What are the guidelines for immunotherapy in a patient with surgically resected metastatic melanoma with lung metastases only?

Adjuvant Immunotherapy for Surgically Resected Metastatic Melanoma with Lung-Only Metastases

Nivolumab monotherapy 240 mg IV every 2 weeks (or 480 mg IV every 4 weeks) for up to 1 year is the preferred adjuvant immunotherapy for completely resected stage IV melanoma with lung-only metastases (M1a disease). 1, 2

Primary Treatment Algorithm

Start nivolumab within 13 weeks of complete surgical resection and continue for 52 weeks unless disease recurrence or unacceptable toxicity occurs. 1

• The FDA has approved nivolumab for adjuvant treatment of completely resected Stage IV melanoma in patients 12 years and older 2
• ESMO designates nivolumab monotherapy as the preferred regimen for resected stage IV melanoma with M1a (lung-only) disease 1
• The CheckMate 238 trial demonstrated a hazard ratio of 0.63 for recurrence-free survival in patients with M1a or M1b disease, compared to 1.00 for M1c disease 1

Alternative Regimen with Higher Efficacy but Greater Toxicity

Combination nivolumab plus ipilimumab offers superior recurrence-free survival but substantially higher toxicity and should be reserved for carefully selected patients. 1

• The IMMUNED trial showed combination therapy achieved HR 0.23 (95% CI 0.13-0.41) for recurrence-free survival versus placebo in resected stage IV disease 3, 4
• Combination therapy demonstrated HR 0.40 (95% CI 0.22-0.73) versus nivolumab monotherapy 3
• The significantly increased toxicity profile makes this a secondary option requiring careful patient selection 1

Other Acceptable Options

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. 1, 5

• The FDA has approved pembrolizumab for adjuvant treatment of Stage IV melanoma following complete resection 5
• ESMO guidelines list pembrolizumab as a preferred treatment option with Level I evidence and Grade A recommendation for resected stage III melanoma 3
• Evidence quality for stage IV disease specifically is lower than for nivolumab 1

What NOT to Use

Do not use dabrafenib plus trametinib unless there is a contraindication to immunotherapy, and only if BRAF V600E/K mutation is present. 1

• BRAF/MEK inhibitors are only effective in BRAF-mutated melanoma and should not be used in BRAF wild-type disease 4, 6
• The COMBI-AD trial excluded patients with resected stage IV melanoma, providing only Level V evidence with Strength C recommendation from ESMO for this indication 3, 1
• Immunotherapy is preferred over targeted therapy even in BRAF-mutated resected stage IV disease 1

Do not use single-agent ipilimumab as it has inferior efficacy and substantially higher toxicity compared to anti-PD-1 therapy. 1, 4

Do not use chemotherapy (dacarbazine or temozolomide) in the adjuvant setting as it provides no survival benefit. 3, 4

Do not pursue observation alone given the high recurrence risk and strong evidence supporting active adjuvant treatment. 3, 4

Critical Timing Considerations

Initiate adjuvant therapy within 13 weeks of achieving complete surgical resection with negative margins. 1

• Complete resection (R0) with negative margins is essential before starting adjuvant therapy 4
• Comprehensive staging must confirm no residual disease before initiating treatment 4
• Delaying immunotherapy beyond this window may compromise outcomes 4

Monitoring for Immune-Related Adverse Events

Monitor closely for immune-related adverse events including colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic toxicities. 1, 4

• PD-1 blockade significantly increases susceptibility to severe infections, particularly tuberculosis and bacterial infections 1, 4
• Approximately 32% of patients discontinue adjuvant anti-PD-1 therapy due to toxicity in real-world practice 7
• Management of toxicity should follow established algorithms for metastatic disease 3

Management of Treatment Interruptions

If severe toxicity requires treatment discontinuation, do not restart immunotherapy or switch to alternative adjuvant therapy. 3

• Patients who discontinue adjuvant anti-PD-1 prematurely without recurrence have similar outcomes as those completing planned therapy 7
• ESMO provides Level V evidence with Strength D recommendation against restarting treatment after severe toxicity 3
• This recommendation applies specifically to severe toxicity requiring permanent discontinuation 3

Common Pitfalls to Avoid

Do not delay treatment while waiting for molecular testing results if BRAF status is unknown, as immunotherapy is appropriate regardless of mutation status. 3

Do not use single-agent BRAF inhibition even in BRAF-mutated disease, as combination BRAF/MEK inhibition is the only acceptable targeted therapy approach. 6

Do not perform incomplete surgical resection, as R0 resection is mandatory before considering adjuvant therapy. 4

Do not continue ineffective therapy beyond evidence of disease progression. 1