Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder,…

• LC
  Lung Cancer Research Foundation
• MS
  Memorial Sloan-Kettering Cancer Center
• SF
  Starr Foundation
• GB
  Geoffrey Beene Cancer Research Center