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Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.

  • Author(s): Cristescu, Razvan
  • Mogg, Robin
  • Ayers, Mark
  • Albright, Andrew
  • Murphy, Erin
  • Yearley, Jennifer
  • Sher, Xinwei
  • Liu, Xiao Qiao
  • Lu, Hongchao
  • Nebozhyn, Michael
  • Zhang, Chunsheng
  • Lunceford, Jared K
  • Joe, Andrew
  • Cheng, Jonathan
  • Webber, Andrea L
  • Ibrahim, Nageatte
  • Plimack, Elizabeth R
  • Ott, Patrick A
  • Seiwert, Tanguy Y
  • Ribas, Antoni
  • McClanahan, Terrill K
  • Tomassini, Joanne E
  • Loboda, Andrey
  • Kaufman, David
  • et al.
Abstract

Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.

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