What immunotherapy regimen is indicated for stage 4 melanoma with metastases (Mets) limited to the lungs after complete surgical resection of the primary tumor?

Adjuvant Immunotherapy for Completely Resected Stage IV Melanoma with Lung-Only Metastases

For stage 4 melanoma with lung-only metastases after complete surgical resection, nivolumab monotherapy (240 mg IV every 2 weeks or 480 mg IV every 4 weeks for 1 year) is the preferred adjuvant immunotherapy regimen, with combination nivolumab plus ipilimumab as an alternative offering superior recurrence-free survival but substantially higher toxicity. 1

Primary Treatment Algorithm

First-Line Recommendation: Nivolumab Monotherapy

• Nivolumab 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks for up to 1 year is the standard adjuvant approach for resected stage IV melanoma with M1a disease (lung metastases only). 1, 2
• The CheckMate 238 trial demonstrated clear benefit in resected stage IV melanoma, with a hazard ratio for recurrence-free survival of 0.63 for patients with M1a or M1b disease (compared to 1.00 for M1c disease). 1
• This represents moderate-quality evidence as stage IV patients were a subset of the overall trial population. 1

Alternative Option: Combination Nivolumab Plus Ipilimumab

• Nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks for up to 1 year offers superior efficacy but with significantly increased toxicity. 1
• The IMMUNED trial (phase II, 167 patients with resected stage IV disease) showed combination therapy had superior recurrence-free survival versus nivolumab alone (HR 0.40,95% CI 0.22-0.73) and versus placebo (HR 0.23,95% CI 0.13-0.41). 1
• However, grade 3-4 treatment-related adverse events occurred in 71% with combination versus 27% with nivolumab monotherapy in IMMUNED. 1
• The larger CheckMate 915 trial (245 stage IV patients) showed NO significant difference between combination and nivolumab monotherapy (HR 0.88,95% CI 0.58-1.32), though this used a different dosing schedule. 1, 3

Third Option: Pembrolizumab Monotherapy

• Pembrolizumab 200 mg IV every 3 weeks for 1 year is an acceptable alternative to nivolumab, though evidence in resected stage IV disease is less robust (low-quality evidence). 1
• Pembrolizumab demonstrated efficacy in stage III disease but was not specifically studied in stage IV resected melanoma trials. 1, 4

What NOT to Use

BRAF/MEK Inhibitors Are NOT Indicated

• Dabrafenib plus trametinib should ONLY be considered if there is a contraindication to immunotherapy in patients with BRAF V600E/K mutations. 1
• This is Level V evidence with Strength C recommendation from ESMO, as no prospective trials included resected stage IV patients. 1
• For triple wild-type melanoma (no BRAF mutation), targeted therapy is explicitly NOT recommended and will not work. 5

Single-Agent Ipilimumab Is Obsolete

• Do not use ipilimumab monotherapy as it has inferior efficacy and substantially higher toxicity compared to anti-PD-1 therapy. 5, 2
• CheckMate 238 showed nivolumab was superior to ipilimumab with 12-month recurrence-free survival of 70.5% versus 60.8% (HR 0.65, P<0.001). 2

Observation Alone Is Inadequate

• Do not simply observe after complete resection given the high recurrence risk and strong evidence supporting adjuvant therapy. 1, 5
• Patients with resected stage IV melanoma have recurrence risk equal to or exceeding stage III disease, for which adjuvant therapy is clearly indicated. 1

Critical Decision-Making Framework

When to Choose Nivolumab Monotherapy (Preferred)

• Lower toxicity profile: grade 3-4 adverse events in 14.4% versus 45.9% with ipilimumab and 32.6% with combination therapy. 3, 2
• Treatment discontinuation due to adverse events: 9.7% with nivolumab versus 42.6% with ipilimumab. 2
• Established efficacy specifically in M1a disease (lung metastases). 1

When to Consider Combination Nivolumab Plus Ipilimumab

• Younger patients with excellent performance status who can tolerate higher toxicity. 1
• High-risk features suggesting aggressive biology (though specific criteria are not well-defined in guidelines). 1
• Critical caveat: The conflicting results between IMMUNED (showing benefit) and CheckMate 915 (showing no benefit) create uncertainty about whether combination therapy truly offers advantage over monotherapy in stage IV disease. 1, 3

Timing and Duration

Treatment Initiation

• Begin adjuvant therapy within 13 weeks of complete surgical resection, as this was the maximum allowed in pivotal trials. 6
• Ensure complete staging confirms no residual disease before starting therapy. 5

Treatment Duration

• Continue for 1 year (52 weeks) unless disease recurrence, unacceptable toxicity, or patient withdrawal occurs. 1, 7

Monitoring for Immune-Related Adverse Events

Essential Surveillance

• Monitor for immune-related adverse events including colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic toxicities. 1, 5
• Pembrolizumab and nivolumab significantly increase susceptibility to severe infections, particularly tuberculosis and bacterial infections, as PD-1 blockade impairs normal immune responses to pathogens. 5, 7
• Management of toxicity should follow established algorithms for metastatic disease. 1

Toxicity Management Principles

• If severe toxicity occurs requiring treatment discontinuation, do NOT restart immunotherapy or switch to alternative adjuvant therapy. 1
• This is Level V evidence, Strength D recommendation, but reflects the risk-benefit balance in the adjuvant setting where many patients would never relapse. 1

Common Pitfalls to Avoid

Do Not Delay Treatment

• Starting adjuvant immunotherapy promptly after surgical recovery optimizes outcomes; do not unnecessarily delay beyond the 13-week window. 5, 6

Do Not Use Chemotherapy

• Chemotherapy has no role in the adjuvant setting for resected stage IV melanoma and should only be considered for unresectable metastatic disease after immunotherapy failure. 8, 5

Do Not Ignore M1 Substage

• The benefit of nivolumab was clear for M1a/M1b disease (HR 0.63) but not for M1c disease (HR 1.00), though lung-only metastases represent M1a disease where benefit is established. 1

Evidence Quality Summary

The recommendation for nivolumab monotherapy is based on:

• Moderate-quality evidence from CheckMate 238 subset analysis (169 stage IV patients, 128 with M1a/M1b). 1, 2
• ESMO consensus supporting adjuvant therapy for resected stage IV melanoma (Level V evidence, Strength C recommendation). 1
• ASCO 2023 guidelines listing nivolumab as a reasonable option with moderate evidence quality for stage IV disease. 1

The combination approach has conflicting evidence:

• Low-quality evidence from small phase II IMMUNED trial showing benefit. 1
• Contradictory findings from CheckMate 915 showing no benefit over monotherapy. 1, 3