Background
Phase III RCT of 1,670 patients with resected stage IIIB, IIIC, M1a, or M1b cutaneous melanoma, comparing adjuvant ipilimumab (two doses) with high-dose interferon (HDI).
Interventions and follow up
Arm A (ipi3): ipilimumab 3mg/kg IV q3wk x4 (induction) then q12wk (maintenance)
Arm B (HDI): high-dose interferon 20 MU/m2/d 5d/wk x4wk (induction), then 10 MU/m2 q other day 3d/wk x48wk
Arm C (ipi10): ipilimumab 10mg/kg IV q3wk x4 (induction) then q12wk (maintenance)
Treatment duration: up to 60wk ipilimumab, 52wk HDI
Primary endpoints: co-primary OS and RFS for ipi3 and ipi10 vs HDI
Arm B (HDI): high-dose interferon 20 MU/m2/d 5d/wk x4wk (induction), then 10 MU/m2 q other day 3d/wk x48wk
Arm C (ipi10): ipilimumab 10mg/kg IV q3wk x4 (induction) then q12wk (maintenance)
Treatment duration: up to 60wk ipilimumab, 52wk HDI
Primary endpoints: co-primary OS and RFS for ipi3 and ipi10 vs HDI
Results
ipi3 vs HDI 5-yr OS: 72% vs 67%; HR 0.78, 95.6%CI 0.61-0.99, P=.044
ipi3 vs HDI median RFS: 4.5yr vs 2.5yr; HR 0.85, 99.4%CI 0.66-1.09, P=.065
ipi10 vs HDI OS: HR 0.88, 95.6%CI 0.69-1.12
ipi10 vs HDI RFS: HR 0.84, 99.4%CI 0.65-1.09
ipi3 vs HDI median RFS: 4.5yr vs 2.5yr; HR 0.85, 99.4%CI 0.66-1.09, P=.065
ipi10 vs HDI OS: HR 0.88, 95.6%CI 0.69-1.12
ipi10 vs HDI RFS: HR 0.84, 99.4%CI 0.65-1.09
Adverse events
Grade ≥3 AEs (ipi3 vs HDI vs ipi10): 38.6% vs 78.9% vs 57.9%
Therapy discontinuation: 35% vs 20% vs 54%
Corticosteroids for AEs: 57.2% vs 10.4% vs 75.7%
Completed planned therapy: 28.4% vs 35.1% vs 21.5%
Therapy discontinuation: 35% vs 20% vs 54%
Corticosteroids for AEs: 57.2% vs 10.4% vs 75.7%
Completed planned therapy: 28.4% vs 35.1% vs 21.5%
Conclusions
Adjuvant ipilimumab 3mg/kg significantly improved OS vs high-dose interferon with less toxicity than the 10mg/kg dose. However, ipilimumab is no longer a preferred adjuvant agent given the superior tolerability and efficacy of anti-PD-1 and BRAF/MEK regimens (CheckMate 238, KEYNOTE-054, COMBI-AD).
Key Limitations
Comparator HDI is obsolete; trial conducted before anti-PD-1 became standard adjuvant therapy, limiting current relevance; high toxicity and discontinuation rates across arms; staging by older AJCC criteria.
Clinical Context
Validated adjuvant ipilimumab 3mg/kg as superior to high-dose interferon, but adjuvant anti-PD-1 (nivolumab, pembrolizumab) has since supplanted ipilimumab as the standard. ESMO no longer recommends adjuvant interferon or ipilimumab as preferred options.