer promising alternatives to antibody-drug conjugates with improved tolerability profiles, better central nervous system penetration, and robust response rates in the 60% to 70% range for second-line treatment.

EP. 6: Looking Ahead: Potential Sequencing Strategies and Focusing On a Patient-Centered Approach to Treatment of HER2-Mutated NSCLC

June 13th 2025

Panelists discuss how sequencing strategies for multiple HER2-targeted therapies will require careful consideration of patient characteristics, disease burden, and prior treatments, with oral tyrosine kinase inhibitors potentially preferred first due to better tolerability and CNS activity, while combination approaches remain investigational pending safety and efficacy data.

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