What are the indications for adjuvant immunotherapy in melanoma?

Indications for Adjuvant Immunotherapy in Melanoma

For completely resected melanoma, adjuvant immunotherapy with pembrolizumab or nivolumab is indicated for Stage IIB-C and Stage III-IV disease, with dabrafenib plus trametinib as an additional option for BRAF-mutant Stage III disease. 1

Stage-Specific Indications

Stage IIB-C Melanoma (Resected)

• Pembrolizumab for 52 weeks is strongly recommended based on the KEYNOTE-716 trial demonstrating substantial recurrence-free survival benefit 1
• Nivolumab for 52 weeks is also recommended based on CheckMate 76K trial showing similar efficacy and toxicity profiles to pembrolizumab 1
• These agents are FDA-approved for Stage IIB-C disease following complete resection 2, 3
• Prior to these approvals, adjuvant therapy was not recommended for Stage II disease outside clinical trials 1

Stage IIIA-D Melanoma (Resected, BRAF Wild-Type)

• First-line options (no particular order): Nivolumab OR pembrolizumab, both for 52 weeks 1
• Both agents demonstrate high-quality evidence with strong recommendation strength 1
• Ipilimumab and high-dose interferon are not recommended for routine use despite FDA approval 1
• FDA approval includes all patients with lymph node involvement who have undergone complete disease resection 2, 3

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

• Three equivalent first-line options: Nivolumab for 52 weeks OR pembrolizumab for 52 weeks OR dabrafenib plus trametinib for 52 weeks 1
• All three regimens have high-quality evidence supporting their use 1
• The COMBI-AD trial demonstrated dabrafenib plus trametinib improved 3-year recurrence-free survival (58% vs 39%) and overall survival (86% vs 77%) compared to placebo 1

Stage IV Melanoma (Completely Resected)

• Same recommendations as Stage III disease apply 1
• CheckMate 238 explicitly included resected Stage IV disease and demonstrated nivolumab superiority over ipilimumab 1, 4

Critical Staging Qualifications

Microscopic Sentinel Node Disease <1mm

• Patients with Stage IIIA disease and sentinel lymph node metastasis <1mm were excluded from pivotal trials (CheckMate 238, KEYNOTE-054) 1
• These patients have relatively better prognosis and lower relapse risk 1
• Treatment should be offered after discussing individual risk-benefit ratio, though both nivolumab and pembrolizumab carry FDA approval for all lymph node involvement 1

Surgical Requirements

• All adjuvant therapy trials required complete resection including primary tumor excision with adequate margins 1
• Historical trials required completion lymph node dissection (CLND) after positive sentinel lymph node biopsy 1
• Based on MSLT-II and DeCOG trials showing CLND did not improve survival, nodal basin ultrasound surveillance is now reasonable instead of CLND 1
• Efficacy of adjuvant therapy without CLND remains unclear, though NCCN considers it reasonable 1

Comparative Efficacy Data

Anti-PD-1 Agents (Nivolumab vs Pembrolizumab)

• No head-to-head trials exist comparing nivolumab versus pembrolizumab in the adjuvant setting 1
• CheckMate 238 and KEYNOTE-054 suggest similar efficacy and safety profiles 1
• CheckMate 238: 12-month recurrence-free survival 70.5% (nivolumab) vs 60.8% (ipilimumab), HR 0.65, P<0.001 1, 4
• KEYNOTE-054: 12-month recurrence-free survival 75% (pembrolizumab) vs 61% (placebo), HR 0.57, P<0.001 1

Nivolumab vs Ipilimumab

• Nivolumab demonstrated superior recurrence-free survival and significantly lower toxicity compared to high-dose ipilimumab 1, 4
• Grade 3-4 adverse events: 14.4% (nivolumab) vs 45.9% (ipilimumab) 1, 4
• Treatment discontinuation due to adverse events: 9.7% (nivolumab) vs 42.6% (ipilimumab) 1, 4

Ipilimumab Efficacy

• EORTC 18071 demonstrated ipilimumab improved 5-year recurrence-free survival (41% vs 30%), distant metastasis-free survival (48% vs 39%), and overall survival (65% vs 54%) compared to placebo 1
• Despite proven efficacy, ipilimumab is not recommended for routine adjuvant use due to inferior tolerability compared to anti-PD-1 agents 1

Treatment Duration and Dosing

Standard Regimens

• Nivolumab: 3 mg/kg IV every 2 weeks OR 480 mg IV every 4 weeks for 52 weeks 1, 2
• Pembrolizumab: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks for 52 weeks 1, 3
• Dabrafenib plus trametinib: Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily for 52 weeks 1

Toxicity Considerations

Adverse Event Rates

• Grade 3-4 adverse events occurred in 25-41% of patients across adjuvant trials with anti-PD-1 agents and BRAF/MEK inhibitors 1
• These rates are substantially lower than historical adjuvant options (interferon-α, biochemotherapy) 1
• Any-grade immune-related adverse events affect up to 90% of patients on ipilimumab 5

Management Requirements

• Review FDA prescribing information before initiating therapy to identify contraindications 1
• Refer to NCCN Guidelines for Management of Immunotherapy-Related Toxicities for monitoring and management 1
• Patients must have adequate performance status to tolerate immune-related adverse events 6
• Active autoimmune disease requiring systemic immunosuppression represents a relative contraindication 6

Molecular Testing Requirements

BRAF Mutation Testing

• Mandatory for all Stage III-IV melanoma to determine eligibility for dabrafenib plus trametinib 1, 7
• Testing should identify V600E or V600K mutations specifically 1
• BRAF wild-type patients receive anti-PD-1 monotherapy only 1
• BRAF-mutant patients have choice of anti-PD-1 monotherapy OR dabrafenib plus trametinib 1

PD-L1 Testing

• Not required for adjuvant therapy selection 1
• Subgroup analyses from CheckMate 238 and KEYNOTE-054 showed benefit regardless of PD-L1 expression status 1

Common Pitfalls to Avoid

Treatment Selection Errors

• Do not use ipilimumab as routine adjuvant therapy despite FDA approval—anti-PD-1 agents have superior tolerability with equivalent or better efficacy 1
• Do not use interferon-α outside clinical trials—it has been superseded by checkpoint inhibitors 1, 7
• Do not delay treatment while awaiting molecular testing in clearly indicated cases—anti-PD-1 therapy does not require mutation-specific selection 6

Staging and Eligibility Errors

• Do not automatically treat Stage IIIA patients with <1mm sentinel node involvement—discuss individual risk-benefit given their exclusion from pivotal trials 1
• Do not offer adjuvant therapy to Stage IIA or lower outside clinical trials—no evidence supports benefit 1
• Do not assume AJCC 7th edition trial data directly translates to AJCC 8th edition staging—substage definitions changed significantly 1

Monitoring and Response Assessment

• Do not use traditional RECIST criteria alone—employ immune-related response criteria as tumor regression may be delayed 6
• Do not discontinue therapy for apparent progression without considering pseudoprogression, which can occur with immunotherapy 6
• Do not underestimate immune-related adverse events—they can affect any organ system and require aggressive management with corticosteroids or immunosuppression 6

Neoadjuvant Therapy

Current Status

• No recommendation can be made for or against routine neoadjuvant therapy for resectable regional or distant metastatic melanoma 1
• Evidence quality remains low for neoadjuvant approaches 1
• Patients should be referred for clinical trial enrollment where possible 1
• Emerging data suggest neoadjuvant approaches may complement adjuvant strategies and demonstrate superior outcomes 8, 9