Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.

Background: Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006.

Methods: KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAF status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued pembrolizumab with stable disease or better after receiving at least 24 months of pembrolizumab or discontinued with complete response after at least 6 months of pembrolizumab and then progressed could receive an additional 17 cycles of pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319.

Findings: Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7-59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5-41·6) in the combined pembrolizumab groups and 15·9 months (13·3-22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61-0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6-11·3) in the combined pembrolizumab groups versus 3·4 months (2·9-4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48-0·67, p<0·0001). Grade 3-4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) of 256 patients in the ipilimumab group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four [<1%] vs three [1%]). Any-grade serious treatment-related adverse events occurred in 75 (14%) patients in the combined pembrolizumab groups and in 45 (18%) patients in the ipilimumab group. One patient assigned to pembrolizumab died from treatment-related sepsis.

Interpretation: Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of pembrolizumab in patients with advanced melanoma.

Funding: Merck Sharp & Dohme.