Background
Phase III RCT (MDX010-20), N=676 previously treated unresectable stage III/IV melanoma (≥1 prior therapy; not BRAF-selected). Three-arm (2:1:1) randomization, 125 sites, enrolled 2004–2008. First immune checkpoint blocker tested in advanced melanoma; predates PD-1 inhibitors.
Interventions and follow up
Arm A: Ipilimumab 3 mg/kg q3wk × 4 + gp100 peptide vaccine (n=403)
Arm B: Ipilimumab 3 mg/kg q3wk × 4 alone (n=137)
Arm C: gp100 peptide vaccine alone (control, n=136)
Primary endpoint: OS (ipi+gp100 vs gp100)
mFollow up: 28 mo
Arm B: Ipilimumab 3 mg/kg q3wk × 4 alone (n=137)
Arm C: gp100 peptide vaccine alone (control, n=136)
Primary endpoint: OS (ipi+gp100 vs gp100)
mFollow up: 28 mo
Results
mOS (ipi+gp100 vs gp100): 10.0 vs 6.4 mo, HR 0.68 (95% CI 0.55–0.85), P<.001
mOS (ipi alone vs gp100): 10.1 vs 6.4 mo, HR 0.66 (95% CI 0.51–0.87), P=.003
mOS (ipi+gp100 vs ipi alone): 10.0 vs 10.1 mo — no difference; gp100 added no benefit
1-yr OS: 45.6% (ipi+gp100), 45.5% (ipi alone), 25.3% (gp100)
mOS (ipi alone vs gp100): 10.1 vs 6.4 mo, HR 0.66 (95% CI 0.51–0.87), P=.003
mOS (ipi+gp100 vs ipi alone): 10.0 vs 10.1 mo — no difference; gp100 added no benefit
1-yr OS: 45.6% (ipi+gp100), 45.5% (ipi alone), 25.3% (gp100)
Adverse events
Immune-related AEs any grade: 60% (ipi+gp100), 61% (ipi alone), 32% (gp100)
Grade 3–4 immune AEs: 10–15% in ipi arms
Immune-related deaths: 14 in ipi+gp100 (2.1%), 7 in ipi alone (~2%) — colitis, hepatitis, hypophysitis, toxic epidermal necrolysis; managed with corticosteroids
Grade 3–4 immune AEs: 10–15% in ipi arms
Immune-related deaths: 14 in ipi+gp100 (2.1%), 7 in ipi alone (~2%) — colitis, hepatitis, hypophysitis, toxic epidermal necrolysis; managed with corticosteroids
Conclusions
Ipilimumab 3 mg/kg significantly improved OS vs gp100 vaccine alone in previously treated advanced melanoma (HR 0.68, P<.001) — the first treatment to improve OS in metastatic melanoma in over 30 years. Adding gp100 to ipilimumab did not improve outcomes.
Key Limitations
Control arm (gp100 vaccine) has essentially no activity — unbalanced comparison; active ipilimumab effect confirmed by ipi-alone arm (HR 0.66). No BRAF selection. mOS ~10 mo remains poor; ~2% treatment-related mortality. Historically superseded in 1L by PD-1 inhibitors (KEYNOTE-006) and ipi+nivo (CheckMate 067).
Clinical Context
Landmark trial: first to show an immune checkpoint inhibitor improves survival in advanced melanoma. Ipilimumab became the first FDA-approved agent to improve OS in metastatic melanoma (FDA 2011), opening the checkpoint era. Ipilimumab 3 mg/kg monotherapy now largely superseded by PD-1 inhibitors and ipi+nivo but remains a historical benchmark. ESMO-MCBS: not applicable (historical).