Background
Phase III RCT of 945 treatment-naïve patients with unresectable stage III/IV melanoma, BRAF status known. This 5-year follow-up established nivolumab plus ipilimumab as a benchmark first-line immunotherapy regimen.
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
Arm C: ipilimumab 3mg/kg q3wk x4
Primary endpoints: OS and PFS
Minimum follow up: 60mo
Arm B: nivolumab 3mg/kg q2wk
Arm C: ipilimumab 3mg/kg q3wk x4
Primary endpoints: OS and PFS
Minimum follow up: 60mo
Results
mPFS: 11.5mo vs 6.9mo vs 2.9mo (A vs B vs C)
5-yr PFS: 36% vs 29% vs 8%
mOS: not reached (>60mo) vs 36.9mo vs 19.9mo
5-yr OS: 52% vs 44% vs 26%
5-yr OS BRAF-mutant: 60% vs 46% vs 30%
5-yr OS BRAF wild-type: 48% vs 43% vs 25%
5-yr OS normal / elevated LDH: 60% vs 53% vs 34% / 38% vs 28% vs 15%
ORR: 58% vs 45% vs 19%
5-yr PFS: 36% vs 29% vs 8%
mOS: not reached (>60mo) vs 36.9mo vs 19.9mo
5-yr OS: 52% vs 44% vs 26%
5-yr OS BRAF-mutant: 60% vs 46% vs 30%
5-yr OS BRAF wild-type: 48% vs 43% vs 25%
5-yr OS normal / elevated LDH: 60% vs 53% vs 34% / 38% vs 28% vs 15%
ORR: 58% vs 45% vs 19%
Adverse events
Grade 3-4 treatment-related AEs: 59% (nivo+ipi) vs 23% (nivo) vs 28% (ipi)
Common (combination): diarrhea, fatigue, rash, pruritus
Hepatic/lab: ALT/AST and lipase elevations among most frequent grade 3-4 events with nivo+ipi
Discontinuation for AEs: highest in combination arm
Common (combination): diarrhea, fatigue, rash, pruritus
Hepatic/lab: ALT/AST and lipase elevations among most frequent grade 3-4 events with nivo+ipi
Discontinuation for AEs: highest in combination arm
Conclusions
Combination nivolumab plus ipilimumab provided superior OS and PFS versus either monotherapy, with durable 5-year survival, at the cost of substantially higher grade 3-4 toxicity than nivolumab alone.
Key Limitations
Not powered for direct nivo+ipi vs nivo comparison; high combination toxicity limits use in frail patients; subsequent therapies in monotherapy arms confound OS interpretation.
Clinical Context
Nivolumab plus ipilimumab is FDA- and EMA-approved for unresectable/metastatic melanoma. CheckMate 067 underpins ASCO and ESMO endorsement of dual checkpoint blockade as a leading first-line option, particularly in high-risk disease.
References
Larkin J et al, NEJM, 2019; PMID:31562797
Larkin J et al, NEJM, 2015; PMID:26027431 (primary report)
Larkin J et al, NEJM, 2015; PMID:26027431 (primary report)