IMPORTANCE: The development of programmed cell death 1 (PD-1)/PD-1 ligand 1 
(PD-L1) checkpoint inhibitors has changed the landscape of non-small-cell lung 
cancer (NSCLC) therapy, with 2 approvals from the US Food and Drug 
Administration of PD-1 inhibitors for second-line therapy. However, the rational 
use of these agents has been limited by the lack of a definitive predictive 
biomarker.
OBSERVATIONS: Tumor PD-L1 expression is associated with an increased likelihood 
of NSCLC response to these agents, although responses can still occur at a low 
rate in PD-L1-negative tumors. The use of PD-L1 as a predictive biomarker for 
use of PD-1/PD-L1 inhibitors is limited by the multitude of PD-L1 antibodies, 
assays, scoring systems, and thresholds for positivity currently used. 
Alternative biomarkers such as tumor neoantigens identified through whole-exome 
sequencing and clinical parameters (eg, smoking or oncogene driver status) may 
also have predictive value. Biomarkers that can direct the rational use of 
PD-1/PD-L1 checkpoint inhibitors are crucial given the risk of life-threatening 
immune-related complications associated with these therapies and the reality 
that most patients still do not benefit from their use.
CONCLUSIONS AND RELEVANCE: The refinement of existing biomarkers and 
identification of novel predictive biomarkers will be key to ensuring the 
effective and safe use of these agents. Since most patients still do not benefit 
from these agents, it is critical to continue to work to define the select 
patient population who will derive durable benefit from PD-1/PD-L1 inhibition 
and identify markers that could have predictive value for combination therapies 
that could expand the population who benefit.