PURPOSE: Blocking the interaction between the programmed cell death (PD)-1 
protein and one of its ligands, PD-L1, has been reported to have impressive 
antitumor responses. Therapeutics targeting this pathway are currently in 
clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 
pathway family of checkpoint inhibitors to gain accelerated approval from the US 
Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory 
melanoma. Nivolumab has been associated with improved overall survival compared 
with dacarbazine in patients with previously untreated wild-type 
serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the 
most mature data are in the treatment of melanoma, the FDA has granted approval 
of nivolumab for squamous cell lung cancer and the breakthrough therapy 
designation to immune- checkpoint inhibitors for use in other cancers: 
nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and 
MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small 
cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and 
focus on the reported clinical studies that have included patients with 
melanoma.
METHODS: PubMed was searched to identify relevant clinical studies of 
PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current 
trials on clinicaltrial.gov was incorporated, as well as data presented in 
abstracts at the 2014 annual meeting of the American Society of Clinical 
Oncology, given the limited number of published clinical trials on this topic.
FINDINGS: The anti-PD-1 and anti-PD-L1 agents have been reported to have 
impressive antitumor effects in several malignancies, including melanoma. The 
greatest clinical activity in unselected patients has been seen in melanoma. 
Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive 
of response to immune-checkpoint blockade. However, tumors expressing little or 
no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination 
checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 
blockade appears to improve response rates in patients who are less likely to 
respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is 
less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 
blockade). Certain adverse events can be severe and potentially life 
threatening, but most can be prevented or reversed with close monitoring and 
appropriate management.
IMPLICATIONS: This family of immune-checkpoint inhibitors benefits not only 
patients with metastatic melanoma but also those with historically less 
responsive tumor types. Although a subset of patients responds to single-agent 
blockade, the initial trial of checkpoint-inhibitor combinations has reported a 
potential to improve response rates. Combination therapies appear to be a means 
of increasing response rates, albeit with increased immune-related adverse 
events. As these treatments become available to patients, education regarding 
the recognition and management of immune-related effects of immune-checkpoint 
blockade will be essential for maximizing clinical benefit.