Adjuvant Therapy for Stage III Melanoma

Introduction to Adjuvant Systemic Therapy

• The American Society of Clinical Oncology recommends adjuvant immunotherapy with nivolumab or pembrolizumab for 52 weeks as the preferred treatment for resected stage III melanoma, with dabrafenib plus trametinib as an equally effective option for BRAF V600E/K mutant disease 1, 2

Surgical Management and Adjuvant Therapy

• 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 3
• 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 4, 5

Adjuvant Systemic Therapy Selection

• For BRAF wild-type disease, nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks for 52 weeks is a recommended option 1, 2
• For BRAF V600E/K mutant disease, dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily for 52 weeks is a recommended option 6, 1, 2

Critical Decision Points Between Treatment Options

• Both immunotherapy and targeted therapy demonstrate similar efficacy with 3-year RFS rates around 60% for BRAF-mutant disease, but targeted therapy provides faster disease control in the first 6-12 months 6
• Grade 3-4 adverse events occur in approximately 29-38% with immunotherapy versus 35-45% with targeted therapy 6

Special Populations Requiring Individualized Approach

• Stage IIIA disease with sentinel node metastasis <1 mm diameter has a relatively better prognosis (5-year survival >80%) and may be considered for observation, discussing the risk-benefit ratio carefully 1, 2, 7

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 8
• Pembrolizumab 200 mg IV every 3 weeks for 3 doses, followed by surgery, then adjuvant pembrolizumab for 15 additional doses, demonstrates a 2-year event-free survival of 72% vs. 49% with adjuvant-only approach 8

Management of Unresectable Stage III Disease

• For unresectable stage III melanoma, treat as metastatic disease with systemic therapy, considering nivolumab plus ipilimumab, nivolumab plus relatlimab, or nivolumab or pembrolizumab monotherapy for BRAF wild-type disease 1
• For BRAF V600 mutant disease, consider dabrafenib plus trametinib, encorafenib plus binimetinib, or vemurafenib plus cobimetinib, in addition to immunotherapy options 1

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, 2, 9, 7

Common Pitfalls to Avoid

• Do NOT use BRAF/MEK inhibitors for mutations other than V600E/K, as efficacy data are lacking 1, 2
• Do NOT delay adjuvant therapy beyond 13 weeks post-surgery, as this was the maximum allowed in pivotal trials 1, 2

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 1
• Oligometastatic recurrence (1-3 lesions) should be considered for surgical resection or stereotactic radiation combined with systemic therapy 6, 3