Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade.
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.
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee. Douglas.b.johnson@vanderbilt.edu.
Douglas B
DB
Johnson
Foundation Medicine Inc., Cambridge, Massachusetts.
Garrett M
GM
Frampton
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.|Department of Bioinformatics, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Matthew J
MJ
Rioth
Adaptive Biotechnologies, Seattle, Washington.
Erik
E
Yusko
Department of Biostatistics, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Yaomin
Y
Xu
Department of Biostatistics, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Xingyi
X
Guo
Foundation Medicine Inc., Cambridge, Massachusetts.
Riley C
RC
Ennis
Foundation Medicine Inc., Cambridge, Massachusetts.
David
D
Fabrizio
Foundation Medicine Inc., Cambridge, Massachusetts.
Zachary R
ZR
Chalmers
Foundation Medicine Inc., Cambridge, Massachusetts.
Joel
J
Greenbowe
Foundation Medicine Inc., Cambridge, Massachusetts.
Siraj M
SM
Ali
Foundation Medicine Inc., Cambridge, Massachusetts.
Sohail
S
Balasubramanian
Foundation Medicine Inc., Cambridge, Massachusetts.
James X
JX
Sun
Foundation Medicine Inc., Cambridge, Massachusetts.
Yuting
Y
He
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Dennie T
DT
Frederick
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Igor
I
Puzanov
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Justin M
JM
Balko
Department of Pathology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Justin M
JM
Cates
Foundation Medicine Inc., Cambridge, Massachusetts.
Jeffrey S
JS
Ross
Adaptive Biotechnologies, Seattle, Washington.
Catherine
C
Sanders
Adaptive Biotechnologies, Seattle, Washington.
Harlan
H
Robins
Department of Biostatistics, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Yu
Y
Shyr
Foundation Medicine Inc., Cambridge, Massachusetts.
Vincent A
VA
Miller
Foundation Medicine Inc., Cambridge, Massachusetts.
Philip J
PJ
Stephens
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Ryan J
RJ
Sullivan
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Jeffrey A
JA
Sosman
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Christine M
CM
Lovly
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology* / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D014408:Biomarkers, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D059467:Transcriptome
D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D061026:Programmed Cell Death 1 Receptor
Nature. 2014 Nov 27;515(7528):563-7
25428504
Lancet. 2016 May 7;387(10031):1909-20
26952546
Cell. 2015 Aug 27;162(5):937
26317459
Nature. 2015 Jul 9;523(7559):231-5
25970248
Nature. 2014 Nov 27;515(7528):568-71
25428505
Science. 2015 Apr 3;348(6230):124-8
25765070
N Engl J Med. 2012 Jun 28;366(26):2443-54
22658127
Cancer Discov. 2016 Feb;6(2):202-16
26645196
Cancer Lett. 2006 Jan 28;232(1):48-57
16221525
Oncologist. 2013 Jun;18(6):726-32
23716015
Cell. 2015 Jun 18;161(7):1681-96
26091043
Science. 2016 Mar 25;351(6280):1463-9
26940869
Nat Genet. 2012 Sep;44(9):1006-14
22842228
Cancer. 2013 Oct 15;119(20):3687-95
23913718
Cancer Immunol Res. 2015 Mar;3(3):288-95
25736262
Science. 2015 Oct 9;350(6257):158-9
26450194
Eur J Cancer. 2009 Jan;45(2):228-47
19097774
N Engl J Med. 2015 Jun 25;372(26):2521-32
25891173
Nat Biotechnol. 2013 Nov;31(11):1023-31
24142049
J Pathol. 2013 Dec;231(4):424-32
24122851
Science. 2015 Oct 9;350(6257):207-11
26359337
Science. 2016 Apr 8;352(6282):227-31
26966191
Cell. 2016 Mar 24;165(1):35-44
26997480
N Engl J Med. 2015 Jul 2;373(1):23-34
26027431
N Engl J Med. 2014 Dec 4;371(23 ):2189-99
25409260
N Engl J Med. 2015 Jun 25;372(26):2509-20
26028255
JAMA Oncol. 2016 Jan;2(1):15-6
26562503