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Immunogenicity of pembrolizumab in patients with advanced tumors.
van Vugt, Marianne J H; Stone, Julie A; De Greef, Rik H J M M; Snyder, Ellen S; Lipka, Leslie; Turner, David C; Chain, Anne; Lala, Mallika; Li, Mengyao; Robey, Seth H; Kondic, Anna G; De Alwis, Dinesh; Mayawala, Kapil; Jain, Lokesh; Freshwater, Tomoko.
Afiliação
  • van Vugt MJH; Integrated Drug Development, Certara, Oss, Netherlands.
  • Stone JA; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • De Greef RHJMM; Integrated Drug Development, Certara, Oss, Netherlands.
  • Snyder ES; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • Lipka L; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • Turner DC; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • Chain A; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • Lala M; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • Li M; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • Robey SH; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • Kondic AG; Decision Analytics, Certara, Princeton, NJ, USA.
  • De Alwis D; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • Mayawala K; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • Jain L; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA.
  • Freshwater T; Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. tomoko.freshwater@merck.com.
J Immunother Cancer ; 7(1): 212, 2019 08 08.
Article em En | MEDLINE | ID: mdl-31395089
ABSTRACT

BACKGROUND:

Pembrolizumab is a potent, humanized, monoclonal anti-programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study. PATIENTS AND

METHODS:

Pembrolizumab immunogenicity was assessed in 3655 patients with advanced or metastatic cancer treated in 12 clinical studies. Patients with melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, urothelial cancer, and Hodgkin lymphoma were treated with pembrolizumab at 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. An additional study involving 496 patients with stage III melanoma treated with 200 mg adjuvant pembrolizumab every 3 weeks after complete resection was analyzed separately.

RESULTS:

Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA-positive; none had neutralizing antibodies.

CONCLUSIONS:

The incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab. TRIAL REGISTRATION ClinicalTrials.gov, NCT01295827 (February 15, 2011), NCT01704287 (October 11, 2012), NCT01866319 (May 31, 2013), NCT01905657 (July 23, 2013), NCT02142738 (May 20, 2014), NCT01848834 (May 8, 2013), NCT02255097 (October 2, 2014), NCT02460198 (June 2, 2015), NCT01953692 (October 1, 2013), NCT02453594 (May 25, 2015), NCT02256436 (October 3, 2014), NCT02335424 (January 9, 2015), NCT02362594 (February 13, 2015).
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Anticorpos Monoclonais Humanizados / Antineoplásicos Imunológicos / Neoplasias Limite: Female / Humans / Male Idioma: En Revista: J Immunother Cancer Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Anticorpos Monoclonais Humanizados / Antineoplásicos Imunológicos / Neoplasias Limite: Female / Humans / Male Idioma: En Revista: J Immunother Cancer Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Holanda