Clinical trialPhase 3Melanoma (skin cancer)

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma

N Engl J Med · 2025945 patients

Wolchok JD, Chiarion-Sileni V, Rutkowski P, Cowey CL, Schadendorf D, Wagstaff J, et al. N Engl J Med. 2025. 392:11-22

Study type: Clinical trial
Study name: CheckMate 067
Phase: Phase 3
Design: Double-blind, three-group randomised trial (1:1:1); final report with a minimum of 10 years of follow-up
Sample size: 945 patients
Source: N Engl J Med · 2025
Trial registration: NCT01844505

In plain words

Before immunotherapy, median survival in advanced melanoma was less than one year. In this study, combining two immunotherapy drugs (nivolumab and ipilimumab) raised median survival to about 6 years, and many patients were alive after 10 years. Almost all patients whose disease was under control 3 years after starting treatment (96 to 97%) did not die of melanoma. The two-drug combination has more side effects, which need careful monitoring.

Key results

71.9 / 36.9 / 19.9 months

Median overall survival

Nivolumab–ipilimumab / nivolumab / ipilimumab

0.53

HR for death: nivolumab–ipilimumab vs ipilimumab

95% CI 0.44–0.65

0.63

HR for death: nivolumab vs ipilimumab

95% CI 0.52–0.76

More than 120 / 49.4 / 21.9 months

Median melanoma-specific survival

Not reached in the combination group; 37% of patients alive at the end of the trial

96% / 97% / 88%

10-year melanoma-specific survival in patients alive and progression-free at 3 years

Drugs in this study:Nivolumab (Opdivo)Ipilimumab (Yervoy)

Dose and schedule cards

Nivolumab + ipilimumab (CheckMate 067)

Unresectable or metastatic melanoma, first line, regardless of BRAF status; the ESMO-preferred option when it can be given safelyOn the page “Melanoma (skin cancer)” · Unresectable or metastatic melanoma: first-line immunotherapy

Unresectable or metastatic melanoma, first line, regardless of BRAF status; the ESMO-preferred option when it can be given safely

Drug	Dose	Route	Schedule
Induction
Nivolumab	1 mg/kg	IV, 30-minute infusion (nivolumab first, then ipilimumab on the same day)	Day 1 every 3 weeks, 4 doses
Ipilimumab	3 mg/kg	IV, 30-minute infusion	Day 1 every 3 weeks, 4 doses
Maintenance
Nivolumab	240 mg (or 480 mg)	IV, 30-minute infusion	Every 2 weeks (480 mg dose: every 4 weeks)

Cycle length: Induction: every 21 days × 4; maintenance: every 14 or 28 days
Duration: Up to 4 combination doses (or until unacceptable toxicity), then nivolumab monotherapy until progression or toxicity

Per the FDA labels; evidence and place in therapy:. Note: the doses are the reverse of the kidney cancer regimen (in melanoma, nivolumab 1 mg/kg and ipilimumab 3 mg/kg). For toxicity, both drugs are withheld or discontinued together.

On the page “Melanoma (skin cancer)” · Unresectable or metastatic melanoma: first-line immunotherapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Nivolumab + ipilimumab

Induction: nivolumab 1 mg/kg IV (60-minute infusion) + ipilimumab 3 mg/kg IV every 3 weeks for 4 doses. Maintenance: nivolumab 3 mg/kg IV every 2 weeks until progression, unacceptable toxicity or withdrawal (treatment beyond progression was allowed at the investigator's discretion if there was clinical benefit and tolerance).

2Nivolumab monotherapy

Nivolumab 3 mg/kg IV (60-minute infusion) every 2 weeks with ipilimumab placebo, until progression or unacceptable toxicity.

3Ipilimumab monotherapy

Ipilimumab 3 mg/kg IV every 3 weeks for 4 doses with nivolumab placebo (placebo was stopped after the primary analysis).

Source of the regimen details: Full text of the paper (PMC12080919), ClinicalTrials.gov NCT01844505 and the FDA label for nivolumab (OPDIVO)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with histologically confirmed, unresectable stage III or stage IV advanced melanoma, with no prior systemic therapy for advanced disease, known BRAF V600 mutation status and ECOG 0 or 1; patients with autoimmune disease, a need for systemic corticosteroids (more than 10 mg prednisone per day) or immunosuppressants, positive hepatitis B or C, or HIV were excluded. Stratified by BRAF status, metastasis stage (AJCC 7th edition) and PD-L1 expression (less than 5% vs 5% or more).

Endpoints

Primary endpoints: progression-free survival and overall survival (nivolumab–ipilimumab or nivolumab vs ipilimumab). In this final report: overall survival, melanoma-specific survival and durability of response.

Safety and side effects

Nivolumab + ipilimumab was associated with more frequent and more severe adverse events than either monotherapy. According to the FDA label, in the combination group vs nivolumab alone: grade 3 or 4 adverse events 72% vs 51%, serious adverse events 74% vs 44%, and permanent discontinuation due to adverse events 47% vs 18%; the most common causes of discontinuation in the combination group were colitis (10%), diarrhoea (8%) and raised ALT/AST. Most adverse events occurred in the first months of treatment and were managed with standard algorithms (mainly corticosteroids). In exploratory analyses, patients who had a grade 3 or 4 adverse event in the first 6 months or who discontinued treatment because of adverse events also had a durable survival benefit (10-year survival 49% with the combination in those with a grade 3–4 event in the first 6 months).

Clinical significance and place in guidelines

CheckMate 067 made anti-PD-1 immunotherapy (as monotherapy or with ipilimumab) the standard first-line treatment for advanced melanoma. The 10-year data show that a substantial proportion of patients achieve long-term control and possibly a "functional cure". The ESMO and NCCN guidelines list nivolumab–ipilimumab, anti-PD-1 monotherapy and nivolumab–relatlimab as first-line options.

Limitations

The trial was not designed for a formal comparison of nivolumab–ipilimumab with nivolumab monotherapy (the comparisons are descriptive); the toxicity of the combination is substantial; patients with active brain metastases and ocular melanoma were not enrolled.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.