Background
Phase III double-blind RCT (EORTC 18071), N=951 completely resected stage III cutaneous melanoma (AJCC 7th ed), including palpable nodal involvement (IIIB/C) or microscopic positive SLN (≥1 mm). Excluded stage IIIA (SLN metastasis <1 mm). Stratified by stage substage, number of positive nodes, region. Enrolled 2008-2011 across 99 EORTC centers. Ipilimumab dose 10 mg/kg.
Interventions and follow up
Arm A: Ipilimumab 10 mg/kg q3wk × 4 doses (induction), then q12wk maintenance up to 3 years
Arm B: Placebo
Primary endpoint: Recurrence-free survival (RFS)
mFollow up: 5.3 years (OS analysis)
Arm B: Placebo
Primary endpoint: Recurrence-free survival (RFS)
mFollow up: 5.3 years (OS analysis)
Results
mRFS: 26.1 vs 17.1 months, HR 0.75, 95% CI 0.64-0.90, P=.0013
OS: HR 0.72, 95% CI 0.58-0.88, P=.001
5-yr OS: 65.4% vs 54.4%
DMFS: HR 0.76, 95% CI 0.64-0.92, P=.002
OS: HR 0.72, 95% CI 0.58-0.88, P=.001
5-yr OS: 65.4% vs 54.4%
DMFS: HR 0.76, 95% CI 0.64-0.92, P=.002
Adverse events
Grade ≥3 immune-related AEs: 41.6% vs 2.7%
Treatment-related deaths: 5 (1.1%) in ipilimumab arm
Discontinuation due to AE: 52% vs 3.5%
Most common Grade ≥3 immune AEs: colitis/diarrhea 16%, hepatitis 11%, hypophysitis 8%, rash 5%
Treatment-related deaths: 5 (1.1%) in ipilimumab arm
Discontinuation due to AE: 52% vs 3.5%
Most common Grade ≥3 immune AEs: colitis/diarrhea 16%, hepatitis 11%, hypophysitis 8%, rash 5%
Conclusions
Adjuvant ipilimumab 10 mg/kg significantly improved RFS and OS vs placebo in resected stage III melanoma (OS HR 0.72, P=.001), the first adjuvant trial to demonstrate an OS benefit in melanoma and establishing immunotherapy as an effective adjuvant modality.
Key Limitations
Ipilimumab 10 mg/kg produces dramatically higher Grade ≥3 immune-related AEs (41.6%) than the 3 mg/kg metastatic dose. CheckMate 238 later showed nivolumab superior to ipilimumab 10 mg/kg with substantially lower toxicity, largely supplanting this regimen. Stage IIIA (small SLN deposits) excluded, limiting applicability to that lower-risk subgroup. No prespecified biomarker-stratified analyses (BRAF status, PD-L1).
Clinical Context
EORTC 18071 was the first phase III trial to demonstrate an OS benefit from adjuvant immunotherapy in melanoma (2016), a historic milestone. Ipilimumab 10 mg/kg has been largely superseded by adjuvant PD-1 inhibitors (nivolumab, pembrolizumab) based on superior RFS and tolerability in CheckMate 238 and KEYNOTE-054; ESMO no longer favors ipilimumab adjuvant given toxicity. The durable 5-year OS benefit (65.4% vs 54.4%) confirmed durability.