PMID- 22658127 OWN - NLM STAT- MEDLINE DCOM- 20120711 LR - 20240104 IS - 1533-4406 (Electronic) IS - 0028-4793 (Print) IS - 0028-4793 (Linking) VI - 366 IP - 26 DP - 2012 Jun 28 TI - Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. PG - 2443-54 LID - 10.1056/NEJMoa1200690 [doi] AB - 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.). FAU - Topalian, Suzanne L AU - Topalian SL AD - Department of Surgery, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. stopali1@jhmi.edu FAU - Hodi, F Stephen AU - Hodi FS FAU - Brahmer, Julie R AU - Brahmer JR FAU - Gettinger, Scott N AU - Gettinger SN FAU - Smith, David C AU - Smith DC FAU - McDermott, David F AU - McDermott DF FAU - Powderly, John D AU - Powderly JD FAU - Carvajal, Richard D AU - Carvajal RD FAU - Sosman, Jeffrey A AU - Sosman JA FAU - Atkins, Michael B AU - Atkins MB FAU - Leming, Philip D AU - Leming PD FAU - Spigel, David R AU - Spigel DR FAU - Antonia, Scott J AU - Antonia SJ FAU - Horn, Leora AU - Horn L FAU - Drake, Charles G AU - Drake CG FAU - Pardoll, Drew M AU - Pardoll DM FAU - Chen, Lieping AU - Chen L FAU - Sharfman, William H AU - Sharfman WH FAU - Anders, Robert A AU - Anders RA FAU - Taube, Janis M AU - Taube JM FAU - McMiller, Tracee L AU - McMiller TL FAU - Xu, Haiying AU - Xu H FAU - Korman, Alan J AU - Korman AJ FAU - Jure-Kunkel, Maria AU - Jure-Kunkel M FAU - Agrawal, Shruti AU - Agrawal S FAU - McDonald, Daniel AU - McDonald D FAU - Kollia, Georgia D AU - Kollia GD FAU - Gupta, Ashok AU - Gupta A FAU - Wigginton, Jon M AU - Wigginton JM FAU - Sznol, Mario AU - Sznol M LA - eng SI - ClinicalTrials.gov/NCT00730639 GR - P30 CA076292/CA/NCI NIH HHS/United States GR - R01 CA142779/CA/NCI NIH HHS/United States GR - 5R01 CA142779/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120602 PL - United States TA - N Engl J Med JT - The New England journal of medicine JID - 0255562 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Ligands) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (Nivolumab) SB - IM CIN - N Engl J Med. 2012 Jun 28;366(26):2517-9. PMID: 22658126 CIN - Nat Rev Clin Oncol. 2012 Aug;9(8):427. PMID: 22710340 CIN - Cancer Cell. 2012 Jul 10;22(1):7-8. PMID: 22789534 CIN - Nat Rev Drug Discov. 2012 Aug;11(8):601. PMID: 22850780 CIN - Expert Rev Anticancer Ther. 2012 Oct;12(10):1279-82. PMID: 23176616 CIN - J Urol. 2012 Dec;188(6):2149. PMID: 23289116 CIN - Eur Urol. 2015 Apr;67(4):816-7. PMID: 25765212 MH - Adult MH - Antibodies, Monoclonal/adverse effects/pharmacology/*therapeutic use MH - Antineoplastic Agents/adverse effects/pharmacology/*therapeutic use MH - Carcinoma, Non-Small-Cell Lung/drug therapy MH - Carcinoma, Renal Cell/drug therapy MH - Colorectal Neoplasms/drug therapy MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Ligands MH - Male MH - Melanoma/drug therapy MH - Neoplasms/*drug therapy/metabolism MH - Nivolumab MH - Programmed Cell Death 1 Receptor/*antagonists & inhibitors/immunology/metabolism MH - Prostatic Neoplasms/drug therapy PMC - PMC3544539 MID - NIHMS396199 COIS- No other potential conflict of interest relevant to this article was reported. EDAT- 2012/06/05 06:00 MHDA- 2012/07/12 06:00 PMCR- 2013/01/14 CRDT- 2012/06/05 06:00 PHST- 2012/06/05 06:00 [entrez] PHST- 2012/06/05 06:00 [pubmed] PHST- 2012/07/12 06:00 [medline] PHST- 2013/01/14 00:00 [pmc-release] AID - 10.1056/NEJMoa1200690 [doi] PST - ppublish SO - N Engl J Med. 2012 Jun 28;366(26):2443-54. doi: 10.1056/NEJMoa1200690. Epub 2012 Jun 2.