HER2-positive intracranial metastases treatment [Neurosurgery Wiki]

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====== HER2-positive intracranial metastases treatment ======

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===== 1. Localized Therapy =====

=== Surgery ===
  * Indicated for large, symptomatic, or surgically accessible metastases.
  * Improves neurological symptoms and reduces tumor burden.

=== Stereotactic Radiosurgery (SRS) ===
  * Preferred for patients with **≤ 4 metastases** or selected cases with more.
  * Delivers high-dose radiation precisely, sparing normal tissue.
  * Can be combined with systemic therapy.

=== Whole-Brain Radiation Therapy (WBRT) ===
  * Used for multiple metastases but less favored due to neurotoxicity.
  * Consider **hippocampal-sparing WBRT with memantine** to reduce cognitive decline.

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===== 2. Systemic Therapy =====

=== HER2-Targeted Therapy Options ===

  * **Tucatinib + Trastuzumab + Capecitabine (HER2CLIMB Trial)**
    * Tucatinib is a selective HER2 TKI with CNS penetration.
    * Improves **progression-free survival (PFS) and overall survival (OS)**.

  * **Trastuzumab Deruxtecan (T-DXd, Enhertu)**
    * Antibody-drug conjugate with high intracranial activity.
    * Effective even in progressive brain metastases.

  * **Lapatinib + Capecitabine**
    * Historically used, but less effective than tucatinib.
    * Option for patients who cannot access newer agents.

  * **Pyrotinib + Capecitabine** (China-based studies)
    * Pan-HER TKI with intracranial efficacy.
    * Limited global availability.

  * **Neratinib + Capecitabine**
    * TKI with CNS penetration.
    * Consider in **progressive brain metastases** after other TKIs.

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===== 3. Combination Approaches =====

  * **Radiation + HER2-targeted therapy** (e.g., **SRS + tucatinib-based regimen**).
  * **Immunotherapy (e.g., pembrolizumab)** under investigation for synergy with HER2-directed agents.

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===== 4. Novel and Emerging Strategies =====

  * **Intrathecal HER2-directed therapy** (experimental, for leptomeningeal disease).
  * **Chimeric antigen receptor (CAR) T-cell therapy targeting HER2** (preclinical/early trials).
  * **Blood-brain barrier modulation strategies** to improve drug delivery.

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===== Conclusion =====

A **multimodal approach** combining systemic therapy (**especially tucatinib-based regimens**), **SRS, and possibly surgery** provides the best outcomes. **Trastuzumab deruxtecan** is a promising option for progressive disease. Clinical trials continue to refine treatment strategies.