What are the treatment options for triple wild type melanoma that has metastasized to the lungs?

Treatment Options for Triple Wild-Type Melanoma with Lung Metastases

For triple wild-type (BRAF/NRAS/NF1 wild-type) metastatic melanoma with lung involvement, you should offer immune checkpoint inhibitor therapy with either: (1) nivolumab plus ipilimumab combination followed by nivolumab maintenance, (2) nivolumab plus relatlimab, (3) single-agent nivolumab, or (4) single-agent pembrolizumab. 1, 2

First-Line Treatment Algorithm

The 2023 ASCO guidelines establish four evidence-based options for BRAF wild-type unresectable/metastatic melanoma, all with strong recommendation strength and high-quality evidence 1:

Combination Immunotherapy Options:

• Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg IV every 3 weeks for 4 doses, followed by nivolumab 240 mg IV every 2 weeks or 480 mg every 4 weeks 1

  • Provides superior progression-free survival compared to monotherapy (median PFS improvement demonstrated in CheckMate 067) 1
  • Carries highest toxicity burden with grade 3-4 treatment-related adverse events in approximately 55-59% of patients 1
  • Consider this option for patients with higher disease burden, elevated LDH, or more aggressive disease tempo 1, 2

• Nivolumab 480 mg plus relatlimab 160 mg IV every 4 weeks 1

  • RELATIVITY-047 trial showed median PFS of 10.12 months versus 4.63 months with nivolumab alone (HR 0.75) 1
  • Lower toxicity profile than nivolumab/ipilimumab combination with grade 3-4 adverse events in 18.9% 1
  • Represents newer alternative with improved PFS over monotherapy but less toxicity than dual checkpoint blockade 1

Monotherapy Options:

• Pembrolizumab 200 mg IV every 3 weeks (or 400 mg every 6 weeks per European approval) 1, 3

  • KEYNOTE-006 demonstrated significant OS benefit over ipilimumab 1
  • Treatment duration typically limited to 2 years in clinical trials, though shorter courses (as brief as 1 year) may be reasonable 1
  • Lower toxicity profile compared to combination regimens 1

• Nivolumab 240 mg IV every 2 weeks or 480 mg every 4 weeks 1, 4

  • CheckMate 067 showed significant OS benefit over ipilimumab 1
  • Can be continued beyond 2 years unlike pembrolizumab 1
  • Lowest grade 3-4 adverse event frequency among all options 1

Clinical Decision-Making Framework

For patients with lung metastases specifically, prioritize:

1. High disease burden or symptomatic disease requiring rapid response: Choose nivolumab/ipilimumab combination despite higher toxicity, as it offers highest response rates and most rapid disease control 1, 2

2. Good performance status but desire to balance efficacy with tolerability: Choose nivolumab/relatlimab combination for improved PFS over monotherapy with manageable toxicity 1

3. Elderly patients, multiple comorbidities, or preference for lower toxicity: Choose single-agent pembrolizumab or nivolumab 1, 2

4. Asymptomatic or oligometastatic lung disease: Single-agent anti-PD-1 therapy is appropriate first-line 2

Critical Monitoring Requirements

• Imaging surveillance: CT chest/abdomen/pelvis every 2-3 months initially to assess response 1
• Brain MRI at baseline and during follow-up due to melanoma's propensity for CNS metastases, even with isolated lung involvement initially 2
• Toxicity monitoring: Watch for immune-related adverse events including pneumonitis (particularly relevant with lung metastases), colitis, hepatitis, and endocrinopathies 1, 4, 3

Second-Line Treatment After Progression

If first-line anti-PD-1 monotherapy fails: Switch to ipilimumab plus nivolumab combination 1, 2

If first-line combination therapy fails: Clinical trial enrollment should be strongly prioritized given limited standard options beyond first-line 2

Important Caveats and Pitfalls

• Retesting for BRAF mutations should be considered at progression, as false-negative results can rarely occur, though uncommon 2
• Expanded molecular profiling may identify rare actionable alterations such as KIT mutations or NTRK fusions that could open targeted therapy options 2
• The microsatellite stable (MSS) status means this tumor does not qualify for the highly responsive MSI-high/dMMR immunotherapy indication, and generally has lower response rates to immunotherapy compared to MSI-high tumors 2
• Do not use chemotherapy as first-line therapy - it is considered only as second-line or bridging treatment after immunotherapy failure 1
• For longer dosing cycles (such as pembrolizumab every 6 weeks), appropriate monitoring for disease progression remains necessary 1

Comparative Effectiveness Evidence

Real-world data from 888 patients showed no statistical difference in overall survival between frontline pembrolizumab (median OS 22.6 months) versus nivolumab (median OS 23.9 months), supporting selection based on dosing convenience and patient/provider preference 5. However, combination regimens demonstrate superior PFS compared to monotherapy, though with increased toxicity 1.