Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer

Arvind Ravi, Matthew D. Hellmann, Monica B. Arniella, Mark Holton, Samuel S. Freeman, Vivek Naranbhai, Chip Stewart, Ignaty Leshchiner, Jaegil Kim, Yo Akiyama, Aaron T. Griffin, Natalie I. Vokes, Mustafa Sakhi, Vashine Kamesan, Hira Rizvi, Biagio Ricciuti, Patrick M. Forde, Valsamo Anagnostou, Jonathan W. Riess, Don L. GibbonsNathan A. Pennell, Vamsidhar Velcheti, Subba R. Digumarthy, Mari Mino-Kenudson, Andrea Califano, John V. Heymach, Roy S. Herbst, Julie R. Brahmer, Kurt A. Schalper, Victor E. Velculescu, Brian S. Henick, Naiyer Rizvi, Pasi A. Jänne, Mark M. Awad, Andrew Chow, Benjamin D. Greenbaum, Marta Luksza, Alice T. Shaw, Jedd Wolchok, Nir Hacohen, Gad Getz, Justin F. Gainor

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.

Original languageEnglish
Pages (from-to)807-819
Number of pages13
JournalNature Genetics
Volume55
Issue number5
DOIs
StatePublished - May 2023

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