What is the recommended treatment for stage III melanoma?

Treatment of Stage III Melanoma

For resected stage III melanoma, adjuvant immunotherapy with nivolumab or pembrolizumab for 52 weeks is the preferred treatment, with dabrafenib plus trametinib as an equally effective option for BRAF V600E/K mutant disease. 1

Surgical Management First

• Complete surgical resection is mandatory before initiating adjuvant therapy, including therapeutic lymph node dissection for clinically positive nodes or completion lymphadenectomy for sentinel node-positive disease 1
• Adjuvant radiotherapy to the nodal bed should be considered for high-risk features: multiple positive nodes, large nodes, or macroscopic extranodal soft tissue extension, particularly in the head and neck region 1

Adjuvant Systemic Therapy Selection

For BRAF Wild-Type Disease (Stage IIIA-D)

Choose one of the following options (no particular order): 1

• Nivolumab 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks for 52 weeks 1
• Pembrolizumab 200 mg IV every 3 weeks (or 400 mg every 6 weeks) for 52 weeks 1, 2

For BRAF V600E/K Mutant Disease (Stage IIIA-D)

Choose one of the following options (no particular order): 1

• Nivolumab 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks for 52 weeks 1
• Pembrolizumab 200 mg IV every 3 weeks for 52 weeks 1, 2
• Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily for 52 weeks 1

Critical Decision Points Between Treatment Options

Immunotherapy vs. Targeted Therapy for BRAF-Mutant Disease

• Both approaches demonstrate similar efficacy with 3-year RFS rates around 60%, but targeted therapy provides faster disease control in the first 6-12 months 1, 3
• Targeted therapy (dabrafenib/trametinib) may be preferred for patients requiring rapid disease control or those with high tumor burden, as it achieves earlier responses 3
• Immunotherapy may be preferred for patients seeking potential long-term durable responses beyond treatment completion 4
• Grade 3-4 adverse events occur in approximately 29-38% with immunotherapy versus 35-45% with targeted therapy 1

Special Populations Requiring Individualized Approach

• **Stage IIIA disease with sentinel node metastasis <1 mm diameter**: These patients have relatively better prognosis (5-year survival >80%) and were excluded from pivotal trials; discuss risk-benefit ratio carefully as observation may be reasonable 1
• Stage IIIB/C with bulky clinically positive nodes: Consider neoadjuvant therapy instead of upfront surgery (see below) 1, 5

Emerging Neoadjuvant Approach for Resectable Stage III

For patients with resectable, clinically positive lymph nodes or bulky stage III disease, neoadjuvant immunotherapy followed by surgery is now preferred over upfront surgery plus adjuvant therapy. 1, 5

Preferred Neoadjuvant Regimens

• Pembrolizumab 200 mg IV every 3 weeks for 3 doses, followed by surgery, then adjuvant pembrolizumab for 15 additional doses (SWOG 1801 regimen): 2-year event-free survival 72% vs. 49% with adjuvant-only approach 1
• Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg IV every 3 weeks for 2 doses, followed by surgery: Major pathologic response rate 59%, with 12-month event-free survival 83.7% vs. 57.2% with adjuvant-only 1, 5

Response-Driven Adjuvant Strategy

• Patients achieving major pathologic response (≤10% viable tumor) after neoadjuvant therapy may omit adjuvant treatment, with 12-month RFS of 95.1% 5
• Patients with partial response (10-50% viable tumor) or nonresponse (>50% viable tumor) should receive adjuvant therapy 5

Treatments NOT Recommended

• Ipilimumab monotherapy and high-dose interferon are NOT recommended for routine adjuvant use due to inferior efficacy and higher toxicity compared to anti-PD-1 agents 1
• Observation alone is inferior to active treatment for all stage III substages except possibly IIIA with <1 mm sentinel node involvement 1

Management of Unresectable Stage III Disease

For unresectable stage III melanoma, treat as metastatic disease with systemic therapy: 1

BRAF Wild-Type

• Nivolumab plus ipilimumab followed by nivolumab maintenance (preferred) 1
• Nivolumab plus relatlimab 1
• Nivolumab or pembrolizumab monotherapy 1

BRAF V600 Mutant

• All immunotherapy options above PLUS 1
• Dabrafenib plus trametinib 1
• Encorafenib plus binimetinib 1
• Vemurafenib plus cobimetinib 1

Common Pitfalls to Avoid

• Do NOT use BRAF/MEK inhibitors for mutations other than V600E/K, as efficacy data are lacking 1
• Do NOT delay adjuvant therapy beyond 13 weeks post-surgery, as this was the maximum allowed in pivotal trials 2
• Do NOT use adjuvant interferon in completely resected stage IV disease, as no evidence supports this practice 1
• Do NOT perform completion lymphadenectomy for sentinel node-positive disease if planning neoadjuvant therapy, as this removes the target for pathologic response assessment 1

Recurrence Management After Adjuvant Therapy

• Patients who relapse during or after adjuvant targeted therapy respond well to subsequent anti-PD-1 therapy, with excellent response rates 4
• Patients who relapse during or after adjuvant immunotherapy may benefit from BRAF/MEK inhibitors (if BRAF-mutant) or alternative immunotherapy combinations 1, 4
• Oligometastatic recurrence (1-3 lesions) should be considered for surgical resection or stereotactic radiation combined with systemic therapy 1