The Challenge Treating Brain Metastases and Leptomeningeal Disease (LMD)

Brain metastases present a significant challenge when managing patients with melanoma who progress after frontline therapy. In cases where progression occurs only in the brain while extracranial disease remains stable, localized treatments such as stereotactic radiosurgery or surgical resection can help stabilize the patient. This approach may allow continuation of systemic therapies, especially dual immune checkpoint inhibitors (ICIs), which could still offer meaningful long-term outcomes. However, when both intracranial and extracranial progression occurs after checkpoint inhibitors, treatment options become more limited, often depending on molecular tumor profiling and the patient’s clinical status.

For patients with symptomatic brain metastases requiring steroids, ICIs alone tend to have poor outcomes. In such cases, identifying actionable mutations like BRAF is critical because targeted therapies with BRAF and MEK inhibitors can provide CNS activity, although durability remains uncertain. Emerging data from smaller studies suggest some promise using combination regimens involving targeted therapy and immunotherapy in symptomatic brain metastasis, but evidence is limited. Additionally, adoptive cell therapies (TIL) have shown some CNS activity but carry risks such as thrombocytopenia and bleeding, indicating a continued need for better therapeutic strategies for brain metastases.

LMD represents an even more difficult scenario with limited effective options. Treatment often focuses on symptom management with steroids and palliative radiation. In less symptomatic or radiologically subtle cases, standard systemic therapies may still be attempted, particularly when molecular targets exist. Intrathecal immunotherapies remain experimental. Honest discussions about prognosis and quality of life are essential for patients with symptomatic CNS involvement. Although therapeutic advances have improved outcomes for many patients with melanoma, managing CNS metastases and LMD remains a critical area needing further research and innovation.