Naiyer A. Rizvi , Matthew D. Hellmann , Alexandra Snyder , Pia Kvistborg , Vladimir Makarov , Jonathan J. Havel , William Lee , Jianda Yuan , Phillip Wong , Teresa S. Ho , Martin L. Miller , Natasha Rekhtman , Andre L. Moreira , Fawzia Ibrahim , Cameron Bruggeman , Billel Gasmi , Roberta Zappasodi , Yuka Maeda , Chris Sander , Edward B. Garon , Taha Merghoub , Jedd D. Wolchok , Ton N. Schumacher , Timothy A. Chan
April 02 2015
March 12 2015
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, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.