Background
Phase III RCT of 906 patients with resected stage IIIB-C (stage IIIA excluded, unlike KEYNOTE-054) or stage IV melanoma, ECOG 0-1. Brain mets, mucosal and acral melanoma were eligible. Key exclusions: ocular melanoma, autoimmune disease, systemic steroid use.
Interventions and follow up
Arm A: Nivolumab 3mg/kg IV q2wk (n=453)
Arm B: Ipilimumab 10mg/kg IV q3wk x4 then q12wk (n=453)
Treatment duration: up to 1yr or until recurrence/unacceptable toxicity/withdrawal
Primary endpoint: RFS
Median follow-up: 51.1mo (~4.2yr)
Arm B: Ipilimumab 10mg/kg IV q3wk x4 then q12wk (n=453)
Treatment duration: up to 1yr or until recurrence/unacceptable toxicity/withdrawal
Primary endpoint: RFS
Median follow-up: 51.1mo (~4.2yr)
Results
Median RFS: 52.4mo vs 24.1mo (nivolumab vs ipilimumab)
4-yr RFS: 51.7% vs 41.2%; HR 0.71, 95%CI 0.60-0.86, P=.0003
Median DMFS: not reached vs 52.9mo
4-yr DMFS: 59.2% vs 53.3%
4-yr OS: 77.9% vs 76.6%; HR 0.87, 95%CI 0.66-1.14, P=.31
Median OS: not reached in either arm
4-yr RFS: 51.7% vs 41.2%; HR 0.71, 95%CI 0.60-0.86, P=.0003
Median DMFS: not reached vs 52.9mo
4-yr DMFS: 59.2% vs 53.3%
4-yr OS: 77.9% vs 76.6%; HR 0.87, 95%CI 0.66-1.14, P=.31
Median OS: not reached in either arm
Adverse events
Grade 3-4 treatment-related AEs: markedly lower with nivolumab vs ipilimumab (14% vs 46% in primary analysis)
Late grade 3-4 events (this update, nivo vs ipi): ~2% each, including nivolumab pneumonitis, DKA, diarrhea; ipilimumab colitis, diarrhea, rash, elevated lipase, marrow failure, immune thrombocytopenia, adrenal insufficiency
Late grade 3-4 events (this update, nivo vs ipi): ~2% each, including nivolumab pneumonitis, DKA, diarrhea; ipilimumab colitis, diarrhea, rash, elevated lipase, marrow failure, immune thrombocytopenia, adrenal insufficiency
Conclusions
Adjuvant nivolumab provided sustained RFS benefit over high-dose ipilimumab with a more favorable safety profile; the OS difference was not statistically significant at this follow-up.
Key Limitations
Active comparator (high-dose ipilimumab) is no longer a standard adjuvant option, complicating interpretation; OS not significant and confounded by subsequent therapies; no placebo or modern anti-PD-1 monotherapy comparator.
Clinical Context
FDA approved adjuvant nivolumab for resected stage III/IV melanoma (2017). EMA approved in the same setting. Together with KEYNOTE-054, established adjuvant anti-PD-1 as standard of care. ESMO endorses adjuvant anti-PD-1 for resected stage III/IV disease.