Pembrolizumab (Keytruda®) is an anti-PD-1 antibody, indicated as monotherapy for the treatment of adult patients with advanced (unresectable or metastatic) melanoma. For this indication, the EMA granted marketing authorisation in July 2015. The FDA approved pembrolizumab under accelerated approval in June 2015 for patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation-positive, a BRAF (proto-oncogene B-Raf) inhibitor.

KEYNOTE-006, a randomised, open-label, phase III study, was conducted to compare two different dosage regimens of pembrolizumab with ipilimumab in patients with advanced melanoma. A total of 834 patients received pembrolizumab at a dose of 10 mg/kg either every two weeks or every three weeks, or four cycles of ipilimumab at a dose of 3 mg/kg every three weeks. Enrolled patients had received no more than one previous systemic therapy for advanced disease. Results showed a significant increase in progression-free survival (PFS) in patients who received pembrolizumab; This group achieved a gain of 2.7 months and 1.3 months in median PFS receiving pembrolizumab every 2 weeks and every 3 weeks compared to the ipilimumab group. 12-month overall survival (OS) was also improved among patients who received pembrolizumab: 74.1% (pembrolizumab every 2 weeks) and 68.4% (pembrolizumab every 3 weeks) compared to 58.2% of patients in the ipilimumab group. Response rates were also higher among patients who received pembrolizumab: 33.7 (pembrolizumab every 2 weeks) and 32.9% (pembrolizumab every 3 weeks) versus 11.9% in ipilimumab-group patients. However, it is notable that efficacy results of the KEYNOTE-006 trial are based on interim analysis. Treatment-related adverse events (AEs) of grade 3–5 were more frequent in ipilimumab-group patients compared to patients in the pembrolizumab groups. In terms of AEs of special interest (autoimmune and immune-related), hypothyroidism and hyperthyroidism were most frequent in the pembrolizumab groups. Due to the superior OS results of the two pembrolizumab groups over the ipilimumab group results, the data and safety monitoring committee recommended to stop the study early and give patients of the ipilimumab group the option to receive pembrolizumab.

Pembrolizumab provides a new option for the treatment of patients with advanced melanoma, showing a significant increase in PFS, an improved 12-month OS and higher response rates compared to ipilimumab. In patients who are refractory to ipilimumab, pembrolizumab offers a new therapeutic option based on phase II studies. For these patients, chemotherapy is the only currently available treatment option and fewer AEs were observed with pembrolizumab by comparison with chemotherapy. In contrast, the situation for patients who were previously untreated is less clear. Furthermore, the role of pembrolizumab for the treatment of patients with/without BRAF mutation is not fully elucidated. Not least, the optimal dosage and schedule of pembrolizumab administration remain unclear. However, phase III long-term data is required to confirm the effectiveness and safety of pembrolizumab. Furthermore, biomarkers must be identified to define the appropriate patient population, not least in light of the high costs of pembrolizumab therapy.