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


Authors: Rizvi, N. A.; Hellmann, M. D.; Snyder, A.; Kvistborg, P.; Makarov, V.; Havel, J. J.; Lee, W.; Yuan, J.; Wong, P.; Ho, T. S. ; Miller, M. L.; Rekhtman, N.; Moreira, A. L.; Ibrahim, F.; Bruggeman, C.; Gasmi, B.; Zappasodi, R.; Maeda, Y.; Sander, C.; Garon, E. B.; Merghoub, T.; Wolchok, J. D.; Schumacher, T. N.; Chan, T. A.
Article Title: Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer
Abstract: 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.
Keywords: survival; treatment response; disease-free survival; gene mutation; gene sequence; genetics; mutation; antineoplastic agents; disease free survival; antineoplastic agent; cd8+ t lymphocyte; cd8-positive t-lymphocytes; dna repair; progression free survival; cohort studies; carcinoma, non-small-cell lung; lung neoplasms; cohort analysis; smoking; drug resistance; drug resistance, neoplasm; inhibitor; monoclonal antibody; cancer regression; immunology; immunity; tumor; disease treatment; programmed death 1 ligand 1; programmed death 1 receptor; non small cell lung cancer; drug; antibodies, monoclonal, humanized; exome; cancer; humans; human; priority journal; article; pembrolizumab; antagonists and inhibitors; pdcd1 protein, human; programmed cell death 1 receptor
Journal Title: Science
Volume: 348
Issue: 6230
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2015-04-03
Start Page: 124
End Page: 128
Language: English
DOI: 10.1126/science.aaa1348
PUBMED: 25765070
PROVIDER: scopus
PMCID: PMC4993154
DOI/URL:
Notes: Export Date: 3 June 2015 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Timothy Chan
    222 Chan
  2. Natasha Rekhtman
    213 Rekhtman
  3. Jedd D Wolchok
    669 Wolchok
  4. Taha Merghoub
    209 Merghoub
  5. Andre L Moreira
    171 Moreira
  6. Naiyer A Rizvi
    157 Rizvi
  7. Phillip Wong
    38 Wong
  8. Martin Lee Miller
    14 Miller
  9. Chris Sander
    196 Sander
  10. Jianda Yuan
    100 Yuan
  11. Matthew David Hellmann
    172 Hellmann
  12. Teresa Rasalan
    25 Rasalan
  13. William Lee
    38 Lee
  14. Billel Gasmi
    13 Gasmi
  15. Yuka Maeda
    2 Maeda
  16. Vladimir Makarov
    32 Makarov
  17. Jonathan Joseph Havel
    12 Havel