What are the treatment options for metastatic melanoma?

Treatment Options for Metastatic Melanoma

For first-line treatment of unresectable or metastatic melanoma, use immune checkpoint inhibitors (anti-PD-1 monotherapy with nivolumab or pembrolizumab, or nivolumab/ipilimumab combination) for all patients, or switch to BRAF/MEK inhibitor combinations specifically for BRAF V600-mutant patients with rapidly progressive or symptomatic disease. 1

Mandatory Initial Testing

• All patients must undergo BRAF mutation testing using an FDA-approved test or CLIA-approved facility before treatment selection to identify any BRAF V600 mutation (V600E, V600K, V600R, V600D, or others). 1

First-Line Treatment Algorithm

For BRAF Wild-Type Patients

Choose from three evidence-based immunotherapy options, all with Category 1/Strong recommendations: 1, 2

• Nivolumab 3 mg/kg IV every 2 weeks (Category 1) - lowest toxicity profile with significant OS benefit over ipilimumab. 3, 1, 4

• Pembrolizumab 2 mg/kg IV every 3 weeks (Category 2A) - demonstrated significant OS benefit over ipilimumab with lower toxicity compared to combination regimens. 3, 1, 5

• Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg IV every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks (Category 2A) - provides superior progression-free survival but carries grade 3-4 adverse events in approximately 55-65% of patients. 3, 1, 2

• Nivolumab 480 mg plus relatlimab 160 mg IV every 4 weeks - newer alternative with median PFS of 10.12 months versus 4.63 months with nivolumab alone, with lower toxicity than nivolumab/ipilimumab combination. 2

Selection criteria between these options: 1, 2

• High disease burden or symptomatic disease requiring rapid response: Use nivolumab/ipilimumab combination despite higher toxicity, as it offers highest response rates and most rapid disease control. 2

• Good performance status but desire to balance efficacy with tolerability: Use nivolumab/relatlimab combination for improved PFS over monotherapy with manageable toxicity. 2

• Elderly patients, multiple comorbidities, or preference for lower toxicity: Use single-agent pembrolizumab or nivolumab. 2

For BRAF V600-Mutant Patients

Treatment selection depends on disease tempo and symptomatology: 1, 6

• Rapidly progressing or symptomatic disease: Use BRAF/MEK inhibitor combinations as first-line. 1, 6

• Low-volume, asymptomatic metastatic disease: Prefer immunotherapy first (same options as BRAF wild-type above) to maximize opportunity for long-term durable control. 1, 6

Approved BRAF/MEK inhibitor combinations (all Category 1): 3, 1

• Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily - COMBI-d trial showed 69% response rate, median PFS 11.0 months, median OS 25.1 months. 3, 1

• Encorafenib 450 mg PO once daily plus binimetinib 45 mg PO twice daily 1

• Vemurafenib 960 mg PO twice daily plus cobimetinib 60 mg PO once daily (21 days on, 7 days off) - response rate 68%, median PFS 9.9 months. 3, 1

Critical Treatment Principles

Never use ipilimumab monotherapy as first-line treatment - CheckMate 067 trial demonstrated superior outcomes with anti-PD-1 monotherapy or combination therapy compared to ipilimumab alone. 3, 1

Never use BRAF inhibitor monotherapy unless combination therapy is absolutely contraindicated - combination therapy provides superior outcomes. 1

Never use MEK inhibitor monotherapy - poor efficacy with response rate only 22% and median PFS 2.8 months. 1

Second-Line Treatment After Progression

After progression on anti-PD-1 therapy in BRAF-mutant patients: 1

• Switch to BRAF/MEK inhibitor combination therapy, or
• Alternatively, offer ipilimumab or ipilimumab-containing regimens

After progression on BRAF/MEK inhibitors: 3, 1

• Switch to anti-PD-1-based immunotherapy
• Critical caveat: Patients who progressed rapidly on first-line BRAF inhibitors (time to progression <6 months) derive minimal benefit from second-line BRAF/MEK combinations (response rate 0% vs 25% for those progressing after ≥6 months; median PFS 1.8 vs 3.9 months). 3

Special Considerations

For Injectable Cutaneous/Subcutaneous/Nodal Lesions

Talimogene laherparepvec (T-VEC) may be offered as primary therapy if patients are not eligible for or decline systemic therapies, or for disease control in limited stage IV disease. 1

For Resectable Limited Metastatic Disease

Surgical resection should be considered for isolated, slowly developing single metastases, including parenchymal organ metastases and CNS lesions, with complete (R0) resection as the goal. 6

Treatment Duration

• Nivolumab and pembrolizumab: Treatment limited to 2 years in pivotal trials, though may be continued beyond 2 years in clinical trials. 1
• No high-quality melanoma-specific data exist on optimal duration beyond 2 years. 1

Monitoring Requirements

Imaging surveillance: CT chest/abdomen/pelvis every 2-3 months initially to assess response. 2

Brain MRI: At baseline and during follow-up due to melanoma's propensity for CNS metastases. 2

Toxicity monitoring: Essential for immune-related adverse events including pneumonitis, colitis, hepatitis, and endocrinopathies. 2

Role of Chemotherapy

Chemotherapy has a limited role and should generally be reserved only for patients who have failed both immunotherapy and targeted therapy, with dacarbazine being the conventional palliative option. 6, 2 Chemotherapy should never be used as first-line therapy. 2

Common Pitfalls to Avoid

• Delaying immunotherapy in BRAF-mutated patients with favorable prognostic features can result in missed opportunities for long-term durable control. 6
• Retesting for BRAF mutations should be considered at progression as false-negative results can rarely occur. 2
• Expanded molecular profiling may identify rare actionable alterations such as KIT mutations or NTRK fusions that could open targeted therapy options. 2