In the current study, we show that

In the current study, we show that in NSCLCs treated with pembrolizumab, elevated nonsynonymous mutation burden strongly associates with clinical efficacy. Additionally, clinical efficacy correlates with a molecular signature characteristic of tobacco carcinogen–related mutagenesis, certain DNA repair mutations, and the burden of neoantigens. The molecular smoking signature correlated with efficacy, whereas self-reported smoking status did not, highlighting the power of this classifier to identify molecularly related tumors within a heterogeneous group.