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Targeted Next Generation Sequencing Identifies Markers Of Response To PD-1 Blockade

D. Johnson, G. Frampton, M. Rioth, Erik C. Yusko, Y. Xu, X. Guo, R. Ennis, David A Fabrizio, Z. Chalmers, J. Greenbowe, S. Ali, S. Balasubramanian, J. Sun, Y. He, D. Frederick, I. Puzanov, J. Balko, J. Cates, J. Ross, C. Sanders, H. Robins, Y. Shyr, V. Miller, P. Stephens, R. Sullivan, J. Sosman, C. Lovly
Published 2016 · Biology, Medicine

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Mutational load, by whole exome sequencing, can correlate with immunotherapy responses. Assessing melanoma mutational load of a fraction of the genome, by hybrid capture-based NGS, provided an accurate surrogate for WES determinations, and predicted response to anti-PD-1. Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti–PD-1 in melanoma. Using archival melanoma samples from anti–PD-1/PD-L1-treated patients, we performed hybrid capture–based NGS on 236–315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti–PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti–PD-1/PD-L1. Cancer Immunol Res; 4(11); 959–67. ©2016 AACR.
This paper references
Genomic correlates of response to CTLA-4 blockade in metastatic melanoma
E. V. Van Allen (2015)
MYC regulates the antitumor immune response through CD47 and PD-L1
S. Casey (2016)
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma
W. Hugo (2016)
PD-L1 Testing in Cancer: Challenges in Companion Diagnostic Development.
A. Hansen (2016)
Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.
W. Peng (2016)
PD-1 blockers. Cell 2015;162:937
JD Wolchok (2015)
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial
J. Rosenberg (2016)
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
M. Valsecchi (2015)
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
S. Topalian (2012)
Clinical activity of ipilimumab for metastatic uveal melanoma
J. Luke (2013)
Common fragile sites, extremely large genes, neural development and cancer.
D. Smith (2006)
CANCER. The odds of immunotherapy
MM Gubin (2015)
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
N. Rizvi (2015)
The odds of immunotherapy success
M. M. Gubin (2015)
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
E. Eisenhauer (2009)
Pembrolizumab versus Ipilimumab in Advanced Melanoma.
C. Robert (2015)
CANCER. The odds of immunotherapy success
M M Gubin (2015)
Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma
M. Krauthammer (2012)
Genomic Classification of Cutaneous Melanoma
Rehan Akbani (2015)
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
R. Herbst (2014)
PD-1 blockade induces responses by inhibiting adaptive immune resistance
P. Tumeh (2014)
Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity
Stefani Spranger (2015)
PD-1 blockade in tumors with mismatch repair deficiency.
J. Uram (2015)
Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing
G. Frampton (2013)
BaoR,Gajewski TF.Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity
S Spranger (2015)
Ipilimumab for patients with advanced mucosal melanoma.
M. Postow (2013)
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade
N. McGranahan (2016)
PD-1 Blockers
J. Wolchok (2015)
Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas
M. Gerlinger (2013)
Genetic basis for clinical response to CTLA-4 blockade in melanoma.
A. Snyder (2014)
Impact of NRAS Mutations for Patients with Advanced Melanoma Treated with Immune Therapies
D. Johnson (2015)
Grant Support This study was supported by ASCO Conquer Cancer Foundation Young Investigator and Career Development Awards
D B Johnson (2015)

This paper is referenced by
Improving radiotherapy in cancer treatment: Promises and challenges.
H. H. Chen (2017)
D-loop Mutations in Renal Cell Carcinoma Improve Predictive Accuracy for Cancer-Related Death by Integrating with Mutations in the NADH Dehydrogenase Subunit 1 Gene
H. Kim (2019)
Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type.
X. Zhou (2018)
Comparison of Large, Medium, and Small Solid Tumor Gene Panels for Detection of Clinically Actionable Mutations in Cancer
Eric Vail (2020)
Tumor Microenvironment
S. Rosen (2020)
Recent Advances in the Treatment of Metastatic Soft Tissue Sarcoma
E. J. Davis (2018)
Approach to evaluating tumor mutational burden in routine clinical practice.
John Truesdell (2018)
P5 eHealth: An Agenda for the Health Technologies of the Future
G. Pravettoni (2019)
Efficacy of PD-1 Blockade in Refractory Microsatellite-Stable Colorectal Cancer With High Tumor Mutation Burden.
J. Gong (2019)
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial
Y. Kang (2017)
Genomic subtyping of liver cancers with prognostic application
Z. Wu (2020)
Interaction of molecular alterations with immune response in melanoma
R. S. Szczepaniak Sloane (2017)
1 Emerging biomarkers for cancer immunotherapy in melanoma
Margaret Axelrod (2017)
Clinical Correlates of Response to Anti-PD-1–based Therapy in Patients With Metastatic Melanoma
E. J. Davis (2019)
Characteristics of TCR Repertoire Associated With Successful Immune Checkpoint Therapy Responses
Joel Kidman (2020)
Clinicopathological, immune and molecular correlates of PD-L2 methylation in gastric adenocarcinomas.
P. Lingohr (2019)
Genomic characterization of six virus-associated cancers identifies changes in the tumor microenvironment and altered genetic programming
F. S. Varn (2018)
Review of immunogenomics and the role of tumor mutational burden as a biomarker for immunotherapy response
J. Ros (2019)
Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors.
D. Sha (2020)
Immunomodulatory effects of current cancer treatment and the consequences for follow-up immunotherapeutics.
M. Mooradian (2017)
Comparison of Biomarker Modalities for Predicting Response to PD-1/PD-L1 Checkpoint Blockade: A Systematic Review and Meta-analysis.
Steve Lu (2019)
Identification of a prognostic immune signature for cervical cancer to predict survival and response to immune checkpoint inhibitors
Si Yang (2019)
Immunologic Biomarkers and Biomarkers for Immunotherapies in Gastrointestinal Cancer
B. Martin (2019)
NF1 mutations in conjunctival melanoma
S. L. Scholz (2018)
Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.
Ohad Oren (2020)
High tumor mutation burden is associated with DNA damage repair gene mutation in breast carcinomas
P. Mei (2020)
The Role of Immune Checkpoint Inhibition in the Treatment of Brain Tumors
A. Luksik (2017)
Whole exome sequencing for determination of tumor mutation load in liquid biopsy from advanced cancer patients
Florence Koeppel (2017)
Clinical Significance of Genes in the NeoTYPE Brain Tumor Profile
The immune microenvironment of sarcomas : a comprehensive evaluation of infiltrating immune cells and checkpoint biomarkers in musculoskeletal tumors
Amanda R. Dancsok (2019)
Pembrolizumab in men with heavily treated metastatic castrate‐resistant prostate cancer
Matthew D Tucker (2019)
A germline variant of TP53 in paediatric diffuse leptomeningeal glioneuronal tumour
Grace I. L. Tan (2019)
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