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Cancer Cell. 2018 May 14;33(5):843-852.e4. doi: 10.1016/j.ccell.2018.03.018. Epub 2018 Apr 12.

Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.

Author information

1
Department of Medicine, Memorial Sloan Kettering Cancer Center, 885 2(nd) Avenue, New York, NY 10017, USA; Weill Cornell School of Medicine, New York, NY, USA; Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: hellmanm@mskcc.org.
2
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
5
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Marie-Josèe and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7
Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
8
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9
Department of Medicine, Memorial Sloan Kettering Cancer Center, 885 2(nd) Avenue, New York, NY 10017, USA; Weill Cornell School of Medicine, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
10
Department of Medicine, Memorial Sloan Kettering Cancer Center, 885 2(nd) Avenue, New York, NY 10017, USA; Weill Cornell School of Medicine, New York, NY, USA; Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
11
Department of Medicine, Memorial Sloan Kettering Cancer Center, 885 2(nd) Avenue, New York, NY 10017, USA; Weill Cornell School of Medicine, New York, NY, USA.
12
Bristol Myers Squibb, Princeton, NJ, USA.
13
Fox Chase Cancer Center, Philadelphia, PA, USA.
14
Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Translational Cancer Therapeutics Laboratory, Francis Crick Institute, London, UK.
15
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
16
Department of Medicine, Memorial Sloan Kettering Cancer Center, 885 2(nd) Avenue, New York, NY 10017, USA; Weill Cornell School of Medicine, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
17
Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
18
Department of Medicine, Memorial Sloan Kettering Cancer Center, 885 2(nd) Avenue, New York, NY 10017, USA.

Abstract

Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.

KEYWORDS:

CTLA-4; PD-1; TMB; immunotherapy; lung cancer; mutation burden

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