Biomarkers for the Clinical Use of PD-1/PD-L1 Inhibitors in Non-Small-Cell Lung Cancer: A Review.
OBJECTIVE
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.


METHODS
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
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.
New York-Presbyterian/Columbia University Medical Center, New York.
Adrian G
AG
Sacher
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts3Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Leena
L
Gandhi
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D004257:DNA Polymerase II / Q000235:genetics; D004258:DNA Polymerase III / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D000077594:Nivolumab; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C117307:KRAS protein, human; C105992:PDCD1 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C000594389:atezolizumab; C582435:pembrolizumab; C512478:EGFR protein, human; D066246:ErbB Receptors; C434055:POLD1 protein, human; D004257:DNA Polymerase II; D004258:DNA Polymerase III; C119525:POLE protein, human; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D016283:Proto-Oncogene Proteins p21(ras)