BACKGROUND: The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab 
has shown potent antitumour activity at different doses and schedules in 
patients with melanoma. We compared the efficacy and safety of pembrolizumab at 
doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with 
ipilimumab-refractory advanced melanoma.
METHODS: In an open-label, international, multicentre expansion cohort of a 
phase 1 trial, patients (aged ≥18 years) with advanced melanoma whose disease 
had progressed after at least two ipilimumab doses were randomly assigned with a 
computer-generated allocation schedule (1:1 final ratio) to intravenous 
pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease 
progression, intolerable toxicity, or consent withdrawal. Primary endpoint was 
overall response rate (ORR) assessed with the Response Evaluation Criteria In 
Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was 
done on the full-analysis set (all treated patients with measurable disease at 
baseline). This study is registered with ClinicalTrials.gov, number NCT01295827.
FINDINGS: 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). 
Median follow-up duration was 8 months. ORR was 26% at both doses--21 of 81 
patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 
95% CI -14 to 13; p=0·96). Treatment was well tolerated, with similar safety 
profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most 
common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg 
groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and 
rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in 
the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse 
event reported in more than one patient.
INTERPRETATION: The results suggest that pembrolizumab at a dose of 2 mg/kg or 
10 mg/kg every 3 weeks might be an effective treatment in patients for whom 
there are few effective treatment options.
FUNDING: Merck Sharp and Dohme.