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Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer
Suzanne Louise Topalian (Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center), Frank Stephen Hodi (Dana-Farber Cancer Institute), Julie Renee Brahmer (Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center), Scott N. Gettinger (Yale Cancer Center, Yale University), David Carl Smith (University of Michigan), David F. McDermott (Beth Israel Deaconess Medical Center), John D. Powderly (Carolina BioOncology Institute), Richard D. Carvajal (Memorial Sloan Kettering Cancer Center), Jeffrey Alan Sosman (Vanderbilt University Medical Center), Michael B. Atkins (Beth Israel Deaconess Medical Center), Philip D. Leming (New York Oncology Hematology, Oncology Hematology Care), David Robert Spigel (Sarah Cannon Research Institute, Tennessee Oncology), Scott Joseph Antonia (Moffitt Cancer Center), Leora Horn (Vanderbilt University Medical Center), Charles G. Drake (Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center), Drew M. Pardoll (Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center), Lieping Chen (Yale Cancer Center, Yale University), William Howard Sharfman (Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center), Robert A. Anders (Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center), Janis Marie Taube (Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center), Tracee L. McMiller (Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center), Haiying Xu (Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center), Alan J. Korman (Bristol-Myers Squibb (United States)), Maria Jure‐Kunkel (Bristol-Myers Squibb (United States)), Shruti Agrawal (Bristol-Myers Squibb (United States)), Daniel McDonald (Bristol-Myers Squibb (United States)), Georgia D. Kollia (Bristol-Myers Squibb (United States)), Ashok Kumar Gupta (Bristol-Myers Squibb (United States)), Jon M. Wigginton (Bristol-Myers Squibb (United States)), Mario Sznol (Yale Cancer Center, Yale University)
Résumé : 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.).