Background
Randomised, double-blind, placebo-controlled phase 2 trial of 167 patients with resected stage IV melanoma rendered free of disease by surgery and/or radiation. Evaluated adjuvant immunotherapy versus observation/placebo.
Interventions and follow up
Arm A: nivolumab 1mg/kg + ipilimumab 3mg/kg q3wk x4, then nivolumab 3mg/kg q2wk
Arm B: nivolumab 3mg/kg q2wk + placebo
Arm C: placebo
Primary endpoint: RFS by ITT analysis
Median follow up: 28.4mo
Arm B: nivolumab 3mg/kg q2wk + placebo
Arm C: placebo
Primary endpoint: RFS by ITT analysis
Median follow up: 28.4mo
Results
mRFS: not reached vs 12.4mo vs 6.4mo (A vs B vs C)
RFS arm A vs C: HR 0.23, 97.5%CI 0.12-0.45, P<.0001
RFS arm B vs C: HR 0.56, 97.5%CI 0.33-0.94, P=.011
1-yr RFS: 75% vs 52% vs 32%
2-yr RFS: 70% vs 42% vs 14%
RFS arm A vs C: HR 0.23, 97.5%CI 0.12-0.45, P<.0001
RFS arm B vs C: HR 0.56, 97.5%CI 0.33-0.94, P=.011
1-yr RFS: 75% vs 52% vs 32%
2-yr RFS: 70% vs 42% vs 14%
Adverse events
Grade 3-4 treatment-related AEs: 71% (nivo+ipi) vs 27% (nivo) vs 0% (placebo)
Immune-related (combination): colitis, hepatitis, endocrinopathies, pneumonitis; frequent and dose-limiting
Discontinuation for AEs: high in the nivo+ipi arm
Immune-related (combination): colitis, hepatitis, endocrinopathies, pneumonitis; frequent and dose-limiting
Discontinuation for AEs: high in the nivo+ipi arm
Conclusions
In resected stage IV melanoma with no evidence of disease, adjuvant nivolumab alone or with ipilimumab significantly improved RFS over placebo, establishing immunotherapy as superior to observation after definitive treatment.
Key Limitations
Small phase 2 sample; RFS not yet translated to mature OS; high combination toxicity; placebo arm raises modern equipoise concerns now that adjuvant anti-PD-1 is standard.
Clinical Context
Supports adjuvant anti-PD-1 (alone or with ipilimumab) for resected stage IV melanoma with no evidence of disease; consistent with ASCO and ESMO recommendations endorsing adjuvant checkpoint inhibition in high-risk resected melanoma.