Blocking the programmed cell death 1 (PD-1) pathway with
monoclonal antibodies has shown promising antitumor responses in clinical trials, with less toxicity than has been seen with prior immune
therapies such as
interleukin 2 and
ipilimumab.
Pembrolizumab, an anti-PD-1 antibody, recently gained US Food and Drug Administration (FDA) accelerated approval for the treatment of patients with
ipilimumab-refractory
melanoma, while
nivolumab, another anti-PD-1 antibody, and
MPDL3280A, an anti-programmed cell death 1
ligand (PD-L1) antibody, have been granted FDA "breakthrough designation" for treatment of subsets of patients with refractory
Hodgkin lymphoma and metastatic
bladder cancer, respectively. Encouraging antitumor activity has also been seen with these agents in patients with other
malignancies, including
non-small-cell lung cancer and
head and neck cancer,
tumors not previously thought to be immune-responsive. PD-L1 expression has emerged as a potential predictive
biomarker for PD-1-directed
therapy. Multiple, distinct, companion assays for PD-L1 positivity have been developed, but there is as yet no comparison, standardization, or prospective validation of these assays. PD-L1 expression on
tumor cells and/or the
tumor-immune infiltrate is likely only part of the predictive model necessary for selecting patients predisposed to respond to monotherapy. Additional predictive
biomarkers are necessary to identify patients most likely to benefit from PD-1-based combination
therapy, since
tumor cell PD-L1 expression appears to have limited predictive value in this setting.