What are the management options for brain metastases (brain mets) in melanoma?

Management of Brain Metastases in Melanoma

For patients with melanoma brain metastases, ipilimumab plus nivolumab is the preferred first-line systemic therapy for asymptomatic patients regardless of BRAF status, while local therapy (stereotactic radiosurgery or surgery) should be offered based on symptom burden, number of lesions, and disease trajectory. 1

Initial Assessment and Triage

Symptomatic vs. Asymptomatic Status Determines Immediate Management:

• Symptomatic patients (neurologic deficits, seizures, significant edema) require immediate local therapy (surgery or stereotactic radiosurgery) regardless of planned systemic therapy 1
• Initiate dexamethasone 4-8 mg/day for moderate symptoms, escalating to 16 mg/day for severe symptoms with marked mass effect 2
• Asymptomatic patients may defer local therapy and proceed directly to systemic therapy if appropriate 1

MRI with gadolinium is mandatory for accurate lesion characterization and treatment planning 2

Systemic Therapy Selection Algorithm

For Asymptomatic Brain Metastases:

First-Line: Ipilimumab plus Nivolumab (All Patients)

• Ipilimumab plus nivolumab achieves 54% intracranial response rate in asymptomatic patients with median intracranial progression-free survival not reached 1
• This combination is effective regardless of BRAF mutation status 1
• Local therapy may be deferred until intracranial progression when using this regimen 1
• 55% of patients experience grade 3-4 adverse effects, but toxicity profile is identical to patients without brain metastases 1

Alternative: Dabrafenib plus Trametinib (BRAF V600E Mutation Positive)

• Reserved for BRAF-mutant patients with rapidly progressive disease, visceral crisis, or bulky disease requiring rapid response 1
• Can defer local therapy until progression when using this combination 1
• Consider this option when immunotherapy response time is too slow for clinical situation 1

For Symptomatic Brain Metastases or Steroid-Dependent Patients:

Critical Limitation: Dual-agent immunotherapy shows dramatically reduced efficacy in symptomatic patients, with only 22% intracranial response rate and median intracranial PFS of just 1.2 months 1

Management Approach:

• Prioritize local therapy (surgery or SRS) first to achieve symptom control 1
• After local control achieved, proceed with systemic therapy as outlined above 1
• Avoid high-dose interleukin-2 in patients with untreated or active brain involvement due to risk of worsening edema 1

Local Therapy Selection

Stereotactic Radiosurgery (SRS):

Preferred for 1-4 unresected brain metastases:

• SRS alone (without whole-brain radiotherapy) should be offered for 1-4 lesions, generally <3-4 cm diameter 1
• SRS alone to surgical cavity for 1-2 resected metastases 1
• SRS may be preferred when effective systemic therapy is available 1

Surgical Resection:

Indications:

• Large tumors causing significant mass effect 2
• Symptomatic lesions refractory to steroids 2
• Solitary accessible metastases 2
• Diagnostic uncertainty requiring tissue 2

Whole-Brain Radiotherapy (WBRT):

Reserved for:

• More than 4 unresected or more than 2 resected brain metastases with good performance status (KPS ≥70) 1
• If WBRT used, add memantine and hippocampal avoidance for patients with expected survival ≥4 months and no hippocampal lesions 2

Treatment Sequencing Strategy

Asymptomatic Patients with Low Disease Burden:

1. Start with ipilimumab plus nivolumab (preferred for durable response) 1
2. Monitor with serial MRI
3. Add local therapy only at progression 1

Asymptomatic BRAF-Mutant Patients with Rapid Progression:

1. Consider dabrafenib plus trametinib first for rapid response 1
2. Local therapy at progression 1
3. Switch to immunotherapy after targeted therapy failure for durability 1

Symptomatic Patients:

1. Local therapy first (surgery or SRS based on number/location) 1, 2
2. Systemic therapy (ipilimumab plus nivolumab or dabrafenib plus trametinib if BRAF-mutant) after local control 1

Critical Pitfalls to Avoid

Do not use high-dose interleukin-2 in patients with untreated brain metastases - it has low efficacy and may worsen peritumoral edema 1

Do not defer local therapy in symptomatic patients expecting systemic therapy alone to provide rapid symptom relief - even dual-agent immunotherapy has poor response rates (22%) in symptomatic patients 1

Do not assume steroid-dependent patients will respond to immunotherapy - patients requiring >4 mg dexamethasone daily have significantly worse outcomes with immunotherapy 1

Do not use prophylactic anti-seizure medications - only treat if seizures have occurred 2

Performance Status Considerations

Patients with KPS <70 and no effective systemic therapy options do not benefit from radiation therapy and should receive best supportive care 2