Research in context
Evidence before this study
Immunotherapy using the PD-1 inhibitors pembrolizumab and nivolumab and the cytotoxic T-lymphocyte-associated antigen-4 inhibitor ipilimumab has improved survival in patients with advanced melanoma. For reports of clinical trials involving checkpoint inhibitors with long-term follow-up of patients with advanced melanoma, we searched PubMed on Feb 5, 2019, for papers published since database inception using the search terms “nivolumab AND melanoma”, “pembrolizumab AND melanoma”, and “ipilimumab AND melanoma”, without any language restrictions. We narrowed the search results to include reports of prospective trials in advanced melanoma with overall survival as a study endpoint. We found a phase 3 study of ipilimumab plus dacarbazine versus placebo plus dacarbazine showing 5-year overall survival of 18·2% and 8·8%, respectively. A report of the 4-year follow-up of the CheckMate 067 trial showed 4-year overall survival of 53% for nivolumab plus ipilimumab, 46% for nivolumab alone, and 30% for ipilimumab alone, respectively. We did not find any reports of 5 years of follow-up in a randomised controlled trial of nivolumab or pembrolizumab in advanced melanoma. We also searched PubMed for reports of second-course treatment or re-treatment in patients with advanced melanoma using the search terms “nivolumab AND re-treatment AND melanoma”, but we found no articles presenting results from randomised controlled trials of patients re-treated with nivolumab. We found a pooled analysis of six trials with different patient populations (previously treated or treatment naive) and doses of ipilimumab (3–20 mg/kg), which limited interpretation of results. The proportion of patients with an overall response was 23%. Grade 3–4 immune-related adverse events occurred in 5·9–25·0% of re-treated patients, depending on ipilimumab dose.
Added value of this study
This report of 5 years' follow-up of KEYNOTE-006 is, to our knowledge, the longest follow-up to date in a randomised phase 3 trial of pembrolizumab in patients with advanced cancer. Pembrolizumab continued to show superiority over ipilimumab, irrespective of line of therapy, BRAFV600 status, or exposure to previous BRAF or MEK inhibitors for those patients with BRAFV600E-mutant or BRAFV600K-mutant disease. We present outcomes in patients who completed 2 years of pembrolizumab treatment. Additionally, we present an exploratory analysis of best overall response in patients treated with a second course of pembrolizumab.
Implications of all the available evidence
Our results show that median overall survival in patients treated with pembrolizumab versus ipilimumab continued to show superiority in the overall population after almost 5 years of follow-up. Pembrolizumab conferred sustained disease control over a long period, whereby 78% of patients who completed 2 years of pembrolizumab treatment with at least stable disease remained progression free 24 months after pembrolizumab completion. The safety profile of pembrolizumab remained consistent with previous reports. Preliminary findings suggest that re-treatment with pembrolizumab after disease progression can provide additional antitumour activity and second-course pembrolizumab was generally well tolerated.