JOURNAL ARTICLE

Cancer immunology. 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
Science 2015 April 3, 348 (6230): 124-8
25765070
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.

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