What are the recommended adjuvant treatments for high-risk melanoma?

Recommended Adjuvant Treatments for High-Risk Melanoma

For patients with high-risk melanoma, adjuvant therapy with immune checkpoint inhibitors (nivolumab or pembrolizumab) should be offered for stage IIB-C and stage III disease, while patients with BRAF V600E/K mutations should receive either immune checkpoint inhibitors or BRAF/MEK inhibitor combination therapy. 1

Stage-Specific Recommendations

Stage IIB-IIC Melanoma

• First-line recommendation: Adjuvant pembrolizumab or nivolumab for 52 weeks 1
  • Pembrolizumab: 200 mg IV every 3 weeks
  • Nivolumab: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks
• Key consideration: While these treatments significantly improve recurrence-free survival, the potential for immune-related toxicity must be weighed against the current lack of overall survival data in stage II disease 1

Stage IIIA-D Melanoma (BRAF Wild-Type)

• First-line recommendation: Either nivolumab or pembrolizumab for 52 weeks 1
  • Dosing as above
• Not recommended: Ipilimumab and high-dose interferon are not recommended for routine use in adjuvant therapy 1
• Special consideration: For patients with stage IIIA disease with microscopic sentinel nodal metastasis <1 mm, treatment decisions should be individualized as these patients have better prognosis and were not included in pivotal trials 1

Stage IIIA-D Melanoma (BRAF V600E/K Mutant)

• First-line recommendation: One of the following options (in no particular order) 1:
  • Nivolumab for 52 weeks
  • Pembrolizumab for 52 weeks
  • Dabrafenib plus trametinib for 52 weeks (dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily)
• Note: For BRAF mutations other than V600E/K, no recommendation can be made for or against BRAF/MEK inhibitor therapy 1

Stage IV (Resected) Melanoma

• First-line recommendation: Same options as for stage III disease based on BRAF mutation status 1

Neoadjuvant Therapy

• For clinical and resectable stage IIIB-IV: Neoadjuvant pembrolizumab (maximum of three courses of 200 mg every 3 weeks) followed by resection and adjuvant pembrolizumab (maximum of 15 courses) should be offered 1
• Clinical trials of neoadjuvant therapy should be considered where possible 1

Treatment Selection Algorithm

1. Determine disease stage (AJCC 8th edition staging)
2. Test for BRAF V600E/K mutation status in all patients with stage III-IV disease
3. For stage IIB-IIC: Offer nivolumab or pembrolizumab
4. For stage IIIA-D, BRAF wild-type: Offer nivolumab or pembrolizumab
5. For stage IIIA-D, BRAF V600E/K mutant: Consider these factors when choosing therapy:
   • Favor immune checkpoint inhibitors when:
     • Long-term durability of response is prioritized
     • Patient has good performance status and can tolerate potential immune-related adverse events
   • Favor dabrafenib plus trametinib when:
     • Rapid response is needed
     • Patient has symptomatic disease
     • Patient has contraindications to immunotherapy

Monitoring and Management

• Regular clinical assessment for treatment-related toxicities
• Radiologic surveillance as per institutional protocols
• Prompt management of immune-related adverse events according to established guidelines

Important Considerations and Caveats

• The CheckMate 915 trial showed that combination nivolumab plus ipilimumab did not improve recurrence-free survival compared to nivolumab alone in the adjuvant setting, while significantly increasing toxicity 2
• Patients with stage IIIA disease with <1 mm sentinel node involvement have better prognosis and were not included in pivotal trials; treatment decisions should be made carefully in this population 1
• The full 52-week treatment duration is recommended for optimal benefit
• Molecular testing for BRAF mutations is essential to guide treatment decisions 3

Adjuvant therapy decisions should prioritize treatments with proven survival benefits while considering the risk-benefit profile for each individual patient's disease characteristics.