The NSCLC Mutational Landscape Influences Response to PD-1 Blockade

Inhibition of the immune checkpoint receptor programmed cell death 1 (PD-1) has shown clinical activity in a subset of patients with non–small cell lung cancer (NSCLC), but the mechanisms underlying sensitivity to PD-1 blockade are not well understood. To gain insight into the genetic determinants of response to anti–PD-1 therapy, Rizvi, Hellmann, Snyder, and colleagues performed whole-exome sequencing of NSCLCs and matched normal tissues from patients enrolled in a phase I study of the anti–PD-1 antibody pembrolizumab. A significantly greater number of patients with a high nonsynonymous mutation burden experienced a durable partial or stable response than patients with a low mutation burden, and the objective response rate and progression-free survival were significantly higher in patients with a high nonsynonymous mutation burden than those with a lower burden. Of note, pembrolizumab efficacy was greatest in patients with a smoking-associated mutational signature, which correlated with nonsynonymous mutation burden. A high nonsynonymous mutational burden was correlated with a higher quantity of putative neoantigens with high binding affinity to patient-specific HLA alleles, and patients who had a durable clinical response had a higher neoantigen burden than those who did not, suggesting that T-cell responses to neoantigens created by somatic mutations may underlie pembrolizumab activity in NSCLC. Indeed, a T-cell response against a mutation-associated neoantigen was detected in peripheral blood lymphocytes from one responder after the initiation of pembrolizumab treatment and correlated with tumor regression, also raising the possibility that a blood-based assay may be used to assess response to PD-1 blockade. Collectively, these observations suggest that recognition of neoantigens created by nonsynonymous mutations may underlie the activity of PD-1 inhibition in NSCLC, that nonsynonymous mutation burden may be a predictive biomarker of response to anti–PD-1 therapy, and that immunotherapy may be especially beneficial for smoking-associated lung cancers.

Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124–8..

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