HER2-Mutated NSCLC: Testing and Emerging Treatment Approaches - Episode 6
Looking Ahead: Potential Sequencing Strategies and Focusing On a Patient-Centered Approach to Treatment of HER2-Mutated NSCLC
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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Treatment sequencing decisions for patients with HER2-mutated non–small cell lung cancer (NSCLC) require careful consideration of patient characteristics, disease features, and available therapeutic options. Dr Preeshagul advocates for oral tyrosine kinase inhibitors (TKIs) in the second-line setting, particularly for patients with central nervous system (CNS) progression or those experiencing chemotherapy-related toxicities from first-line platinum therapy. The smaller molecular size of TKIs provides superior blood-brain barrier penetration compared with bulky ADCs, making them preferable for patients with symptomatic brain metastases.
The strategic approach to therapy selection involves matching patient characteristics with drug properties: TKIs for CNS disease or chemotherapy-intolerant patients, versus ADCs for systemic disease control. Both experts prefer using oral targeted therapy first, followed by ADCs in later lines, based on tolerability profiles and efficacy data. This sequencing strategy maximizes patient exposure to active agents while minimizing cumulative toxicity, particularly important given the aggressive nature of HER2-mutated NSCLC.
Future combination strategies raise important questions about optimal treatment intensification versus toxicity management. While combining zongertinib with trastuzumab deruxtecan appears theoretically attractive, the practical implications for patient tolerability remain unclear. Subset analyses may identify specific patient populations requiring combination therapy, such as those with high tumor burden, liver metastases, or elevated circulating tumor DNA. Clinical trials will be essential for determining the optimal integration of these promising agents while maintaining acceptable safety profiles for patients with lung cancer.
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