Managing CNS Metastases in HER2-Mutated NSCLC

Central nervous system involvement is a major clinical challenge in HER2-mutated NSCLC, and this segment explores the decision-making framework for intracranial disease. Approximately 30–50% of patients present with or eventually develop brain metastases, necessitating routine baseline MRIs and proactive surveillance.

The experts review intracranial activity data for both T-DXd and zongertinib, acknowledging that while T-DXd has established CNS activity in breast cancer and emerging data in lung cancer, HER2-targeted TKIs are demonstrating increasingly meaningful CNS penetration. Zongertinib has shown promising intracranial responses, though not at the level seen with highly CNS-penetrant ALK inhibitors.

Dr. Riess describes his approach: for small, asymptomatic lesions, he often initiates targeted therapy with close radiographic follow-up. For larger or symptomatic metastases, he leans toward early stereotactic radiation (SRS), emphasizing multidisciplinary collaboration with neuro-oncology and radiation oncology. Leptomeningeal disease presents a more complex scenario, where CNS activity of systemic agents becomes especially important.

Both experts agree on minimizing whole-brain radiation when possible due to long-term neurocognitive toxicity. Instead, the goal is to coordinate targeted therapy and focal radiation to maximize disease control while preserving quality of life.

This segment highlights how evolving systemic therapies, including TKIs with increasing CNS penetration, may shift the treatment paradigm for HER2-mutated NSCLC with brain metastases.