Background
Phase III double-blind RCT (CA184-024), N=502 previously untreated unresectable stage III/IV melanoma. Stratified by ECOG PS, metastatic stage, region. 96 sites, enrolled 2006–2009. Ipilimumab 10 mg/kg (3× the standard 3 mg/kg dose) + dacarbazine as first-line therapy.
Interventions and follow up
Arm A: Ipilimumab 10 mg/kg q3wk × 4 + dacarbazine 850 mg/m² q3wk × 4, then ipilimumab 10 mg/kg q12wk maintenance
Arm B: Placebo + dacarbazine 850 mg/m² q3wk × 4, then placebo maintenance
Primary endpoint: OS
mFollow up: 4.8 yr
Arm B: Placebo + dacarbazine 850 mg/m² q3wk × 4, then placebo maintenance
Primary endpoint: OS
mFollow up: 4.8 yr
Results
mOS: 11.2 vs 9.1 mo, HR 0.72 (95% CI 0.59–0.87), P<.001
3-yr OS: 20.8% vs 12.2%
5-yr OS: 18.2% vs 8.8%
ORR: 15.2% vs 10.3%
3-yr OS: 20.8% vs 12.2%
5-yr OS: 18.2% vs 8.8%
ORR: 15.2% vs 10.3%
Adverse events
Grade 3–4 AEs: 56.3% vs 27.5%
Grade 3–4 ALT/AST elevation: 31.6% vs 2.8% (most common AE; hepatotoxicity from ipi+DTIC)
Immune-related AEs any grade: 82.5% vs 28.6%
Treatment-related deaths: 2 (0.8%) ipilimumab arm; hepatotoxicity substantially higher at 10 mg/kg than 3 mg/kg
Grade 3–4 ALT/AST elevation: 31.6% vs 2.8% (most common AE; hepatotoxicity from ipi+DTIC)
Immune-related AEs any grade: 82.5% vs 28.6%
Treatment-related deaths: 2 (0.8%) ipilimumab arm; hepatotoxicity substantially higher at 10 mg/kg than 3 mg/kg
Conclusions
Ipilimumab 10 mg/kg + dacarbazine significantly improved OS vs dacarbazine alone in untreated advanced melanoma (HR 0.72, P<.001), with durable long-term survival in a subset (5-yr OS 18.2%). With MDX010-20, confirmed ipilimumab's OS benefit in both treated and untreated melanoma.
Key Limitations
Ipilimumab 10 mg/kg causes substantially higher toxicity (ALT/AST 31.6%) than 3 mg/kg without survival advantage in direct dose comparison (CA184-169). Dacarbazine has minimal single-agent activity — weak combination partner. No BRAF selection. Subsequently superseded: PD-1–based regimens (CheckMate 067, KEYNOTE-006) achieve mOS 15–38 mo vs 11.2 mo here. The ipi+DTIC regimen never adopted due to hepatotoxicity.
Clinical Context
Confirmed OS benefit of ipilimumab in the first-line setting and durable long-term survival in ~18–20% — novel at the time. The 10 mg/kg + dacarbazine combination was never adopted as standard due to excessive hepatotoxicity; ipilimumab 3 mg/kg (MDX010-20) became the approved single-agent dose. Quickly superseded by nivolumab+ipilimumab (CheckMate 067) and pembrolizumab (KEYNOTE-006). Primarily of historical significance.