Safety, activity, and immune correlates of anti-PD-1 antibody in cancer

Suzanne Topalian, F. Stephen Hodi, Julie Brahmer, Scott N. Gettinger, David C. Smith, David F. McDermott, John D. Powderly, Richard D. Carvajal, Jeffrey A. Sosman, Michael B. Atkins, Philip D. Leming, David R. Spigel, Scott J. Antonia, Leora Horn, Charles G. Drake, Andrew Mark Pardoll, Lieping Chen, William Sharfman, Robert A Anders, Janis M TaubeTracee L. McMiller, Haiying Xu, Alan J. Korman, Maria Jure-Kunkel, Shruti Agrawal, Daniel McDonald, Georgia D. Kollia, Ashok Gupta, Jon M. Wigginton, Mario Sznol

Research output: Contribution to journalArticle

Abstract

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.)

Original languageEnglish (US)
Pages (from-to)2443-2454
Number of pages12
JournalNew England Journal of Medicine
Volume366
Issue number26
DOIs
StatePublished - Jun 28 2012

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Safety
Antibodies
Neoplasms
Renal Cell Carcinoma
Non-Small Cell Lung Carcinoma
Melanoma
Costimulatory and Inhibitory T-Cell Receptors
Maximum Tolerated Dose
Castration
Drug-Related Side Effects and Adverse Reactions
Disease Progression
Colorectal Neoplasms
Prostatic Neoplasms
Body Weight
Ligands
Lung
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Topalian, S., Hodi, F. S., Brahmer, J., Gettinger, S. N., Smith, D. C., McDermott, D. F., ... Sznol, M. (2012). Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New England Journal of Medicine, 366(26), 2443-2454. https://doi.org/10.1056/NEJMoa1200690

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. / Topalian, Suzanne; Hodi, F. Stephen; Brahmer, Julie; Gettinger, Scott N.; Smith, David C.; McDermott, David F.; Powderly, John D.; Carvajal, Richard D.; Sosman, Jeffrey A.; Atkins, Michael B.; Leming, Philip D.; Spigel, David R.; Antonia, Scott J.; Horn, Leora; Drake, Charles G.; Pardoll, Andrew Mark; Chen, Lieping; Sharfman, William; Anders, Robert A; Taube, Janis M; McMiller, Tracee L.; Xu, Haiying; Korman, Alan J.; Jure-Kunkel, Maria; Agrawal, Shruti; McDonald, Daniel; Kollia, Georgia D.; Gupta, Ashok; Wigginton, Jon M.; Sznol, Mario.

In: New England Journal of Medicine, Vol. 366, No. 26, 28.06.2012, p. 2443-2454.

Research output: Contribution to journalArticle

Topalian, S, Hodi, FS, Brahmer, J, Gettinger, SN, Smith, DC, McDermott, DF, Powderly, JD, Carvajal, RD, Sosman, JA, Atkins, MB, Leming, PD, Spigel, DR, Antonia, SJ, Horn, L, Drake, CG, Pardoll, AM, Chen, L, Sharfman, W, Anders, RA, Taube, JM, McMiller, TL, Xu, H, Korman, AJ, Jure-Kunkel, M, Agrawal, S, McDonald, D, Kollia, GD, Gupta, A, Wigginton, JM & Sznol, M 2012, 'Safety, activity, and immune correlates of anti-PD-1 antibody in cancer', New England Journal of Medicine, vol. 366, no. 26, pp. 2443-2454. https://doi.org/10.1056/NEJMoa1200690
Topalian, Suzanne ; Hodi, F. Stephen ; Brahmer, Julie ; Gettinger, Scott N. ; Smith, David C. ; McDermott, David F. ; Powderly, John D. ; Carvajal, Richard D. ; Sosman, Jeffrey A. ; Atkins, Michael B. ; Leming, Philip D. ; Spigel, David R. ; Antonia, Scott J. ; Horn, Leora ; Drake, Charles G. ; Pardoll, Andrew Mark ; Chen, Lieping ; Sharfman, William ; Anders, Robert A ; Taube, Janis M ; McMiller, Tracee L. ; Xu, Haiying ; Korman, Alan J. ; Jure-Kunkel, Maria ; Agrawal, Shruti ; McDonald, Daniel ; Kollia, Georgia D. ; Gupta, Ashok ; Wigginton, Jon M. ; Sznol, Mario. / Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. In: New England Journal of Medicine. 2012 ; Vol. 366, No. 26. pp. 2443-2454.
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abstract = "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.)",
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TY - JOUR

T1 - Safety, activity, and immune correlates of anti-PD-1 antibody in cancer

AU - Topalian, Suzanne

AU - Hodi, F. Stephen

AU - Brahmer, Julie

AU - Gettinger, Scott N.

AU - Smith, David C.

AU - McDermott, David F.

AU - Powderly, John D.

AU - Carvajal, Richard D.

AU - Sosman, Jeffrey A.

AU - Atkins, Michael B.

AU - Leming, Philip D.

AU - Spigel, David R.

AU - Antonia, Scott J.

AU - Horn, Leora

AU - Drake, Charles G.

AU - Pardoll, Andrew Mark

AU - Chen, Lieping

AU - Sharfman, William

AU - Anders, Robert A

AU - Taube, Janis M

AU - McMiller, Tracee L.

AU - Xu, Haiying

AU - Korman, Alan J.

AU - Jure-Kunkel, Maria

AU - Agrawal, Shruti

AU - McDonald, Daniel

AU - Kollia, Georgia D.

AU - Gupta, Ashok

AU - Wigginton, Jon M.

AU - Sznol, Mario

PY - 2012/6/28

Y1 - 2012/6/28

N2 - 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.)

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.)

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