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Mutational Landscape Determines Sensitivity To PD-1 Blockade In Non–small Cell Lung Cancer

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

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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.