What is the treatment for metastatic melanoma?

Treatment for Metastatic Melanoma

For patients with metastatic melanoma, immunotherapy with checkpoint inhibitors is the preferred first-line treatment, specifically combination ipilimumab plus nivolumab for most patients, or single-agent anti-PD-1 therapy (pembrolizumab or nivolumab) as alternatives, with BRAF/MEK inhibitor combinations reserved for BRAF-mutated disease requiring rapid disease control. 1, 2, 3, 4

First-Line Treatment Selection

For BRAF Wild-Type Metastatic Melanoma

• Combination immunotherapy with ipilimumab plus nivolumab is the standard first-line treatment, achieving durable responses in 45-50% of patients and a 10-year overall survival rate of 43%. 1, 5
• Single-agent anti-PD-1 therapy (pembrolizumab or nivolumab) is an alternative option for patients who may not tolerate combination therapy. 2, 3, 4
• Immunotherapy induces durable clinical responses that can persist even after treatment discontinuation, which is the primary advantage over other modalities. 1

For BRAF-Mutated Metastatic Melanoma

The choice between immunotherapy and targeted therapy depends on specific clinical characteristics: 1

Choose Immunotherapy First When:

• Patient has good performance status and can tolerate several months of treatment before response 1
• Disease progression is slow to moderate 1
• LDH is normal or only mildly elevated 1
• Tumor burden is manageable without urgent cytoreduction 1
• Goal is long-term durable disease control (immunotherapy provides very long-term control even after stopping treatment) 1

Choose BRAF/MEK Inhibitor Combination First When:

• Rapid symptom control is required due to high tumor burden 1
• Significantly elevated LDH levels 1
• Rapidly progressive disease requiring immediate response 1
• Symptomatic visceral metastases requiring urgent control 1
• Poor performance status where waiting for immunotherapy response is not feasible 1

BRAF/MEK inhibitor combinations achieve response rates of approximately 70% with rapid onset, but patients with poor prognostic features are likely to progress and require subsequent treatment. 1

Specific Treatment Regimens

Immunotherapy Options

• Ipilimumab plus nivolumab combination: FDA-approved for unresectable or metastatic melanoma in adults and pediatric patients 12 years and older 2, 3
• Nivolumab monotherapy: 3 mg/kg intravenously every 2 weeks 3
• Pembrolizumab monotherapy: FDA-approved for unresectable or metastatic melanoma 4

Targeted Therapy Options

• BRAF/MEK inhibitor combinations (such as dabrafenib plus trametinib) for BRAF V600 mutation-positive disease achieve approximately 70% response rates 1, 6
• These provide better progression-free survival and 12-month outcomes compared to immunotherapy, but meta-analyses suggest front-line immunotherapy may yield superior long-term outcomes 1

Role of Surgery in Metastatic Disease

• Surgical resection should be considered for isolated, slowly developing single metastases, including parenchymal organ metastases and central nervous system lesions 1
• Complete (R0) resection is the goal when surgery is undertaken 1
• Detailed staging with CT or PET scans is necessary before aggressive local surgical treatment to exclude additional metastases 1
• In the era of effective immunotherapy and targeted therapy, an expanded role for surgery in oligometastatic disease is emerging 7

Role of Chemotherapy

• Chemotherapy has a limited role in modern metastatic melanoma treatment and should generally be reserved for patients who have failed immunotherapy and targeted therapy 1
• Dacarbazine was historically the conventional palliative chemotherapy, but polychemotherapy has not been shown superior to dacarbazine alone for survival 1
• A small subgroup of patients may still respond to dacarbazine-based chemotherapy even after failing modern therapies, particularly those with specific genetic features 8
• Chemotherapy typically results in tumor regression with median duration of remission of 4-5 months 1

Special Considerations

Brain Metastases

• Systemic immunotherapy or targeted therapy can be effective for brain metastases 1
• Palliative radiotherapy should be considered for symptomatic brain metastases 1

In-Transit Metastases

• Surgical excision is standard treatment when feasible 1
• For numerous metastases confined to a limb, isolated limb perfusion with melphalan and tumor necrosis factor can be considered, but should only be performed by specialized experienced teams 1

Common Pitfalls to Avoid

• Do not delay immunotherapy in BRAF-mutated patients with favorable prognostic features simply because targeted therapy is available—long-term durable control favors immunotherapy first 1
• Do not use targeted therapy in BRAF wild-type melanoma—these patients should receive immunotherapy 1, 5
• Do not continue ineffective chemotherapy when modern immunotherapy and targeted therapy options are available 1, 9
• Do not perform aggressive surgical resection without comprehensive staging to rule out additional metastases 1
• Avoid single-agent BRAF inhibition—combination BRAF/MEK inhibition is the standard for targeted therapy 1, 6