Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
BACKGROUND
Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1.


METHODS
We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred.


RESULTS
A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006).


CONCLUSIONS
Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).
Department of Surgery, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. stopali1@jhmi.edu
Suzanne L
SL
Topalian
F Stephen
FS
Hodi
Julie R
JR
Brahmer
Scott N
SN
Gettinger
David C
DC
Smith
David F
DF
McDermott
John D
JD
Powderly
Richard D
RD
Carvajal
Jeffrey A
JA
Sosman
Michael B
MB
Atkins
Philip D
PD
Leming
David R
DR
Spigel
Scott J
SJ
Antonia
Leora
L
Horn
Charles G
CG
Drake
Drew M
DM
Pardoll
Lieping
L
Chen
William H
WH
Sharfman
Robert A
RA
Anders
Janis M
JM
Taube
Tracee L
TL
McMiller
Haiying
H
Xu
Alan J
AJ
Korman
Maria
M
Jure-Kunkel
Shruti
S
Agrawal
Daniel
D
McDonald
Georgia D
GD
Kollia
Ashok
A
Gupta
Jon M
JM
Wigginton
Mario
M
Sznol
D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab