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

NA Rizvi, MD Hellmann, A Snyder, P Kvistborg… - Science, 2015 - science.org
Science, 2015science.org
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 …
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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